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CONFIDENTIAL107876 (Rota-061)

Annex

Final: 20 Mar 2008 1

GlaxoSmithKline Biologicals

Study title

A study in infants to test two formulations (freeze-dried or liquid) of the rotavirus vaccine(human rotavirus [HRV] vaccine).

Study detailed title

A phase III, randomised study to evaluate the clinical consistency in terms ofimmunogenicity and reactogenicity of three production lots of the liquid formulation ofGlaxoSmithKline (GSK) Biologicals� oral live attenuated human rotavirus (HRV)vaccine and to evaluate the liquid formulation as compared to the lyophilised formulationof the HRV vaccine in terms of immunogenicity, reactogenicity and safety whenadministered as a two-dose primary vaccination in healthy infants previously uninfectedwith HRV.

Annex Clinical Study Report for Study 107876 (Rota-061)(Development Phase III)EudraCT number: 2006-003239-61Indication Studied: Two-dose immunisation at 3 and 4 months of age in healthyinfants previously uninfected with HRV.Study initiation date: 10 November 2006

Study completion date for the active phase of the study [i.e.from Day 0 (day of administration of Dose 1 of the HRVvaccine) up to final study visit (Visit 3): 18 April 2007

Study completion date for the extended safety follow-upphase (six months after the last dose of the HRV vaccine): 13 September 2007Date of Annex report: 20 March 2008Report Scope: This annex report presents the final data on serious adverse events

reported during the entire study period (i.e. Dose 1 of the HRVvaccine up to the end of the extended safety follow-up phasewhich is six months after the last dose of the HRV vaccine).

Earlier Clinical Study Report (Primary study report): 1 August 2007

Sponsor Signatory: M.B., B.S.Director, Rotavirus VaccinesGlobal Clinical Research and DevelopmentGlaxoSmithKline Biologicals

This study was performed in compliance with Good Clinical Practice including thearchiving of essential documents.Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved.Unauthorised copying or use of this information is prohibited.

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SYNOPSIS

Name of company: GlaxoSmithKlineBiologicals, Rixensart, Belgium

Name of finished product: HRV vaccine

Name of active substance: RIX4414 vaccinestrain

TABULAR FORMATREFERRING TO PARTOF THE DOSSIER

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(for national authorityonly)

Title of the study : A phase III, randomised study to evaluate the clinical consistency in terms ofimmunogenicity and reactogenicity of three production lots of the liquid formulation ofGlaxoSmithKline (GSK) Biologicals� oral live attenuated human rotavirus (HRV) vaccine and toevaluate the liquid formulation as compared to the lyophilised formulation of the HRV vaccine in termsof immunogenicity, reactogenicity and safety when administered as a two-dose primary vaccination inhealthy infants previously uninfected with HRV.Principal investigator: This study was conducted by 11 investigators and Prof. was theprincipal investigator for this study.Study centres: The study was conducted at 12 centres in Finland.Publication (reference): Not published as of 20 March 2008.Study period:Study initiation date: 10 November 2006Study completion date (Active phase): 18 April 2007Study completion date (Extended safety follow-up phase up to six months afterthe last dose of the HRV vaccine): 13 September 2007

Clinical phase: III

Objective: The study objective pertaining to the extended safety follow-up phase is listed below. Referto the primary study report Rota-061 (107876) Report Part I Main for objectives pertaining to the activephase of the study.Secondary:• To assess the safety of the study vaccines in terms of occurrence of serious adverse events (SAEs)

after Visit 3 up to the safety contact.Study design: Randomised (1:1:1:1), multi-centric study with four parallel groups as mentioned below:• Group HRV vaccine liquid formulation Lot A (referred to as Liq_A group)• Group HRV vaccine liquid formulation Lot B (referred to as Liq_B group)• Group HRV vaccine liquid formulation Lot C (referred to as Liq_C group)• Group HRV vaccine lyophilised formulation (referred to as Lyo group)The study was double blind for three lots of the liquid formulation of GSK Biologicals� HRV vaccine,and open-label for the liquid formulation versus the lyophilised formulation. Subjects received HRVvaccine (liquid or lyophilised formulation) at Visit 1 and Visit 2 (at approximately 3 and 4 months ofage). Data collection was done by remote data entry (RDE) using individual electronic case report forms(eCRF).Data on analyses of immunogenicity, solicited symptoms, unsolicited symptoms and SAEs reportedfrom Dose 1 of HRV vaccine up to Visit 3 are presented in the primary study report Rota-061 (107876)Report Part I Main (Active phase of the study). The active phase included the period starting from Day 0up to the final study visit (Visit 3) for post-vaccination blood sampling at approximately one month post-dose 2 of the HRV vaccine.The extended safety follow-up phase included the period starting from the day after Visit 3 up to thecontact at Month 7 (i.e. up to six months after the last dose of the HRV vaccine). This annex reportpresents the final data on SAEs from Dose 1 of HRV vaccine up to the end of the extended safetyfollow-up phase.

107876 (Rota-061) Synopsis page 1 of 4

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Number of subjects: Total Liq_Agroup

Liq_Bgroup

Liq_Cgroup

Lyogroup

Planned 1200 300 300 300 300Enrolled and vaccinated [Total vaccinated cohort (TVC)] 1200 298 302 300 300Completed active phase of the study (up to Visit 3) 1193 297 301 298 297Completed the extended safety follow-up phase 1188 295 300 297 296Diagnosis and criteria for inclusion: Healthy, male/female infants between, and including, 10 � 17weeks (70 � 125 days) of age at the time of the first study vaccination with birth weight > 2000g and forwhom the investigator believed that their parents/guardians would comply with the requirements of theprotocol. Written informed consent was obtained from the parents/guardians of each subject.Study vaccine, dose, mode of administration, lot no.:Vaccination schedule/site: A single dose of HRV vaccine liquid formulation was administered as an oraldose at 3 and 4 months of age.Vaccine composition/ dose/ lot number: Each dose (1.5 ml) of the GSK Biologicals� HRV vaccine liquidformulation contained at least 106.0 median Cell Culture Infective Dose (CCID50) RIX4414 HRV strain,2.26 mg Dulbecco�s Modified Eagle Medium (DMEM), 132.74 mg di-sodium adipate, 55.0% (w/w)sucrose in 1.5 ml water for injection. Refer primary study report Rota-061 (107876) Report Part I Mainfor lot number details of the study vaccines.Reference vaccine /Comparator, dose and mode of administration, lot no.:Vaccination schedule/site: Lyophilised HRV vaccine was reconstituted with the supplied diluent (buffer)and the resuspended product was administered as a single oral dose at 3 and 4 months of age.Vaccine composition/ dose/ lot number: Each dose (1.0 ml) of GSK Biologicals� lyophilised formulationof HRV vaccine contained at least 106.0 CCID50 RIX4414 HRV strain, 2.25 mg DMEM, 9 mg sucrose,18 mg dextran, 13.5 mg sorbitol and 9 mg amino acids in liquid diluent containing 60 mg calciumcarbonate and 2.5 mg xanthane in 1.0 ml water for injection. Refer primary study report Rota-061(107876) Report Part I Main for lot number details of the reference vaccines.Duration of the study: The total duration of the study, per subject was approximately 7 months whichincluded the 6-month extended safety follow-up phase after the last dose of the HRV vaccine.Criteria for evaluation of safety:• Occurrence of SAEs from Dose 1 of HRV vaccine up to six months after the last dose of HRV

vaccine.Statistical methods: All analyses were performed according to the protocol and as described in thestudy Reporting and Analysis Plan (RAP).Additional analyses were performed to summarise the SAEs classified by Medical Dictionary forRegulatory Activities (MedDRA) system organ class and preferred term from Dose 1 up to the extendedsafety follow-up contact (i.e. Month 7). Also, the p-value for the difference between the three pooled lotsof the HRV liquid formulation (Liq pooled) and Lyo group in terms of percentage of subjects with SAEsfrom Dose 1 up to the extended safety follow-up contact was computed. P-values less than 0.05 wereused as an aid to highlight potential imbalance between groups.Analysis of safety: SAEs reported after Visit 3 up to the extended safety follow-up contact weresummarised by group. SAEs reported for the active phase of the study were also summarised by group.Summary:Serious adverse events: A total of 36 subjects reported at least one SAE during the entire study period(Dose 1 up to six months after the last dose of the HRV vaccine).


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Active phase:A total of 18 subjects (2 subjects in the Liq_A group, 7 subjects in the Liq_B group, 3 subjects in theLiq_C group and 6 subjects in the Lyo group) reported at least one SAE within the 31-day (Day 0�30)follow-up period after each vaccination. Most of the SAEs were under the System Organ Class (SOC) ofinfections and infestations. All the SAEs had resolved and one SAE had resolved with sequelae.

The subject was discharged in good conditionafter 51 days of hospitalisation and the medication is continuing to prevent new seizures. Thesubject has recovered with sequelae. The investigator considered that there was no reasonablepossibility that the infantile spasms might have been caused by the HRV vaccine.

The symptom was reported 12 days after Dose 1 of the HRVvaccine. The subject recovered after 29 days of hospitalisation.

However, following a few reports of the association of Kawasaki disease with otherrotavirus vaccine, the principal investigator retrospectively concluded that Kawasaki disease waspossibly related to vaccination in this case.

Extended safety follow-up phase:During the extended safety follow-up phase, a total of 18 subjects (3 subjects in the Liq_A group, 2subjects in the Liq_B group, 11 subjects in the Liq_C group and 2 subjects in the Lyo group) reported atleast one SAE. Most of the SAEs reported during the extended safety follow-up phase (n = 13) wereunder the SOC �Infections and infestations� and there were 3 SAEs reported under the SOC of �Nervoussystem disorders�. All the SAEs had resolved.

Both the cases were resolved.

The investigator considered that thes medical condition, gastroesophageal

reflux.The

event was possibly due to an incidental illness as the subject had a family history of epilepsy.

The subject had recovered after 5 days ofhospitalisation.

Entire study period:• The percentage of subjects reporting at least one SAE from Dose 1 of the HRV vaccine up to the

extended safety follow-up phase was 1.7% in Liq_A group, 3.0% in the Liq_B group, 4.7% inLiq_C group and 2.7% in the Lyo group.

• The p-value for the difference between Liq pooled and Lyo groups was 0.696 suggesting that therewas no potential imbalance between the groups in terms of SAEs (p-value >0.05).

• None of the SAEs were assessed by the investigator to be causally related to vaccination.

This subject developed infantile spasmstwo days after Dose 2 of the HRV vaccine.


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Conclusions:• A total of 36 subjects reported at least one SAE during entire study period, of whom 18 subjects

reported SAEs during the extended safety follow-up phase.• None of the SAEs were causally related to vaccination. No intussusception cases and no fatal events

were reported during the study.• Two doses of HRV vaccine (liquid or lyophilised formulation) were found to have a similar safety

profile.• There are no clinical concerns with respect to obtained safety data.Date of report: 20 March 2008


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TABLE OF CONTENTS

PAGE

SYNOPSIS......................................................................................................................2

LIST OF ABBREVIATIONS............................................................................................9

GLOSSARY OF TERMS...............................................................................................11

TRADEMARKS.............................................................................................................13

1. ETHICS..................................................................................................................141.1. Independent Ethics Committee (IEC) or Institutional Review Board

(IRB) ...........................................................................................................141.2. Ethical conduct of the study ........................................................................141.3. Subject information and consent.................................................................14

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE.......................142.1. Administrative structure ..............................................................................14

3. INTRODUCTION....................................................................................................15

4. STUDY OBJECTIVES............................................................................................164.1. Secondary objective ...................................................................................16

5. INVESTIGATIONAL PLAN ....................................................................................175.1. Study design...............................................................................................17

5.1.1. Overall study design � Description...............................................175.2. Study procedures........................................................................................18

5.2.1. Outline of study procedures .........................................................185.2.2. Intervals between study visits ......................................................20

5.3. Selection of study population ......................................................................205.3.1. Subject completion and withdrawal from study ............................20

5.3.1.1. Subject completion .....................................................205.3.1.2. Subject withdrawal......................................................205.3.1.3. Subject withdrawal from the study ..............................21

5.4. Composition and administration of vaccines ...............................................215.4.1. Description of vaccines ................................................................215.4.2. Treatment allocation and randomisation ......................................215.4.3. Blinding........................................................................................21

5.5. Prior and concomitant medication /vaccination ...........................................215.6. Assessment of immunogenicity variables....................................................225.7. Assessment of safety variables...................................................................22

5.7.1. Serious adverse events ...............................................................225.8. Data quality assurance ...............................................................................235.9. Statistical methods......................................................................................23

5.9.1. Secondary endpoint.....................................................................245.9.2. Determination of sample size.......................................................245.9.3. Study cohorts /data sets analysed ...............................................245.9.4. Analysis of demographics ............................................................245.9.5. Analysis of safety.........................................................................24

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5.9.6. Interim analysis............................................................................255.10. Changes in the conduct of the study or planned analyses ..........................25

5.10.1. Protocol amendment....................................................................255.10.2. Other changes .............................................................................25

5.11. Study Population Results............................................................................255.12. Study dates.................................................................................................255.13. Subject eligibility and attrition from the study ..............................................25

5.13.1. Number of subjects......................................................................255.13.2. Study completion and withdrawal from study ...............................265.13.3. Protocol deviations ......................................................................26

5.14. Demographic characteristics.......................................................................27

6. IMMUNOGENICITY RESULTS..............................................................................27

7. SAFETY RESULTS ...............................................................................................277.1. Data sets analysed .....................................................................................277.2. Serious adverse events ..............................................................................27

7.2.1. Fatal events .................................................................................277.2.2. Non-fatal events...........................................................................27

7.3. Adverse events leading to premature discontinuation of studyvaccine and/or study...................................................................................38

7.4. Other significant adverse events.................................................................387.5. Concomitant medications/vaccinations .......................................................38

8. CONCLUSIONS.....................................................................................................38

9. REFERENCES.......................................................................................................39

10. STUDY REPORT AUTHORS /CONTRIBUTING AUTHORS .................................40

11. SERIOUS ADVERSE EVENTS..............................................................................41

MODULAR APPENDICES

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LIST OF TABLES

PAGE

Table 1 List of study procedures .........................................................................19

Table 2 Intervals between study visits.................................................................20

Table 3 Number of subjects vaccinated, completed and withdrawn withreason for withdrawal at last contact (Total vaccinated cohort)...............26

Table 4 Percentage of subjects with SAEs classified by MedDRA systemorgan class and preferred term from Dose 1 of HRV vaccine upto the extended safety follow-up contact (Total vaccinatedcohort)....................................................................................................30

Table 5 Percentage of subjects with SAEs classified by MedDRA systemorgan class and preferred term from Dose 1 of HRV vaccine upto the extended safety follow-up contact in the pooled HRVvaccine liquid formulation group and in the HRV vaccinelyophilised formulation group (Total vaccinated cohort) ..........................32

Table 6 Subjects with Serious Adverse Events reported up to Visit 3(Total vaccinated cohort)........................................................................34

Table 7 Subjects with serious adverse events reported after Visit 3 up tothe extended safety follow-up contact (Total vaccinated cohort).............36

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LIST OF ABBREVIATIONS

AE Adverse event

CCID50 Median Cell Culture Infective dose (quantity of viruscausing infection in 50% of exposed cells)

CI Confidence interval

DMEM Dulbecco�s Modified Eagle Medium

eCRF Electronic Case Report Form

GCP Good clinical practice

GE Gastroenteritis

GSK GlaxoSmithKline

HRV Human rotavirus

IDMC Independent Data Monitoring Committee

IEC Independent Ethics Committee

IRB Institutional Review Board

IS Intussusception

LL Lower Limit

MedDRA Medical Dictionary for Regulatory Activities

RAP Reporting and Analysis Plan

RDE Remote Data Entry

RV Rotavirus

SAE Serious adverse event

SAS Statistical Analysis System

SOC System Organ Class

SOP Standard Operating Procedure

SPC Summary of Product Characteristics

TVC Total Vaccinated Cohort

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UL Upper Limit

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GLOSSARY OF TERMS

Active Phase: Active Phase included the period starting from Day 0 up tofinal study visit (Visit 3) for post-vaccination bloodsampling at approximately one month after Dose 2 of thestudy vaccine.

Adverse event: Any untoward medical occurrence in a patient or clinicalinvestigation subject, temporally associated with the use of amedicinal product, whether or not considered related to themedicinal product.

An AE can therefore be any unfavorable and unintendedsign (including an abnormal laboratory finding), symptom,or disease (new or exacerbated) temporally associated withthe use of a medicinal product. For marketed medicinalproducts, this also includes failure to produce expectedbenefits (i.e. lack of efficacy), abuse or misuse.

Completed: Subjects who completed the last study visit (i.e. Visit 3)were considered to have completed the active phase of thestudy.

Subjects who could be contacted for the concluding contactforeseen at the end of the extended safety follow-upassessment were considered to have completed the extendedsafety follow-up phase of the study.

Eligible: Qualified for enrolment into the study based upon strictadherence to inclusion/exclusion criteria.

Enrolled: Participated in the first visit of the study after writteninformed consent obtained from parents/guardians,determined to be eligible for inclusion in the study basedupon strict adherence to inclusion/exclusion criteria.

Evaluable: Meeting all eligibility criteria, complying with theprocedures defined in the protocol, and, therefore, includedin the analysis.

Extended safetyfollow-up phase:

Period starting from the day after Visit 3 up to the safetycontact at Month 7.

Randomisation: Process of random attribution of treatment to subjects inorder to reduce bias of selection.

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Serious adverseevent:

Any untoward medical occurrence that resulted in death,was life-threatening, required hospitalisation or prolongationof existing hospitalisation, resulted in disability/ incapacity,was a congenital anomaly/ birth defect in the offspring of astudy subject, an important medical event that may not havebeen immediately life-threatening or resulted in death orhospitalisation but might have jeopardised the subject ormight have required medical or surgical intervention toprevent one of the other outcomes listed in the abovedefinition i.e. intussusception.

Subject(s): Term used throughout the protocol to denote an individualthat has been contacted in order to participate in the clinicalstudy, either as a recipient of the investigational product(s)or as a control.

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TRADEMARKS

The following trademarks are used in the present report.

Trademarks of the GlaxoSmithKline groupof companies

Generic description

Infanrix hexa� Combined diphtheria, tetanus, acellular pertussis, hepatitis B,inactivated poliovirus vaccine and Haemophilus influenzae typeb vaccine

Rotarix� Live attenuated human rotavirus vaccine

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1. ETHICS

1.1. Independent Ethics Committee (IEC) or Institutional ReviewBoard (IRB)

The study protocol, protocol amendment, the informed consent and other information thatrequired pre-approval were reviewed and approved by the ethics committee at the jointauthority for Finland.

1.2. Ethical conduct of the study

This study was conducted in accordance with "good clinical practice" (GCP) and allapplicable regulatory requirements, including, where applicable, the Declaration ofHelsinki.

1.3. Subject information and consent

Written informed consent for participation of the subject was obtained from theparents/guardians of each subject prior to the performance of any study-specificprocedures on Visit 1 (Day 0) of the study.

Electronic case report forms (eCRFs) were provided for each subject�s data to berecorded.

2. INVESTIGATORS AND STUDY ADMINISTRATIVESTRUCTURE

2.1. Administrative structure

This study was conducted by 11 investigators at 12 centres in Finland.

Prof. at the Finland was the principal investigator for this study.

GlaxoSmithKline (GSK) Biologicals, Rixensart, Belgium was the study sponsor and wasresponsible for administration of the study, including, clinical trial supply management.

An Independent Data Monitoring Committee (IDMC), consisting of clinical experts and abiostatistician, monitored the safety aspects of the human rotavirus (HRV) vaccineclinical development. Therefore, the IDMC periodically reviewed all the serious adverseevents (SAEs) reported during the study period.

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3. INTRODUCTION

Rotavirus (RV), the leading cause of acute gastroenteritis (GE) episodes among infantsand children, accounts for 20% of diarrhoea-related deaths worldwide [Phua, 2005]. Thevirus is not only responsible for a huge number of hospitalisations and physician visitseach year, but also causes severe consequences, especially in the developing andunderdeveloped countries. RV alone accounts for around 87 000 hospitalisations and700 000 physician visits in children less than 5 years of age in the European Union[Bernstein, 2007].

In order to combat the increasing rate of morbidity and mortality associated with RVinfections which is a major health concern in several countries worldwide, an effectiveintervention against RV was developed by GSK Biologicals. The vaccine is an oral liveattenuated HRV vaccine containing the RIX4414 vaccine strain of G1P1A P[8],developed from the parent 89-12 vaccine [Bernstein, 1998; Bernstein 1999; Bernstein,2002].

GSK Biologicals� HRV vaccine is a lyophilised preparation to be reconstituted withcalcium carbonate buffer. The vaccine is administered as two oral doses to infantsbetween 6 and 12 weeks of age. Previous studies have shown that the lyophilisedformulation was well tolerated, immunogenic and highly effective against RV GEhospitalisations, severe RV GE and any RV GE due to multiple circulating RV strains(G1 and non-G1 RV types) [Ruiz Palacios, 2006; Salinas, 2005; Vesikari, 2004; Vesikari,2006; Vesikari, 2007]. The SAE profile of the HRV vaccine was also similar to theplacebo. The vaccine was also not associated with an increased risk of intussusception(IS). This formulation of the HRV vaccine is licensed in more than 103 countriesworldwide as Rotarix.

In addition, GSK Biologicals developed a liquid formulation of the HRV vaccine to beadministered as two oral doses to infants. The liquid formulation of the vaccine hasseveral advantages over the lyophilised formulation such as ease in administration, lowercost implications in terms of shipment and storage, and higher output capacity. Aprevious study conducted in Finland tested the immunogenicity, reactogenicity and safetyof the HRV vaccine liquid formulation as compared to the lyophilised formulation,showed that no statistically significant difference was detected between the twoformulations in terms of anti-RV immunoglobulin A (IgA) seroconversion rates. Thereactogenicity and safety profiles of the two formulations were similar to the placebo[Vesikari, 2007].

The primary phase of the current study was conducted to evaluate the lot-to-lotconsistency of three consecutive production lots of the HRV vaccine liquid formulationin terms of immunogenicity and reactogenicity. This study also evaluated theimmunogenicity, reactogenicity and safety of the HRV vaccine liquid formulationcompared to the HRV vaccine lyophilised formulation when administered concomitantlywith routine childhood vaccine. In this study, 1200 subjects were randomised to receivetwo doses of the HRV vaccine (liquid or lyophilised formulation) at approximately 3 and4 months of age. Routine childhood vaccine, Infanrix hexa (GSK Biologicals� combineddiphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus vaccine and

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Haemophilus influenzae type b vaccine) was administered at 3, 4 and 5 months of ageduring the study.

It was found that lot-to-lot consistency was met for the three consecutive production lotsof the HRV vaccine liquid formulation. Also, non-inferiority of HRV vaccine liquidformulation to HRV vaccine lyophilised formulation was demonstrated in the primarystudy. Preliminary data on SAEs up to Visit 3 were provided in the primary study reportRota-061 (107876) Report Part I Main (Active phase of the study). The active phase ofthe study included the period starting from Day 0 up to final study visit (Visit 3) for post-vaccination blood sampling at approximately one month post-dose 2 of the HRV vaccine.The extended safety follow-up phase included the period starting from the day after Visit3 up to the extended safety follow-up contact at Month 7 (i.e. up to six months after thelast dose of HRV vaccine).

This annex report presents the results of the SAEs which have been reported from Dose 1of the HRV vaccine up to end of the extended safety follow-up phase.

4. STUDY OBJECTIVES

The objectives pertaining to the extended safety follow-up phase is listed below. Theobjectives of the primary study can be found in the primary study report Rota-061(107876) Report Part I Main.

4.1. Secondary objective

• To assess the safety of the study vaccines in terms of occurrence of SAEs after Visit3 up to the safety contact.

Refer Section 5.9.1 for the definition of the secondary endpoint.

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5. INVESTIGATIONAL PLAN

5.1. Study design R andom isation

(1:1 :1:1)

V isit 1 A ge: 10-17 w eeks (70 -125 days) D ay 0 D ose 1 B lood sam pling

V accination visits

V isit 3 M onth 2 B lood sam pling Study conclusion

H RV vacc ine liq uid fo rm ulation (Lot A), N = 300

H RV vaccine lyophilized form ulation, N = 300

V isit 2 M onth 1 D ose 2

Follow -up visit

E xtended safety contact� Safety follow -up conclusion

HRV vaccine liquid form ulation (Lot B ), N = 300

HRV vaccine liquid form ulation (Lot C), N = 300

�Contact (by telephone call or any other convenient procedure) for safety follow-up took place six months after the lastdose of HRV vaccineN = number of subjects planned to be enrolled

5.1.1. Overall study design – Description

• Experimental design: Phase III, multicentric study with four parallel treatmentgroups:

− Group HRV vaccine liquid formulation Lot A (referred to as Liq_A group)

− Group HRV vaccine liquid formulation Lot B (referred to as Liq_B group)

− Group HRV vaccine liquid formulation Lot C (referred to as Liq_C group)

− Group HRV vaccine lyophilised formulation (referred to as Lyo group)

• Treatment allocation: randomised (1:1:1:1).

• Blinding: Double blind for three lots of HRV vaccine liquid formulation andopen-label for liquid formulation versus the lyophilised formulation.

• Vaccination schedules

− Two doses of HRV vaccine were administered at 3 and 4 months of age ininfants aged between 10 and 17 weeks (70 � 125 days) at the time of the firstdose and previously uninfected with HRV.

− During the study, routine childhood vaccine (Infanrix hexa) was administered at3, 4 and 5 months of age. The first two doses of Infanrix hexa were

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co-administered with each dose of the HRV vaccine. All routine vaccinationsadministered from birth up to Visit 3 were recorded in the eCRF. Subjects alsoreceived a booster dose of Infanrix hexa according to the approved prescribinginformation outside the scope of this study.

• Blood samples were collected from all subjects at Visits 1 and 3 to measure serumanti-RV IgA antibody concentrations using Enzyme-Linked Immunosorbent Assay(ELISA) (cut-off was 20 U/ml). Immunogenicity results were presented in theprimary study report Rota-061 (107876) Report Part I Main.

• Results of solicited symptoms occurring between the day of each HRV vaccine doseand the following 7 days (Day 0 to Day 7), unsolicited symptoms occurring within31 days (Day 0 to Day 30) after each HRV vaccine dose. GE episodes occurringfrom Dose 1 of HRV vaccine up to Visit 3 [i.e two months post-dose 2] and SAEsreported from Dose 1 of HRV vaccine up to Visit 3 were presented in the primarystudy report Rota-061 (107876) Report Part I Main.

• SAEs occurring from Dose 1 of HRV vaccine up to six months after the last dose ofHRV vaccine were evaluated. Final data on SAEs from Dose 1 of HRV vaccine upto the end of the extended safety follow-up phase are presented in this annex report.

• Type of study: This is an extended safety follow-up study with the subjects in theprimary study having received two doses of the HRV vaccine (liquid or lyophilisedformulation) at 3 and 4 months of age.

• Data collection: Data collection was done by Remote Data Entry (RDE) usingindividual eCRF.

• Duration of the study: Duration of the study, per subject was approximately 7months including the 6-month extended safety follow-up period after last dose of theHRV vaccine.

5.2. Study procedures

5.2.1. Outline of study procedures

The list of study procedures is presented in Table 1.

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Table 1 List of study procedures

Age 10 - 17 weeks(70 - 125 days)

4 months 5 months 10 months

Visit VISIT 1 VISIT 2 VISIT 3 CONTACTTiming Day 0 Month 1 Month 2 Month 7

Sampling time point Pre Post-vacc 2Informed consent •Check inclusion criteria •Check exclusion criteria •Check elimination criteria • •Check contraindications • •Medical history •Physical examination • •� •�Pre-vaccination body temperature • •Measure/record height and weight •Randomisation •Blood sampling:for antibody determination (2.0 ml) • •Study vaccination • •Routine vaccination (Infanrix hexa)� • • •Recording of oral vaccine intakecharacteristics*

• •

Daily post-vaccination recording of solicitedsymptoms (Day 0 to Day 7 after each HRVvaccine dose) by subjects� parents/guardians

• •

Recording of non-serious adverse eventswithin 31 days post-vaccination, byinvestigator

• • •

Recording of GE • • •Collection of stool samples if the childdevelops GE

• • •

Return of diary cards • •Diary card transcription • •Record any concomitantmedication/vaccination§

• • • •

Reporting of Serious Adverse Events • • • •Study Conclusion •Contact for safety follow-up •Safety follow-up conclusion •Note: The triple-line border following Month 2 indicated the final analysis of immunogenicity, solicited symptoms,unsolicited AEs and SAEs reported up to Visit 3, as soon as all the data were available and cleaned (Results areavailable in primary study report Rota-061 (107876) Report Part I Main).The shaded area refers to the extended safety follow-up. Final data on SAEs from Dose 1 of HRV vaccine up to theend of the extended safety follow-up is presented in this annex report.• Used to indicate a study procedure that required documentation in the individual eCRF.� Physical examination at this visit took place in case of request from the nurse or parents/guardians and could belimited appropriate with local requirements for routine physical examination for a child at this age and appropriate forintervention that was to be followed (blood draw etc.).�During the study, the routine childhood vaccine (Infanrix hexa) was administered at 3, 4 and 5 months of age. Thefirst two doses of Infanrix hexa were co-administered with each dose of HRV vaccine. All routine vaccinationsadministered from birth up to Visit 3 were recorded in the eCRF. Subjects received a booster dose of Infanrix hexaaccording to the approved prescribing information outside the scope of this study.

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Footnotes of Table 1 continued*Vaccine intake characteristics were recorded in the eCRF as smooth vaccine intake, vaccine intake interrupted due tocoughing or choking, regurgitation after vaccine intake or vomiting after vaccine intake.§Recording of medications/vaccinations at each visit/contact was according to the guidelines in Section 5.5 of primarystudy report (Rota-061) 107876 Report Part I Main.

5.2.2. Intervals between study visits

Table 2 presents the protocol defined intervals between visits.

Table 2 Intervals between study visits

Interval Length of interval asspecified in the protocol

Length of adapted interval

1 (Visit 1→ Visit 2) 30 - 48 days 21 - 48 days2 (Visit 2→ Visit 3) 30 - 48 days 21 - 48 daysContact� 168-202 days after the last

dose of HRV vaccineNo subject will be eliminated for not respecting this

time intervalThe shaded area refers to the time point not considered for this report.�A safety follow-up contact (by telephone call or any other convenient procedure) to collect information on SAEs sincethe last visit.

5.3. Selection of study population

Refer to the primary study report Rota-061 (107876) Report Part I Main for details on theeligibility criteria, subject completion and withdrawal from the active phase of the study.

5.3.1. Subject completion and withdrawal from study

5.3.1.1. Subject completion

A subject who returned for Visit 3 (i.e. one month post-dose 2) was considered to havecompleted the active phase of the study.

A subject who could be contacted for the concluding contact foreseen at the end of theextended safety follow-up assessment was considered to have completed the extendedsafety follow-up phase. The analysis of subjects who completed the extended safetyfollow-up assessment is presented in this annex report.

5.3.1.2. Subject withdrawal

Subjects who were withdrawn because of SAE/adverse events (AEs) were clearlydistinguished from subjects who were withdrawn for other reasons. Investigatorsfollowed subjects who were withdrawn as result of a SAE/AE until resolution of theevent (see Section 5.7).

Withdrawals were not replaced.

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5.3.1.3. Subject withdrawal from the study

A subject who could not be contacted for the concluding contact foreseen at the end ofthe extended safety follow-up assessment (up to six months after the last dose of theHRV vaccine) was considered to have withdrawn from the extended safety follow-upphase.

Information relative to the withdrawal was documented on the Study Conclusion page ofthe eCRF. The reason for not completing the extended safety follow-up phase was notedas either consent withdrawal or lost to follow-up.

5.4. Composition and administration of vaccines

5.4.1. Description of vaccines

All subjects received two doses of the HRV vaccine (liquid or lyophilised as per groupallocation) that contained not less than 106.0 median Cell Culture Infective dose (CCID50)of RIX4414 HRV strain according to a 0, 1 month schedule.

Routine childhood vaccine (Infanrix hexa) was administered at 3, 4 and 5 months of age.

Refer to the primary study report Rota-061 (107876) Report Part I Main for details on thevaccine composition, lot numbers, dosage and vaccine administration pertaining to theactive phase of the study.

5.4.2. Treatment allocation and randomisation

Refer to the primary study report Rota-061 (107876) Report Part I Main for details ontreatment allocation and randomisation.

5.4.3. Blinding

The study was double-blind with respect to the three lots of HRV vaccine liquidformulation. The parents/guardians of the subjects and the study personnel were unawareof the administered lot of the HRV vaccine liquid formulation. The study personnel andin certain circumstances the parents/guardians, were aware if the subject receivedlyophilised or liquid formulation, since blinding between the two different formulationswas technically not possible. The study was open label for the liquid formulation versusthe lyophilised formulation.

The blinding was maintained during the extended safety follow-up phase.

5.5. Prior and concomitant medication /vaccination

Refer to the primary study report Rota-061 (107876) Report Part I Main for details onprior and concomitant medication/vaccinations administered during the active phase of

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the study. Any investigational medication or vaccine administered from Dose 1 of HRVvaccine up to the extended safety follow-up contact were recorded in the eCRF.

5.6. Assessment of immunogenicity variables

Refer to the primary study report Rota-061 (107876) Report Part I Main for details on theassessment of immunogenicity variables.

5.7. Assessment of safety variables

Refer to the primary study report Rota-061 (107876) Report Part I Main for details on theassessment of safety variables, including preliminary data on SAEs up to Visit 3.

Assessment of safety included recording of SAEs during the entire study period (fromDose 1 up to six months after the last dose of the HRV vaccine), which will be presentedin this annex report.

5.7.1. Serious adverse events

A SAE was any untoward medical occurrence that:

a. resulted in death,

b. was life-threatening,

NOTE: The term 'life-threatening' in the definition of 'serious' referred to an event inwhich the subject was at risk of death at the time of the event. It did not refer to an event,which hypothetically might have caused death, if it were more severe.

c. required hospitalisation or prolongation of existing hospitalisation,

NOTE: In general, hospitalisation signified that the subject had been detained (usuallyinvolving at least an overnight stay) at the hospital or emergency ward for observationand/or treatment that would not have been appropriate in the physician�s office or out-patient setting. Complications that occurred during hospitalisation were AEs. If acomplication prolonged hospitalisation or fulfilled any other serious criteria, the eventwas serious. When in doubt as to whether �hospitalisation� occurred or was necessary,the AE was considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen frombaseline was not considered an AE.

d. resulted in disability/incapacity,

NOTE: The term disability meant a substantial disruption of a person�s ability to conductnormal life functions. This definition was not intended to include experiences of relativelyminor medical significance such as uncomplicated headache, nausea, vomiting,diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may haveinterfered or prevented everyday life functions but did not constitute a substantialdisruption.

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e. was a congenital anomaly/birth defect in the offspring of a study subject,

f. medical or scientific judgement was exercised in deciding whether reporting wasappropriate in other situations, such as important medical events i.e. IS that may notbe immediately life-threatening or resulted in death or hospitalisation but might havejeopardised the subject or might have required medical or surgical intervention toprevent one of the other outcomes listed in the above definition. These were alsoconsidered serious. Examples of such events were invasive or malignant cancers,intensive treatment in an emergency room or at home for allergic bronchospasm,blood dyscrasias or convulsions that do not result in hospitalisation.

SAEs that were related to study participation (e.g. procedures, invasive tests, and achange from existing therapy) or were related to a concurrent medication were collectedand recorded from the time the subject's parents consented to participate in the study untilshe/he was discharged.

The investigator inquired about the occurrence of SAEs at every visit during the study.SAEs were reported promptly to GSK once the investigator determined that the event metthe protocol definition of an SAE. The investigator provided an assessment of causality,as described in Section 5.7.1, at the time of the initial report.

5.8. Data quality assurance

To ensure that the study procedures conformed across all investigator sites, the protocol,eCRF and safety reporting were reviewed with the investigator(s) and his/her/theirpersonnel responsible for the conduct of the study by the Company representative(s) priorto study start.

Adherence to the protocol requirements and verification of data generation accuracy wereachieved through monitoring visits to each investigator site. Computer checks andblinded review of subject tabulations were performed to ensure consistency ofCRF/eCRF completion. All procedures were performed according to methodologiesdetailed in GlaxoSmithKline Biologicals Standard Operating Procedures (SOPs).

Independent Audit statement:

• No study specific audits were performed for this study.

5.9. Statistical methods

All statistical analyses were performed using Statistical Analysis System software (SASVersion 8.2) and Proc StatXact-5. Analyses were performed according to the protocoland the study Reporting and Analysis Plan (RAP).

For additional analyses performed on the data pertaining to the SAEs refer Section 5.9.5.Refer to Section 5.10.2 for changes to analyses specified in the protocol.

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5.9.1. Secondary endpoint

The study endpoint pertaining to the analysis of safety data for the extended safetyfollow-up phase is presented below. The endpoints pertaining to the primary study can befound in the primary study report Rota-061 (107876) Report Part I Main.

• Occurrence of SAEs from Dose 1 of HRV vaccine up to six months after the lastdose of HRV vaccine.

5.9.2. Determination of sample size

Target enrolment was 1200 subjects (300 subjects in each of the liquid formulation ofHRV vaccine group and 300 subjects in the lyophilised formulation of HRV vaccinegroup) to obtain 960 evaluable subjects (240 subjects in each of the liquid formulation ofHRV vaccine group and 240 subjects in the lyophilised formulation of HRV vaccinegroup) for the evaluation of the primary objectives during the primary phase of the study.All subjects were to be followed for safety throughout the study period.

5.9.3. Study cohorts /data sets analysed

The only cohort used for safety analysis was Total Vaccinated Cohort (TVC).

The TVC included all subjects with at least one study vaccine administrationdocumented:

• a safety analysis based on the TVC included all vaccinated subjects.

5.9.4. Analysis of demographics

The number of subjects who could not be contacted at the end of the extended safetyfollow-up phase was tabulated by group according to the reason for withdrawal. Refer toprimary study report Rota-061 (107876) Report Part I Main for details on the analysis ofdemographics.

5.9.5. Analysis of safety

Serious adverse events reported after Visit 3 up to the extended safety follow-up contactwere summarised by group. SAEs reported for the active phase of the study were alsosummarised by group.

Additional analyses were performed to include the following:

• SAEs were summarised based on Medical Dictionary for Regulatory Activities(MedDRA) system organ class and preferred term from Dose1 up to the extendedsafety follow-up contact (i.e. Month 7).

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• The p-value for the difference between the Liq pooled and Lyo group in percentageof subjects with SAEs from Dose1 up to the extended safety follow-up contact (i.e.Month 7) was computed. P-values less than 0.05 were used as an aid to highlightpotential imbalance between groups. However, care must be taken when interpretingputative statistically significant findings since no multiplicity adjustment and clinicalsignificance have been taken into account.

5.9.6. Interim analysis

No interim analysis was planned for this study.

5.10. Changes in the conduct of the study or planned analyses

5.10.1. Protocol amendment

The study protocol dated 5 July 2006 was amended on 06 October 2006. This amendmentwas done to implement specific changes requested by the investigator in order to alignthe exclusion criteria with the approved version of the summary of product characteristics(SPC) and also to implement changes to the GSK Biologicals� standard protocoltemplate.

5.10.2. Other changes

Additional analyses were performed to compute the percentage of subjects based onMedDRA system organ class and preferred term. Also, the p-value for the differencebetween the pooled three lots of the HRV liquid formulation (Liq pooled) and Lyo groupwas computed from Dose 1 of the vaccine up to the safety contact (i.e. Month 7).

5.11. Study Population Results

5.12. Study dates

The first subject, first visit (Visit 1) took place on 10 November 2006 and the last studyvisit for the active phase (i.e. Visit 3) took place on 18 April 2007.

The last subject was contacted for the extended safety follow-up on 13 September 2007.

5.13. Subject eligibility and attrition from the study

5.13.1. Number of subjects

A total of 1200 subjects (298 subjects in the Liq_A group, 302 subjects in the Liq_Bgroup, 300 subjects in the Liq_C group and 300 subjects in the Lyo group) who receivedat least one dose of the study vaccine (liquid or lyophilised formulation of the HRVvaccine) were included in the TVC.

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5.13.2. Study completion and withdrawal from study

Table 3 presents the number of subjects vaccinated in the active phase, completed theextended safety follow-up phase and withdrawn from the extended safety follow-upphase with reasons for withdrawal.

• Of the 1200 subjects vaccinated in the active phase, a total of 1188 subjects (295subjects in the Liq_A group, 300 subjects in the Liq_B group, 297 subjects in theLiq_C group and 296 subjects in the Lyo group) completed the extended safetyfollow-up phase.

• A total of 12 subjects (3 subjects in the Liq_A group, 2 subjects in the Liq_B group,3 subjects in the Liq_C group and 4 subjects in the Lyo group) withdrew during theextended safety follow-up phase. The reasons for withdrawal were as follows:

− The parents/guardians of 9 subjects (3 subjects in the Liq_A group, 2 subjects inthe Liq_C group and 4 subjects in the Lyo group) withdrew the consent for theirchildren to participate in the study. This was not due to an adverse event.

− A total of 3 subjects (2 subjects in the Liq_B group and 1 subject in the Liq_Cgroup) could not be contacted for the extended safety follow-up as they werelost to follow-up.

Table 3 Number of subjects vaccinated, completed and withdrawn withreason for withdrawal at last contact (Total vaccinated cohort)

Liq_A Liq_B Liq_C Lyo TotalNumber of subjects vaccinated 298 302 300 300 1200Number of subjects completed (Extended safety follow-up phase)

295 300 297 296 1188

Number of subjects withdrawn (Extended safety follow-up phase)

3 2 3 4 12

Reasons for withdrawal :Serious Adverse Event 0 0 0 0 0Non-serious adverse event 0 0 0 0 0Protocol violation 0 0 0 0 0Consent withdrawal (not due to an adverse event) 3 0 2 4 9Migrated/moved from study area 0 0 0 0 0Lost to follow-up (subjects with incomplete vaccinationcourse)

0 0 0 0 0

Lost to follow-up (subjects with complete vaccination course) 0 2 1 0 3Others 0 0 0 0 0LIQ_A = HRV vaccine liquid formulation Lot ALIQ_B = HRV vaccine liquid formulation Lot BLIQ_C = HRV vaccine liquid formulation Lot CLYO = HRV vaccine lyophilised formulationVaccinated = number of subjects who were vaccinated in the studyCompleted = number of subjects who were contacted at the end of the extended safety follow-upWithdrawn = number of subjects who could not be contacted at the end of the extended safety follow-upData source = Appendix table IEi

5.13.3. Protocol deviations

None.

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5.14. Demographic characteristics

Refer to primary study report Rota-061 (107876) Report Part I Main for details on thedemographic characteristics.

6. IMMUNOGENICITY RESULTS

Refer to primary study report Rota-061 (107876) Report Part I Main for allimmunogenicity results.

7. SAFETY RESULTS

7.1. Data sets analysed

The analysis of safety was performed on the TVC. See Section 5.9.3 for the definition ofthe cohort identified for analyses.

7.2. Serious adverse events

The SAE CIOMS and Summary Table are provided in Section 11.

7.2.1. Fatal events

There were no fatal events reported in the study.

7.2.2. Non-fatal events

Table 4 presents the percentage of subjects with SAEs classified by MedDRA systemorgan class and preferred term from Dose 1 of HRV vaccine up to extended safetyfollow-up contact, by group.

Table 5 presents the percentage of subjects with SAEs classified by MedDRA systemorgan class and preferred term from Dose 1 of HRV vaccine up to extended safetyfollow-up contact in the pooled HRV vaccine liquid formulation group and in the HRVvaccine lyophilised formulation group.

Table 6 and Table 7 present the subjects with SAEs reported up to Visit 3 and after Visit3 up to the extended safety follow-up contact, respectively.

A total of 36 subjects reported at least one SAE during the entire study period (Dose 1 upto six months after last dose of HRV vaccine).

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Active phase:

A total of 18 subjects (2 subjects in the Liq_A group, 7 subjects in the Liq_B group, 3subjects in the Liq_C group and 6 subjects in the Lyo group) reported at least one SAEwithin the 31-day (Day 0 �30) follow-up period after each vaccination. Most of the caseswere under the System Organ Class (SOC) of infections and infestations. All the SAEshad resolved and one SAE had resolved with sequelae.

The subjectwas discharged in good condition after 51 days of hospitalisation and the medicationis continuing to prevent new seizures. The subject has recovered with sequelae. Theinvestigator considered that there was no reasonable possibility that the infantilespasms might have been caused by the HRV vaccine.

The symptom was reported12 days after Dose 1 of the HRV vaccine. The subject recovered after 29 days ofhospitalisation.

However, following a few reports of the associationof Kawasaki disease with other rotavirus vaccine, the principal investigatorretrospectively concluded that Kawasaki disease was possibly related to vaccination inthis case.

Extended safety follow-up phase:

During the extended safety follow-up phase, a total of 18 subjects (3 subjects in theLiq_A group, 2 subjects in the Liq_B group, 11 subjects in the Liq_C group and 2subjects in the Lyo group) reported at least one SAE. Most of the SAEs reported duringthe extended safety follow-up phase (n = 13) were under the SOC �Infections andinfestations� and there were 3 SAEs reported under the SOC of �Nervous systemdisorders�. All the SAEs had resolved.

There was nocausal relationship of the episodes to the HRV vaccine. Both the cases wereresolved.

The investigatorconsidered that the seizure-like episodes was caused due to the subject�s medicalcondition, gastroesophageal reflux.

The event was possibly due to an incidental illness as the subject had afamily history of epilepsy.

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Thesubject had recovered after 5 days of hospitalisation.

Entire study period:

• The percentage of subjects reporting at least one SAE from Dose 1 of the HRVvaccine up to the extended safety follow-up phase (i.e. Month 7) was 1.7% in Liq_Agroup, 3.0% in the Liq_B group, 4.7% in Liq_C group and 2.7% in the Lyo group(Table 4).

• The p-value for the difference between Liq pooled and Lyo groups was 0.696suggesting that there was no potential imbalance between the groups in terms ofSAEs (p-value >0.05) (Table 5).

• None of the SAEs were assessed by the investigator to be causally related tovaccination.

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Table 4 Percentage of subjects with SAEs classified by MedDRA systemorgan class and preferred term from Dose 1 of HRV vaccine up tothe extended safety follow-up contact (Total vaccinated cohort)

Liq_A N = 298

Liq_B N = 302

Liq_C N = 300

Lyo N = 300

95% CI 95% CI 95% CI 95% CIPrimary System OrganClass (CODE)

PreferredTerm (CODE)

n % LL UL n % LL UL n % LL UL n % LL UL

At least one symptom 5 1.7 0.5 3.9 9 3.0 1.4 5.6 14 4.7 2.6 7.7 8 2.7 1.2 5.2Blood and lymphaticsystem disorders(10005329)

Lymphadenitis(10025188)

0 0.0 0.0 1.2 1 0.3 0.0 1.8 0 0.0 0.0 1.2 0 0.0 0.0 1.2

Gastrointestinaldisorders (10017947)

Inguinal hernia(10022016)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 1 0.3 0.0 1.8 0 0.0 0.0 1.2

Infections andinfestations (10021881)

Bronchiolitis(10006448)

0 0.0 0.0 1.2 2 0.7 0.1 2.4 0 0.0 0.0 1.2 0 0.0 0.0 1.2

Bronchitis(10006451)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 0 0.0 0.0 1.2 1 0.3 0.0 1.8

Dacryocystitis(10011844)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 1 0.3 0.0 1.8 0 0.0 0.0 1.2

Gastroenteritis(10017888)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 3 1.0 0.2 2.9 1 0.3 0.0 1.8

Influenza(10022000)

0 0.0 0.0 1.2 1 0.3 0.0 1.8 0 0.0 0.0 1.2 0 0.0 0.0 1.2

Kawasaki�sdisease(10023320)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 0 0.0 0.0 1.2 1 0.3 0.0 1.8

Laryngitis(10023874)

1 0.3 0.0 1.9 1 0.3 0.0 1.8 1 0.3 0.0 1.8 1 0.3 0.0 1.8

Otitis media(10033078)

1 0.3 0.0 1.9 2 0.7 0.1 2.4 0 0.0 0.0 1.2 1 0.3 0.0 1.8

Pharyngitis(10034835)

1 0.3 0.0 1.9 0 0.0 0.0 1.2 0 0.0 0.0 1.2 0 0.0 0.0 1.2

Pneumonia(10035664)

1 0.3 0.0 1.9 1 0.3 0.0 1.8 0 0.0 0.0 1.2 0 0.0 0.0 1.2

Pneumoniaviral(10035737)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 0 0.0 0.0 1.2 1 0.3 0.0 1.8

Pyelonephritis(10037596)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 1 0.3 0.0 1.8 1 0.3 0.0 1.8

Pyelonephritisacute(10037597)

0 0.0 0.0 1.2 1 0.3 0.0 1.8 0 0.0 0.0 1.2 0 0.0 0.0 1.2

Respiratorysyncytial virusbronchiolitis(10038718)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 2 0.7 0.1 2.4 0 0.0 0.0 1.2

Respiratorysyncytial virusinfection(10061603)

1 0.3 0.0 1.9 0 0.0 0.0 1.2 1 0.3 0.0 1.8 0 0.0 0.0 1.2

Upperrespiratorytract infection(10046306)

0 0.0 0.0 1.2 1 0.3 0.0 1.8 0 0.0 0.0 1.2 0 0.0 0.0 1.2

Urinary tract 0 0.0 0.0 1.2 0 0.0 0.0 1.2 1 0.3 0.0 1.8 0 0.0 0.0 1.2

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Liq_A N = 298

Liq_B N = 302

Liq_C N = 300

Lyo N = 300

95% CI 95% CI 95% CI 95% CIPrimary System OrganClass (CODE)

PreferredTerm (CODE)

n % LL UL n % LL UL n % LL UL n % LL UL

infection(10046571)

Nervous systemdisorders (10029205)

Convulsion(10010904)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 2 0.7 0.1 2.4 0 0.0 0.0 1.2

Febrileconvulsion(10016284)

1 0.3 0.0 1.9 0 0.0 0.0 1.2 0 0.0 0.0 1.2 0 0.0 0.0 1.2

Infantilespasms(10021750)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 0 0.0 0.0 1.2 1 0.3 0.0 1.8

Respiratory, thoracicand mediastinaldisorders (10038738)

Bronchialobstruction(10006440)

0 0.0 0.0 1.2 0 0.0 0.0 1.2 1 0.3 0.0 1.8 1 0.3 0.0 1.8

LIQ_A = HRV vaccine liquid formulation Lot ALIQ_B = HRV vaccine liquid formulation Lot BLIQ_C = HRV vaccine liquid formulation Lot CLYO = HRV vaccine lyophilised formulationAt least one symptom = number of subjects reporting at least one symptom regardless of the MedDRA Preferred TermN = number of subjects with at least one administered dosen/% = number/percentage of subjects reporting at least once the specified symptom95% CI= exact 95% confidence interval; LL = Lower Limit, UL = Upper LimitData source = Appendix table IICiii and IICiv

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Table 5 Percentage of subjects with SAEs classified by MedDRA systemorgan class and preferred term from Dose 1 of HRV vaccine up tothe extended safety follow-up contact in the pooled HRV vaccineliquid formulation group and in the HRV vaccine lyophilisedformulation group (Total vaccinated cohort)

Liq POOL N = 900

Lyo N = 300

Differencebetween

LIQ POOL - LYO

P-Value

95% CI 95% CI 95% CI*Primary SystemOrgan Class(CODE)

Preferred Term(CODE)

n % LL UL n % LL UL % LL UL

At least onesymptom

28 3.1 2.1 4.5 8 2.7 1.2 5.2 0.44 -2.22 2.35 0.696

Blood and lymphaticsystem disorders(10005329)

Lymphadenitis(10025188)

1 0.1 0.0 0.6 0 0.0 0.0 1.2 0.11 -1.15 0.63 0.564

Gastrointestinaldisorders(10017947)

Inguinal hernia(10022016)

1 0.1 0.0 0.6 0 0.0 0.0 1.2 0.11 -1.15 0.63 0.564

Infections andinfestations

Bronchiolitis(10006448)

2 0.2 0.0 0.8 0 0.0 0.0 1.2 0.22 -1.04 0.81 0.414

(10021881) Bronchitis (10006451) 0 0.0 0.0 0.4 1 0.3 0.0 1.8 -0.33 -1.86 0.09 0.083Dacryocystitis(10011844)

1 0.1 0.0 0.6 0 0.0 0.0 1.2 0.11 -1.15 0.63 0.564

Gastroenteritis(10017888)

3 0.3 0.1 1.0 1 0.3 0.0 1.8 0.00 -1.54 0.71 1.000

Influenza (10022000) 1 0.1 0.0 0.6 0 0.0 0.0 1.2 0.11 -1.15 0.63 0.564Kawasaki�s disease(10023320)

0 0.0 0.0 0.4 1 0.3 0.0 1.8 -0.33 -1.86 0.09 0.083

Laryngitis (10023874) 3 0.3 0.1 1.0 1 0.3 0.0 1.8 0.00 -1.54 0.71 1.000Otitis media(10033078)

3 0.3 0.1 1.0 1 0.3 0.0 1.8 0.00 -1.54 0.71 1.000

Pharyngitis (10034835) 1 0.1 0.0 0.6 0 0.0 0.0 1.2 0.11 -1.15 0.63 0.564Pneumonia (10035664) 2 0.2 0.0 0.8 0 0.0 0.0 1.2 0.22 -1.04 0.81 0.414Pneumonia viral(10035737)

0 0.0 0.0 0.4 1 0.3 0.0 1.8 -0.33 -1.86 0.09 0.083

Pyelonephritis(10037596)

1 0.1 0.0 0.6 1 0.3 0.0 1.8 -0.22 -1.76 0.34 0.414

Pyelonephritis acute(10037597)

1 0.1 0.0 0.6 0 0.0 0.0 1.2 0.11 -1.15 0.63 0.564

Respiratory syncytialvirus bronchiolitis(10038718)

2 0.2 0.0 0.8 0 0.0 0.0 1.2 0.22 -1.04 0.81 0.414

Respiratory syncytialvirus infection(10061603)

2 0.2 0.0 0.8 0 0.0 0.0 1.2 0.22 -1.04 0.81 0.414

Upper respiratory tractinfection (10046306)

1 0.1 0.0 0.6 0 0.0 0.0 1.2 0.11 -1.15 0.63 0.564

Urinary tract infection(10046571)

1 0.1 0.0 0.6 0 0.0 0.0 1.2 0.11 -1.15 0.63 0.564

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Liq POOL N = 900

Lyo N = 300

Differencebetween

LIQ POOL - LYO

P-Value

95% CI 95% CI 95% CI*Primary SystemOrgan Class(CODE)

Preferred Term(CODE)

n % LL UL n % LL UL % LL UL

Nervous system Convulsion (10010904) 2 0.2 0.0 0.8 0 0.0 0.0 1.2 0.22 -1.04 0.81 0.414disorders(10029205)

Febrile convulsion(10016284)

1 0.1 0.0 0.6 0 0.0 0.0 1.2 0.11 -1.15 0.63 0.564

Infantile spasms(10021750)

0 0.0 0.0 0.4 1 0.3 0.0 1.8 -0.33 -1.86 0.09 0.083

Respiratory,thoracic andmediastinaldisorders(10038738)

Bronchial obstruction(10006440)

1 0.1 0.0 0.6 1 0.3 0.0 1.8 -0.22 -1.76 0.34 0.414

LIQPOOL = Pooled HRV vaccine liquid formulationLYO = HRV vaccine lyophilised formulationAt least one symptom = at least one symptom experienced regardless of the MedDRA Preferred TermN = number of subjects with at least one administered dosen/% = number/percentage of subjects reporting at least once a specified unsolicited symptom95% CI= exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit95% CI* = asymptotic standardised 95% confidence interval; L.L. = lower limit, U.L. = upper limitP-Value = 2-sided P-value (Standardised asymptotic)Data source = Appendix table IICiii and IICiv

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Table 6 Subjects with Serious Adverse Events reported up to Visit 3 (Total vaccinated cohort)


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Table 7 Subjects with serious adverse events reported after Visit 3 up to the extended safety follow-up contact (Totalvaccinated cohort)


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7.3. Adverse events leading to premature discontinuation ofstudy vaccine and/or study

This medical condition occurred two days after Dose 2 of the HRVvaccine and the subject was hospitalised. After 51 days of hospitalisation, the subject wasdischarged in good condition and the medication was continued to prevent new seizures.The subject recovered with sequelae. The investigator considered that there was noreasonable possibility that the infantile spasms may have been caused by the HRVvaccine.

7.4. Other significant adverse events

No cases of intussusception were reported during the entire study period (i.e. Dose 1 ofthe HRV vaccine up to the end of the extended safety follow-up phase which is sixmonths after the last dose of the HRV vaccine).

7.5. Concomitant medications/vaccinations

Refer to Study report 107876 (Rota-061) Report Part I Main for details on theconcomitant medications/vaccinations.

8. CONCLUSIONS

• A total of 36 subjects reported at least one SAE during entire study period, of whom18 subjects reported SAEs during the extended safety follow-up phase (six monthsafter the last dose of the HRV vaccine).

• None of the SAEs were causally related to vaccination. No intussusception cases andno fatal events were reported during the study.

• Two doses of HRV vaccine (liquid or lyophilised formulation) were found to have asimilar safety profile.

• There are no clinical concerns with respect to obtained safety data

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9. REFERENCES

Bernstein DI, Sack DA, Reisinger K, et al. Second year follow-up evaluation of liveattenuated human rotavirus vaccine 89-12 in healthy infants. J Infect Dis. 2002; 186:1487�9.

Bernstein DI, Sack DA, Rothstein E, et al. Efficacy of live attenuated human rotavirusvaccine 89-12 in infants. Lancet. 1999; 354: 287�90.

Bernstein DI, Smith VE, Sherwood JR et al. Safety and immunogenicity of a liveattenuated human rotavirus 89-12 vaccine. Vaccine. 1998; 16: 381�7.

Bernstein DI. A live attenuated human rotavirus vaccine. Drugs of Today. 2007; 43 (5)281�291.

Phua KB, Quak SH, Lee BW, et al. Evaluation of RIX4414, A Live, AttenuatedRotavirus Vaccine, in a Randomized, Double-Blind, Placebo-Controlled Phase 2 TrialInvolving 2464 Singaporean Infants. J Infect Dis. 2005; 192 (Suppl 1): S6�16.

Ruiz Palacios GM, Perez-Schael I, Velazques FR, et al. Safety and efficacy of anattenuated vaccine against severe rotavirus gastroenteritis. NEJM. 2006; 354: 11�22.

Salinas B, Perez-Schael I, Linhares AC, et al. Evaluation of safety, immunogenicity andefficacy of an attenuated rotavirus vaccine RIX4414: a randomized, placebo-controlledtrial in Latin American infants. Pediatr Infect Dis J. 2005; 807�16.

Vesikari T, Karvonen A, Prymula R, et al. Human rotavirus vaccine Rotarix�(RIX4414) is highly efficacious in Europe. Presented at the 24th Annual Meeting of theEuropean Society for Pediatric Infectious Diseases (ESPID), Basel, Switzerland, 3-5 May2006.

Vesikari T, Karvonen A, Prymula R, et al. Human rotavirus vaccine Rotarix� is highlyefficacious in Europe during the first two years of life. Presented at the 25th meeting ofEuropean society for Paediatric Infectious Diseases (ESPID), Porto, Portugal, 2-4 May-2007.

Vesikari T, Karvonen A, Puustinen L et al. Efficacy of RIX4414 live attenuated humanrotavirus vaccine in Finnish infants. Pediatr Infect Dis J. 2004; 23: 937�43.

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10. STUDY REPORT AUTHORS /CONTRIBUTING AUTHORS

Scientific Writer:

Statistician:

Project Statistician:

Central Study Coordinator:

Central Safety Contact:

Clinical Development Manager:

Regulatory Affairs representative:

Director, Rotavirus VaccinesClinical Research and Development:

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11. SERIOUS ADVERSE EVENTS

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11.1. Serious Adverse Events CIOMS

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107876 (Rota-061)

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11.2. Serious Adverse Events Summary Table

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107876 (Rota-061)

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Annex

1

Modular Appendices

List of modular appendices available for the study report and ICH-specificappendices - Study Information equivalent numbering

Modular appendices ICH numbering

Sponsor information -

Protocol and protocol amendments. 16.1.1

Sample Case Report form (unique pages only). 16.1.2

List of IECs or IRBs (plus name of committee chair if required byregulatory authority)

16.1.3

Representative written information for patient and sample consentforms.

16.1.3

List of investigators and other important participants in the study 16.1.4

Investigator CVs or equivalent summaries of training andexperience relevant to the performance of the clinical study

16.1.4

Signatures of principal or coordinating investigator(s) or sponsor�sresponsible medical officer, depending on the regulatoryauthority�s requirement

16.1.5

Listings of patients receiving test drug(s) /investigationalproduct(s) from specific batches, where more than one batch wasused (if applicable).

16.1.6

Randomisation list (patient identification and treatment assigned). 16.1.7

Audit certificates (if available). 16.1.8

Documentation of statistical methods 16.1.9

Documentation of inter-laboratory standardisation methods andquality assurance procedures, if used

16.1.10

Publications based on the study. 16.1.11

Important publications referenced in the report 16.1.12

Individual listings 16.2

Case report forms (CRFs /eCRFs)CRFs /eCRFs for deaths, other SAEs and withdrawals due toadverse events

16.316.3.1

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Sponsor Information

eTrack study numberand abbreviated title

107876 (rota-061)

EudraCT number 2006-003239-61

1. (Principal) Investigator

Prof.

Finland.

Phone: Fax: email:

2. Medical Monitor

GlaxoSmithKlinePO Box 24 (Piispansilta 9A), 02231 Espoo, Finland

Phone: Mobile: Fax: email:

3. Study Monitor



4. Study Contact for Reporting of Serious Adverse Event(s)


Phone: Mobile: Fax: (Backup: email:

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CONFIDENTIAL 107876 (Rota-061)

5. Study Contact for Emergency Code Break

Not applicable.

6. Study Centres

Multiple sites.

Central co-ordinating unit: Finland.

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Protocol and Protocol Amendments

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107876 CONFIDENTIAL Amendment 1 (06 Oct 2006)(rota-061)

1 GSK Biologicals� Protocol DS V 12.2Copyright 2006 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or useof this information is prohibited. CARS Id : CLIN_200607_167/ Version : 2.3,Admin. QC/ Modify Date : 26/10/2006

Sponsor:GlaxoSmithKline Biologicals

Rue de l'Institut 89B-1330 Rixensart Belgium

Investigational vaccines GSK Biologicals� oral live attenuated human rotavirus(HRV) vaccine (lyophilised formulation and liquidformulation)

Study vaccine number

(Amendment 1: 06 October2006)

444563 (lyophilised formulation of the HRV vaccine)and GSK357941A (liquid formulation of the HRVvaccine)

eTrack study number andabbreviated title

107876 (rota-061)


Date of approval 05 July 2006 � Final Protocol

Date of approval forsubstantial amendment 1

06 October 2006

Detailed Title


A phase III, randomised study to evaluate the clinicalconsistency in terms of immunogenicity andreactogenicity of three production lots of the liquidformulation of GlaxoSmithKline (GSK) Biologicals�oral live attenuated human rotavirus (HRV) vaccineand to evaluate the liquid formulation as compared tothe lyophilised formulation of the HRV vaccine interms of immunogenicity, reactogenicity and safetywhen administered as a two-dose primary vaccinationin healthy infants previously uninfected with HRV.

Title (Amendment 1: 06October 2006)

A study in infants to test two preparations (freeze-dried or liquid) of the rotavirus vaccine (HRVvaccine).

Co-ordinating author Scientific Writer

Contributing authors DirectorClinical Immunology

Manager Biostatistics Clinical Development Manager

Central Study Coordinator

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2CARS Id : CLIN_200607_167/ Version : 2.3,Admin. QC/ Modify Date : 26/10/2006


107876 (rota-061)




06 October 2006

Detailed Title



Sponsor signatory approval

Sponsor signatory:Director

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Sponsor Information


107876 (rota-061)


1. (Principal) Investigator

Prof.

Finland.

Phone: Fax: email:

2. Medical Monitor



3. Study Monitor



4. Study Contact for Reporting of Serious Adverse Event(s)


Phone: Mobile: Fax: (Backup: email:

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5. Study Contact for Emergency Code Break

Not applicable.

6. Study Centres

Multiple sites.

Central co-ordinating unit: Finland.

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Investigator Agreement


107876 (rota-061)




06 October 2006

Detailed Title



I agree:

(Amendment 1: 06 October 2006)

• To assume responsibility for the proper conduct of the study at this site.

• To conduct the study in compliance with this protocol, any mutually agreed futureprotocol amendments, and with any other study conduct procedures provided byGlaxoSmithKline Biologicals (GSK Biologicals).

• To ensure that all persons assisting me with the study are adequately informed aboutthe GSK Biologicals investigational product(s) and other study-related duties andfunctions as described in the protocol.

• Not to implement any changes to the protocol without agreement from the sponsorand prior review and written approval from the Institutional Review Board (IRB) orIndependent Ethics Committee (IEC), except where necessary to eliminate animmediate hazard to the subjects, or where permitted by all applicable regulatoryrequirements (for example, for administrative aspects of the study).

• That I am thoroughly familiar with the appropriate use of the vaccine(s), as describedin this protocol, and any other information provided by the sponsor, including, but notlimited to, the following: the current Investigator�s Brochure (IB) or equivalentdocument, IB supplement (if applicable) and prescribing information (in the case of amarketed vaccine).

• That I am aware of, and will comply with, �Good Clinical Practice� (GCP) and allapplicable regulatory requirements.

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• That I have been informed that certain regulatory authorities require the sponsor toobtain and supply, as necessary, details about the investigator�s ownership interest inthe sponsor or the investigational product, and more generally about his/her financialties with the sponsor. GSK Biologicals will use and disclose the information solelyfor the purpose of complying with regulatory requirements.

Hence I:

• Agree to supply GSK Biologicals with any necessary information regardingownership interest and financial ties (including those of my spouse and dependentchildren).

• Agree to promptly update this information if any relevant changes occur during thecourse of the study and for 1 year following completion of the study.

• Agree that GSK Biologicals may disclose any information it has about suchownership interests and financial ties to regulatory authorities.

• Agree to provide GSK Biologicals with an updated Curriculum Vitae and other FDArequired documents.

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Synopsis

Detailed Title

(Amendment 1: 06October 2006)

A phase III, randomised study to evaluate the clinicalconsistency in terms of immunogenicity and reactogenicity ofthree production lots of the liquid formulation ofGlaxoSmithKline (GSK) Biologicals� oral live attenuatedhuman rotavirus (HRV) vaccine and to evaluate the liquidformulation as compared to the lyophilised formulation of theHRV vaccine in terms of immunogenicity, reactogenicity andsafety when administered as a two-dose primary vaccinationin healthy infants previously uninfected with HRV.

Indication/Studypopulation

Two-dose immunisation at 3 and 4 months of age in healthyinfants previously uninfected with HRV.

Rationale In addition to the formulation consisting of a lyophilised HRVvaccine to be reconstituted with a suspension of calciumcarbonate, GSK Biologicals� has also developed a full liquidformulation of the HRV vaccine.

Liquid vaccines are easier to handle for administration, havelower cost implications in terms of shipment and storage, andhave a higher output capacity.

This trial will evaluate the lot-to-lot consistency of threeconsecutive production lots of the liquid formulation of GSKBiologicals� HRV vaccine in terms of immunogenicity andreactogenicity. This study will also evaluate theimmunogenicity, reactogenicity and safety of the liquidformulation of GSK Biologicals' HRV vaccine compared tothe lyophilised formulation of GSK Biologicals� HRV vaccinewhen administered concomitantly with a combinationchildhood vaccine.

Objectives Co-primary objectives

• To demonstrate the lot-to-lot consistency of the liquidformulation of GSK Biologicals� HRV vaccine in termsof immunogenicity as measured by serum anti-rotavirusIgA antibody levels one month after Dose 2.

Consistency will be reached if, for all pairs of lots, the two-sided 95% CIs for the ratio of anti-rotavirus IgA antibodyGMCs one month after Dose 2 are within the [0.5; 2] clinicallimit interval.

• To demonstrate non-inferiority of the liquid formulationof GSK Biologicals' HRV vaccine to that of lyophilisedformulation of GSK Biologicals� HRV vaccine in terms

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of seroconversion rates one month after Dose 2.

Non-inferiority will be reached if the upper limit of the two-sided asymptotic standardised 95% CI for the difference inseroconversion rate between the lyophilised formulation ofHRV vaccine and (minus) the liquid formulation of HRVvaccine is less than or equal to 10%.

Secondary

• To demonstrate non-inferiority of the liquid formulationof GSK Biologicals' HRV vaccine to that of lyophilisedformulation of GSK Biologicals� HRV vaccine in termsof serum anti-rotavirus IgA antibody levels one monthafter Dose 2.

Non-inferiority will be reached if the upper limit of the two-sided 95% CI for the ratio of anti-rotavirus IgA antibodyGMCs one month after Dose 2 between the lyophilisedformulation of HRV vaccine and (over) the liquid formulationof HRV vaccine is less than or equal to 2.

• To assess the lot-to-lot consistency of the liquidformulation of GSK Biologicals� HRV vaccine in termsof reactogenicity.

• To assess the safety of the study vaccines.

Study design • Experimental design: Phase III, randomised study withfour parallel groups. Double blind for three lots of theliquid formulation of GSK Biologicals� HRV vaccine,and open label for liquid formulation versus thelyophilised formulation.

• Randomisation: 1:1:1:1

• Treatment Groups:

Group HRV vaccine liquid formulation Lot A

Group HRV vaccine liquid formulation Lot B

Group HRV vaccine liquid formulation Lot C

Group HRV vaccine lyophilised formulation

• Blinding: Double blind for three lots of the liquidformulation of GSK Biologicals� HRV vaccine, and openlabel for liquid formulation versus the lyophilisedformulation.

• Vaccination schedule: Two-dose immunisation at 3 and 4months of age in healthy infants aged between 10 and 17

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weeks (70 - 125 days) at the time of the first dose andpreviously uninfected with HRV. (Amendment 1: 06October 2006)

• During the study, routine childhood vaccines (Infanrixhexa�) will be administered at 3, 4, 5 months of age.The first two doses of Infanrix hexa will becoadministered with each dose of HRV vaccine. Allroutine vaccinations administered from birth up to Visit 3should be recorded in the eCRF. Subjects will receive abooster dose of Infanrix hexa according to the approvedprescribing information outside the scope of this study.

• The study will be conducted at multiple sites in Finland.

• Three study visits and one contact for extended safetyfollow-up:

Visit 1 (Day 0): Pre-vaccination blood sample, Dose 1 ofHRV vaccine and Dose 1 of routine childhood vaccines(Infanrix hexa).

Visit 2 (Month 1): Dose 2 of HRV vaccine, Dose 2 of routinechildhood vaccines (Infanrix hexa), return reactogenicity diarycards, follow-up for safety (solicited symptoms, unsolicitedAEs and SAEs), record any GE and collection of GE stoolsamples.

Visit 3 (Month 2): Post-vaccination blood sample, returnreactogenicity diary cards, follow-up for safety (solicitedsymptoms, unsolicited AEs and SAEs), record any GE,collection of GE stool samples and study conclusion.

Extended safety contact (at 6 months after Dose 2 of HRVvaccine or Dose 1 of HRV vaccine in case Dose 2 notadministered): Record SAEs since previous visit andconclusion of extended safety follow-up.

• Blood samples will be collected from all subjects at Visits1 and 3 to measure serum anti-rotavirus IgA antibodyconcentrations using ELISA. The assay cut-off is 20U/ml.

• Solicited symptoms occurring between the day of eachHRV vaccine dose and the following 7 days (Day 0 toDay 7) will be recorded daily using diary cards for allsubjects.

• Unsolicited symptoms occurring within 31 days (Day 0 toDay 30) after each HRV vaccine dose will be recordedfor all subjects.

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• SAEs will be recorded from Dose 1 of HRV vaccine upto 6 months after the last dose of HRV vaccine.

• Any GE episodes occurring from Dose 1 of HRV vaccineup to Visit 3 should be recorded in the diary card.Parents/guardians should be instructed to collect stoolsample(s) if the subject develops GE during the periodfrom Dose 1 of HRV vaccine up to Visit 3. Refer to theglossary of terms for definition of GE. A stool sampleshould be collected as soon as possible after illnessbegins and preferably not later than 7 days after the startof diarrhoea. A stool sample should be collected for eachseparate diarrhoea episode. A second stool sample shouldbe collected if the first sample was insufficient. Twooccurrences of diarrhoea should be classified as separateepisodes if there are 5 or more diarrhoea-free daysbetween the episodes.

• Type of study: Self-contained.

• Data collection: By Remote Data Entry (RDE) usingindividual electronic Case Report Forms (eCRF).

• Duration of the study: The intended duration of the study,per subject will be approximately 7 months including the6-month safety follow-up period after Dose 2 of HRVvaccine.

Number of subjects Target enrolment will be 1200 subjects (300 subjects in eachHRV vaccine liquid formulation group and 300 subjects in theHRV vaccine lyophilised formulation group) to obtain 960evaluable subjects (240 subjects in each HRV vaccine liquidformulation group and 240 subjects in the HRV vaccinelyophilised formulation group) for the evaluation of theprimary objectives.

Subjects will be enrolled in multiple sites in Finland.

Primary endpoints • Serum anti-rotavirus IgA antibody concentration at Visit3 in each HRV vaccine liquid formulation group.

• Seroconversion to anti-rotavirus IgA antibody at Visit 3.

Seroconversion is defined as appearance of anti-rotavirus IgAantibody concentration ≥ 20 units (U)/millilitre (ml) insubjects initially (i.e. prior to the first dose of HRV vaccine)seronegative (i.e. with anti-rotavirus IgA antibodyconcentration< 20 U/ml).

Secondary endpoints • Serum anti-rotavirus IgA antibody concentration at Visit3 in the HRV vaccine lyophilised formulation group.

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• Occurrence of each type of solicited symptom within the8-day solicited follow-up period (Day 0 to Day 7) aftereach dose of HRV vaccine.

• Occurrence of unsolicited AEs within 31 days (Day 0 �Day 30) after any dose of HRV vaccine, according to theMedical Dictionary for Regulatory Activities (MedDRA)classification.

• Occurrence of SAEs from Dose 1 of HRV vaccine up to 6months after the last dose of HRV vaccine.

• Presence of RV in GE stools collected from Dose 1 ofHRV vaccine up to Visit 3.

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TABLE OF CONTENTS

PAGE

SPONSOR INFORMATION ............................................................................................3

INVESTIGATOR AGREEMENT ......................................................................................5

SYNOPSIS......................................................................................................................7

LIST OF ABBREVIATIONS...........................................................................................15

GLOSSARY OF TERMS ...............................................................................................17

1. INTRODUCTION....................................................................................................201.1. Background ................................................................................................21

1.1.1. GSK Biologicals� lyophilised HRV vaccine ...................................211.1.2. GSK Biologicals� HRV vaccine liquid formulation .........................23

1.2. Rationale for the study................................................................................24

2. OBJECTIVES.........................................................................................................242.1. Co-primary objectives .................................................................................242.2. Secondary objectives..................................................................................24

3. STUDY DESIGN OVERVIEW ................................................................................25

4. STUDY COHORT...................................................................................................274.1. Number of subjects / centers ......................................................................274.2. Inclusion criteria..........................................................................................274.3. Exclusion criteria for enrolment...................................................................284.4. Elimination criteria during the study ............................................................294.5. Contraindications to subsequent vaccination ..............................................29

5. CONDUCT OF STUDY ..........................................................................................305.1. Ethics and regulatory considerations ..........................................................30

5.1.1. Institutional Review Board/Independent Ethics Committee(IRB/IEC) .....................................................................................30

5.1.2. Informed consent .........................................................................315.2. Independent Data Monitoring Committee....................................................345.3. General study aspects ................................................................................345.4. Subject identification...................................................................................345.5. Outline of study procedures ........................................................................355.6. Detailed description of study visits/contacts ................................................36

5.6.1. Detailed description of study visits ...............................................375.7. Sample handling and analysis ....................................................................40

5.7.1. Treatment and storage of biological samples...............................405.7.2. Laboratory assays .......................................................................405.7.3. Immunological read-outs..............................................................415.7.4. Endpoints for suboptimal response..............................................41

6. INVESTIGATIONAL PRODUCT AND ADMINISTRATION .....................................416.1. Study vaccines............................................................................................41

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6.2. Dosage and administration .........................................................................426.3. Storage.......................................................................................................436.4. Treatment allocation and randomisation .....................................................44

6.4.1. Randomisation of supplies...........................................................446.4.2. Randomisation of subjects...........................................................45

6.5. Method of blinding and breaking the study blind .........................................456.6. Replacement of unusable vaccine doses....................................................466.7. Packaging...................................................................................................466.8. Vaccine accountability ................................................................................466.9. Concomitant medication/treatment .............................................................46

7. HEALTH ECONOMICS ..........................................................................................47

8. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.....................................478.1. Definition of an adverse event.....................................................................478.2. Definition of a serious adverse event ..........................................................48

8.2.1. Disease-related events or outcomes not qualifying asserious adverse events................................................................49

8.3. Lack of efficacy...........................................................................................498.4. Clinical laboratory parameters and other abnormal assessments

qualifying as adverse events and serious adverse events...........................498.5. Time period, frequency, and method of detecting adverse events

and serious adverse events ........................................................................508.5.1. Solicited adverse events ..............................................................51

8.6. Evaluating adverse events and serious adverse events..............................528.6.1. Assessment of intensity ...............................................................528.6.2. Assessment of causality ..............................................................538.6.3. Medically attended visits ..............................................................54

8.7. Follow-up of adverse events and serious adverse events andassessment of outcome..............................................................................54

8.8. Prompt reporting of serious adverse events to GSK Biologicals..................568.8.1. Time frames for submitting serious adverse event reports

to GSK Biologicals .......................................................................568.8.2. Completion and transmission of serious adverse event

reports to GSK Biologicals ...........................................................568.9. Regulatory reporting requirements for serious adverse events ...................578.10. Post-study adverse events and serious adverse events..............................58

8.10.1. Extended safety follow-up............................................................588.11. Treatment of adverse events ......................................................................58

9. SUBJECT COMPLETION AND WITHDRAWAL.....................................................599.1. Subject completion .....................................................................................599.2. Subject withdrawal......................................................................................59

9.2.1. Subject withdrawal from the study ...............................................599.2.2. Subject withdrawal from investigational product...........................59

10. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES ...............6010.1. Co-primary endpoints .................................................................................6010.2. Secondary endpoints ..................................................................................6010.3. Estimated sample size ................................................................................6010.4. Study cohorts to be evaluated.....................................................................6310.5. Derived and transformed data.....................................................................64

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10.6. Final analyses.............................................................................................6510.6.1. Analysis of demographics ............................................................6510.6.2. Analysis of immunogenicity..........................................................6510.6.3. Analysis of safety.........................................................................66

10.7. Planned interim analysis .............................................................................67

11. ADMINISTRATIVE MATTERS ...............................................................................67

12. REFERENCES.......................................................................................................68

LIST OF APPENDICES

PAGE

Appendix A World Medical Association Declaration of Helsinki .................................69

Appendix B Administrative Matters............................................................................73

Appendix C Overview of the Recruitment Plan ..........................................................79

Appendix D Handling of Biological Samples Collected by the Investigator ................80

Appendix E Shipment of Biological Samples .............................................................84

Appendix F Laboratory Assays .................................................................................85

Appendix G Vaccine supplies, packaging and accountability.....................................87

Appendix H Amendments and Administrative Changes to the Protocol .....................88

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List of Abbreviations

AE Adverse event

ATP According-to-Protocol

CCID50 median Cell Culture Infective Dose (quantity of viruscausing infection in 50% of exposed cells)

CI Confidence Interval

DMEM Dulbecco�s Modified Eagle Medium

eCRF Electronic Case Report Form

ELISA Enzyme Linked Immunosorbent Assay

EL.U Elisa Units

GCP Good Clinical Practice

GE Gastroenteritis

GMC Geometric Mean antibody Concentration

GSK GlaxoSmithKline

HRV Human Rotavirus

IB Investigator Brochure

IDMC Independent Data Monitoring Committee

IEC Independent Ethics Committee

IgA Immunoglobulin A

IRB Institutional Review Board

IS Intussusception

MedDRA Medical Dictionary for Regulatory Activities

RDE Remote Data Entry

RV Rotavirus

SAE Serious Adverse Event

SAS Statistical Analysis System

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SD Standard deviation

SOP Standard Operating Procedure

U Units

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Glossary of Terms

Adverse event: Any untoward medical occurrence in a patient or clinicalinvestigation subject, temporally associated with the useof a medicinal product, whether or not considered relatedto the medicinal product.

An AE can therefore be any unfavourable and unintendedsign (including an abnormal laboratory finding),symptom, or disease (new or exacerbated) temporallyassociated with the use of a medicinal product. Formarketed medicinal products, this also includes failure toproduce expected benefits (i.e. lack of efficacy), abuse ormisuse.

Blinding: A procedure in which one or more parties to the trial arekept unaware of the treatment assignment in order toreduce the risk of biased study outcomes. In a single-blind trial, the investigator and/or his staff are aware ofthe treatment assignment but the subject is not. In anobserver-blind study, the subject and the study personnelinvolved in the clinical evaluation of the subjects areblinded while other study personnel may be aware of thetreatment allocation. When the investigator and sponsorstaff who are involved in the treatment or clinicalevaluation of the subjects and review/analysis of data arealso unaware of the treatment assignments, the study isdouble blind. Partially blind is to be used for studydesigns with different blinding levels between differentgroups, e.g. double blinded consistency lots which areopen with respect to the control group. The level ofblinding is maintained throughout the conduct of the trial,and only when the data are cleaned to an acceptable levelof quality will appropriate personnel be unblinded orwhen required in case of a serious adverse event.

Central StudyCo-ordinator:

An individual assigned by and centrally located at GSKBiologicals at Rixensart who is responsible for assuringproper conduct of a clinical study.

Diarrhoea: Passage of three or more looser than normal stools withina day.

Eligible: Qualified for enrolment into the study based upon strictadherence to inclusion/exclusion criteria.

eTrack: GSK�s clinical trials tracking tool

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Evaluable: Meeting all eligibility criteria, complying with theprocedures defined in the protocol, and, therefore,included in the according-to-protocol (ATP) analysis (seeSections 4.4 and 10.4 for details on criteria forevaluability).

Gastroenteritis (GE): Diarrhoea with or without vomiting.

Investigational product: A pharmaceutical form of an active ingredient or placebobeing tested or used as a reference in a clinical trial,including a product with a marketing authorisation whenused in a way different from the approved form, or whenused for an unapproved indication, or when used to gainfurther information about an approved use.

Medical attention: Medical provider contact, advice, visit; emergency roomcontact or visit or hospitalisation.

Medical Monitor: An individual medically qualified to assume theresponsibilities of the sponsor (GSK Biologicals)especially in regards to the ethics, clinical safety of astudy and the assessment of adverse events.

Protocol amendment: ICH defines a protocol amendment as: �A writtendescription of a change(s) to or formal clarification of aprotocol.� GSK Biologicals further details this to includea change to an approved protocol that affects the safety ofsubjects, scope of the investigation, study design, orscientific integrity of the study.

Protocol administrativechange:

A protocol administrative change addresses changes toonly logistical or administrative aspects of the study.N.B. Any change that falls under the definition of aprotocol amendment (e.g. a change that affects the safetyof subjects, scope of the investigation, study design, orscientific integrity of the study) MUST be prepared as anamendment to the protocol.

Randomisation: Process of random attribution of treatment to subjects inorder to reduce bias of selection

SBIR GSK Biologicals� central randomisation system onInternet

Site Monitor: An individual assigned by the sponsor who is responsiblefor assuring proper conduct of clinical studies at one ormore investigational sites.

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Study Monitor: An individual assigned by the sponsor who is responsiblefor assuring proper conduct of a clinical study.

Subject: Term used throughout the protocol to denote anindividual that has been contacted in order to participateor participates in the clinical study, either as a recipient ofthe investigational product(s) or as a control.

Subject number: A unique number identifying a subject, assigned to eachsubject consenting to participate in the study.

Treatment: Term used throughout the clinical study to denote a set ofinvestigational product(s) or marketed product(s) orplacebo intended to be administered to a subject,identified by a unique number, according to the studyrandomisation or treatment allocation.

Treatment number: A unique number identifying a treatment to a subject,according to the study randomisation or treatmentallocation.

Vomiting One or more episodes of forceful emptying of partiallydigested stomach contents ≥ 1 hour after feeding within aday.

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1. INTRODUCTION

Rotavirus (RV) is the most common cause of severe gastroenteritis (GE) among childrenworldwide. Review of epidemiological data estimated that, world-wide, RV causesapproximately 138 -140 million cases of diarrhoea annually accounting for 20% ofoutpatient or clinic visits for diarrhoea, 26% of hospitalisations for diarrhoea and anestimated 440,000 deaths in children under 5 years per year [Parashar, 2003]. Newsurveillance data suggest that previous data are an underestimate and the mortality rate isnow estimated to be as high as 611,000 (range 454,000 � 705,000) annual deaths world-wide [Parashar, 2006]. The majority of these deaths occur in Africa, Indian subcontinentand Latin America. In developed countries, RV infection rarely results in death but RVremains the most common cause of hospitalisation for GE in children and leads to majormedical and societal costs. Based on the CDC model [Parashar, 2003], the burden of RVdisease within the expanded EU was estimated to be of 231 deaths, >87,000hospitalisations and almost 700,000 outpatient visits annually among children youngerthan 5 years of age [Soriano-Gabarro, 2006].

Prevention by vaccination is considered to be critical for effective control of RV infectionsince only non-specific symptomatic therapies are available. A variety of approaches tothe development of RV vaccines have been undertaken, with live oral attenuated vaccinesreceiving the most attention.

To meet this health need, GlaxoSmithKline (GSK) Biologicals has developed anattenuated vaccine which is based on a human rotavirus (HRV) strain designated asRIX4414. The vaccine strain RIX4414 was derived from the parent 89-12 HRV strainbelonging to the serotype G1P1A and genotype [P8] originally obtained from the stool ofa 15-month old child with a mild RV diarrhoea in December 1988. A candidate vaccinebased on the 89-12 HRV strain at passage 33 in African Green Monkey Kidney cells wasshown to be safe, immunogenic and efficacious against RV GE over two consecutive RVseasons in infants [Bernstein, 1998; Bernstein, 1999; Bernstein, 2002].

GSK Biologicals has implemented several process changes to the 89-12 vaccinecandidate to develop a lyophilised HRV vaccine containing RIX4414, a cloned passage43 derivative from 89-12, for oral administration after reconstitution with a separatelysupplied liquid calcium carbonate buffer.

In addition to the formulation consisting of a lyophilised HRV vaccine to be reconstitutedwith a suspension of calcium carbonate, GSK Biologicals� has also developed a fullliquid formulation of the HRV vaccine. Liquid vaccines are easier to handle foradministration, have lower cost implications in terms of shipment and storage, and have ahigher output capacity. The liquid formulation of HRV vaccine contains adipate, anantacid that serves as a buffer in the stomach, since RV infectivity is stable within the pHrange of 4 to 9. The antacid will prevent inactivation of the HRV during passage throughthe stomach. Adipate acid is used as an excipient in other medicines (e.g. Rovamycine(spiramycin) syrup for infants/children, Aventis Pharma). The sucrose stabilizes the virusand improves the taste of the vaccine. The liquid formulation contains the same virusstrain (RIX4414) as the one used in all previously conducted studies and at a similarconcentration.

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1.1. Background

1.1.1. GSK Biologicals’ lyophilised HRV vaccine

GSK Biologicals� lyophilised HRV vaccine (Rotarix�) is currently licensed in severalcountries in Europe, Latin America, Asia, Middle-East and Africa.

GSK Biologicals� HRV vaccine was tested in Phase I studies conducted in adults,previously infected children (1-3 years old), followed by Phase II and Phase III studiesamong infants in Asia, Africa, Europe, Latin America and North America. In all studies,the adverse reaction profile in infants receiving HRV vaccine was similar to infantsreceiving placebo. A large safety trial conducted in Latin America and Finland where63,225 subjects were enrolled gave evidence of no increased risk of intussusception (IS)in the HRV vaccine group when compared with the placebo group. The HRV vaccinewas highly efficacious in protecting infants against RV GE.

The protective efficacy of the HRV vaccine against any or severe RV GE, as well asagainst hospitalisation for RV GE was demonstrated in phase II studies in Finland[Vesikari, 2004] and Latin America (Brazil, Mexico and Venezuela) [Salinas, 2005].

In Finland (Study rota-004) [Vesikari, 2004], two doses of HRV vaccine showed 71.6%(95% confidence interval (CI): 41.6%; 86.8%) efficacy in preventing any RV GE and84.9% (95% CI: 41.5%; 97.3%) efficacy in preventing severe RV GE (an episode with ascore ≥ 11 on the 20-point Vesikari scale [Ruuska, 1990]) during the entire follow-upperiod over two RV epidemic seasons after vaccination. Of note, G1 serotype was themost prevalent circulating serotype during both RV epidemic seasons.

In Latin America (Brazil, Mexico and Venezuela) (Study rota-006) [Salinas, 2005], theefficacy of the HRV vaccine in preventing RV GE was demonstrated in a setting withdifferent circulating serotypes (G1 and non-G1 RV types). Two doses of the HRVvaccine at three virus concentrations (104.7, 105.2 or 105.8 ffu) were given at approximately2 and 4 months of age concomitantly with routine vaccinations (i.e. diphtheria andtetanus toxoids, whole-cell pertussis and hepatitis B [DTPw-HBV] and Hib). For the firstyear efficacy follow-up, the protective efficacy of the HRV vaccine (pooled HRVvaccine groups) was 61.4% (95% CI: 42.3%; 74.1%) against any RV diarrhoea, 74.1%(95% CI: 55.8%; 85.0%) against severe RV diarrhoea (an episode with a score ≥ 11 onthe 20-point Vesikari scale [Ruuska, 1990]) and 79.0% (95% CI: 48.0%; 92.0%) againsthospitalised RV diarrhoea. The vaccine efficacy against severe RV GE was 74.7% (95%CI: 37.7%; 90.1%) over two consecutive efficacy follow-up periods.

A large phase III multinational trial (Rota-023) involving 63,225 infants was undertakenin 11 countries in Latin America and in Finland with a co-primary objective of assessingthe safety of the HRV vaccine in terms of occurrence of definite IS [Ruiz-Palacios,2006]. Definite IS required the diagnosis of IS to be confirmed on the demonstration ofinvagination of the intestine at surgery or autopsy, or by using radiologic techniques:gas/liquid contrast enema or abdominal ultrasound. The primary safety evaluation wasbased on occurrence of definite IS during 31 days (Day 0 to Day 30) after each vaccinedose. The rationale for focusing on the critical risk window of 31 days after vaccination

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was based on the consideration that vaccination-related IS would occur when the vaccinevirus replication and host responses are maximal. Thirteen IS cases (6 in the HRVvaccine group and 7 in the placebo group) diagnosed within the 31 days (Day 0 to Day30) risk window were adjudicated as Definite IS by an independent external expertcommittee. The primary safety objective of the study was met with the Risk Difference of-0.32/10,000 (95% CI: -2.91/10,000; 2.18/10,000) vaccinees and the Relative Risk of0.85 (95% CI: 0.30; 2.42) providing evidence of no increased risk of IS for the HRVvaccine within 31 days after any dose. The overall SAE profile of the HRV vaccine wassimilar to the placebo. The SAE profile appeared to be in favour of the HRV vaccine withrespect to preventing GE-related SAEs.

Study Rota-023 is also one of the largest efficacy trials for a rotavirus vaccine, with atotal of 20,169 vaccinated subjects (10,159 in the HRV vaccine group and 10,010 in thePlacebo group) in the efficacy cohort. Vaccine efficacy at one year of age was a co-primary objective of the study. Active surveillance was conducted to identify severe GEepisodes. Severe GE was defined as a GE episode requiring hospitalisation and/or re-hydration therapy (equivalent to WHO plan B or C) in a medical facility. The efficacyfollow-up visit (Visit 4) at one year of age was completed by 17,882 subjects (88.7%) ofsubjects. Vaccine efficacy against severe RV GE caused by the circulating wild-type RVstrains during the period starting from completion of the immunisation (2 weeks postDose 2) until one year of age was 84.7% (95% CI: 71.7%; 92.4%) (primary efficacyendpoint). The criteria specified for fulfilling the primary efficacy objective was met. TheHRV vaccine was highly effective in protecting against severe RV GE episodes causedby the globally predominant G1 type with a vaccine efficacy of 91.8% (95% CI: 74.1%;98.4%). The HRV vaccine was equally protective against the emerging G9 type, with anefficacy of 90.6% (95% CI: 61.7%; 98.9%). The HRV vaccine also provided significantprotection against severe RV GE due to the G3 type with efficacy of 87.7% (95% CI:8.3%; 99.7%). A protective trend against G2 type was also observed. A subset of childrenwas followed up until 24 months of age. Vaccine efficacy against severe RV GE was79.0% (95% CI: 66.4%; 87.4%) during the second year and 80.5% (95% CI: 71.3%;87.1%) during the entire two year follow-up. Efficacy against G1 and non-G1 RV typeswas consistent during each follow-up period. The results from this study confirm that thishuman attenuated G1P[8] HRV vaccine elicits cross-protection, and provide evidencethat the HRV vaccine effectively protects vaccinated children against the commonlycirculating RV types during the first two years of life. Among the subjects followed untilone year of age and until two years of age, there was no increased risk of definite ISrespectively diagnosed from Dose 1 up to one year of age and from Dose 1 up to twoyears of age in the HRV vaccine group versus placebo.

A phase III study conducted in six European countries (rota-036) evaluated two doses ofthe HRV vaccine when coadministered with routine infant vaccinations: Infanrix hexa(combined diphtheria and tetanus toxoids, acellular pertussis, hepatitis B, inactivatedpolio and Haemophilus influenzae type b vaccine), Infanrix� Polio Hib (combineddiphtheria and tetanus toxoids, acellular pertussis, inactivated polio and Haemophilusinfluenzae type b vaccine), Prevenar� (7-valent pneumococcal polysaccharide conjugatevaccine) and Meningitec� (meningococcal group C conjugate vaccine). This study hasconfirmed the efficacy of HRV vaccine against RV GE hospitalisations, any and severeRV GE due to G1 and non-G1 RV and the important reduction of severe GE of any

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cause. The first efficacy follow-up period started from two weeks after Dose 2 and endedJune �July 2005. A total of 3874 subjects were part of the 1st year according-to-protocol(ATP) cohort for efficacy. Vaccine efficacy was 87.1% (95% CI: 79.6%; 92.1%) againstany episodes of RV GE and 95.8% (95% CI: 89.6%; 98.7%) against severe RV GEepisodes [Ruuska, 1990]. For increasing disease severity with Vesikari scores between 11and 20, VE was increasingly higher, reaching 100% against more severe RV GE(Vesikari score ≥ 17 points). VE against hospitalisation for RV GE was 100% (95% CI:81.8%; 100%) and against RV GE episodes requiring medical attention was 91.8% (95%CI: 84.0%; 96.3%). The HRV vaccine was significantly protective against any and severeRV GE caused by G1, G3, G4 and G9 RV strains. Protective trend was observed againstG2 RV type that does not share any of the outer or inner capsid antigens of the HRVvaccine. A meta analysis of the completed efficacy trials with HRV vaccine (studies rota-004, rota-006, rota-007, rota-023 and rota-036) showed vaccine efficacy of 71.4% [95%CI: 20.1%; 91.1%] against severe rotavirus gastroenteritis episodes [Ruuska, 1990]caused by the G2 type.

Study 036 also provided key coadministration data by evaluating the coadministration ofHRV vaccine with currently used childhood vaccinations given according to the primaryvaccination schedules in each participating country. Coadministration of HRV vaccinewith routinely used Infanrix hexa, Infanrix Polio Hib, Prevenar or Meningitec vaccinesdid not appear to have any effect on the immunogenicity of any of the routine vaccineantigens. The seropositivity rates/seroprotection rates or Geometric Mean antibodyConcentration/Titer (GMCs/GMTs) for antibodies to diphtheria, tetanus, pertussis toxoid(PT), filamentous haemagglutinin (FHA), pertactin (PRN), hepatitis B surface antigen(HBs), poliovirus serotypes 1, 2 and 3, and polyribosyl ribitol phosphate (PRP) weresimilar between the HRV vaccine and Placebo groups after three doses of childhoodvaccinations. Post Dose 3 response to each of the 7 Streptococcus pneumoniae serotypesin France and Germany, as well as the SBA-MenC and anti-PSC response in Spain weresimilar between the HRV vaccine and Placebo groups. Likewise, coadministration ofHRV vaccine with the childhood vaccines did not have any effect on the reactogenicityprofile. Overall, no interference was found when HRV vaccine was coadministered withchildhood vaccinations. Previous studies found no immune interference between HRVvaccine and childhood vaccinations used in the USA and Canada [Dennehy, 2005] and inLatin America [Salinas, 2005].

1.1.2. GSK Biologicals’ HRV vaccine liquid formulation

The liquid formulation of the HRV vaccine has been tested in a clinical feasibility studyconducted in Finland (Study 048) that evaluated the immunogenicity, reactogenicity andsafety of liquid formulation of the HRV vaccine as compared to the lyophilisedformulation. A total of 250 infants were enrolled to receive two doses of the liquidformulation of the HRV vaccine (N=100) or the lyophilised formulation of the HRVvaccine (N=100), or the respective placebo (N=25 for each placebo group). Routinechildhood vaccinations were to be administered at least 14 days apart from each dose ofHRV vaccine/placebo. The anti-rotavirus IgA seroconversion rate on combined doses 1and 2 was 87.9% (95% CI: 79.4%; 93.8%) in the lyophilised HRV vaccine group and90.8% (95% CI: 82.7%; 95.9%) in the liquid HRV vaccine group. A statisticallysignificant difference was not detected between the adipate liquid candidate HRV vaccine

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and the lyophilised formulation in terms of anti-rotavirus IgA seroconversion rates oncombined doses 1 and 2 (P-value > 0.05, one-sided asymptotic standardised test). Thereactogenicity and safety profile of the two formulations were similar to their respectiveplacebo.

Please refer to the latest edition of the Investigator Brochure (IB) for a review of the pre-clinical and clinical studies of GSK Biologicals' HRV vaccine.

1.2. Rationale for the study

This trial will evaluate the lot-to-lot consistency of three consecutive production lots ofthe liquid formulation of GSK Biologicals� HRV vaccine in terms of immunogenicity andreactogenicity. This study will also evaluate the immunogenicity, reactogenicity andsafety of the liquid formulation of GSK Biologicals' HRV vaccine compared to thelyophilised formulation of GSK Biologicals� HRV vaccine when administeredconcomitantly with a combination childhood vaccine.

2. OBJECTIVES

2.1. Co-primary objectives

• To demonstrate the lot-to-lot consistency of the liquid formulation of GSKBiologicals� HRV vaccine in terms of immunogenicity as measured by serum anti-rotavirus IgA antibody levels one month after Dose 2.

Consistency will be reached if, for all pairs of lots, the two-sided 95% CIs for the ratio ofanti-rotavirus IgA antibody GMCs one month after Dose 2 are within the [0.5; 2] clinicallimit interval.

• To demonstrate non-inferiority of the liquid formulation of GSK Biologicals' HRVvaccine to that of lyophilised formulation of GSK Biologicals� HRV vaccine interms of seroconversion rates one month after Dose 2.

Non-inferiority will be reached if the upper limit of the two-sided asymptoticstandardised 95% CI for the difference in seroconversion rate between the lyophilisedformulation of HRV vaccine and (minus) the liquid formulation of HRV vaccine is lessthan or equal to 10%.

Refer to Section 10.1 for the co-primary endpoints.

2.2. Secondary objectives

• To demonstrate non-inferiority of the liquid formulation of GSK Biologicals' HRVvaccine to that of lyophilised formulation of GSK Biologicals� HRV vaccine interms of serum anti-rotavirus IgA antibody levels one month after Dose 2.

Non-inferiority will be reached if the upper limit of the two-sided 95% CI for the ratio ofanti-rotavirus IgA antibody GMCs one month after Dose 2 between the lyophilised

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formulation of HRV vaccine and (over) the liquid formulation of HRV vaccine is less thanor equal to 2.

• To assess the lot-to-lot consistency of the liquid formulation of GSK Biologicals�HRV vaccine in terms of reactogenicity.

• To assess the safety of the study vaccines.Refer to Section 10.2 for secondary endpoints.

3. STUDY DESIGN OVERVIEW


Ra ndo mizatio n (1 :1 :1 :1)

V isit 1 A ge : 1 0 -17 weeks (70 -1 25 da ys) D ay 0 D ose 1 B lo od samp ling

V accination v is its

V isit 3M onth 2 B lo od samp ling Study conc lus ion

H R V v acc in e l iq u id fo rmu la t io n ( Lo t A ), N = 3 00

H R V v acc in e ly o p h il ized fo r m u la t io n , N = 3 00

V isit 2M onth 1 D ose 2

Fo llow -up v is it

Extended sa fe ty contac t� Safe ty follow -up conc lus io n

H R V v acc in e liq u id fo rmu la t io n (Lo t B), N = 3 00

H R V v acc in e liq u id fo rmu la t io n (Lo t C), N = 3 00

�Contact (by telephone call or any other convenient procedure) for safety follow-up will take place 6 months after thelast dose of HRV vaccineN = number of subjects planned to be enrolled

• Experimental design: Phase III, randomised study with four parallel groups. Doubleblind for three lots of the liquid formulation of GSK Biologicals� HRV vaccine, andopen label for liquid formulation versus the lyophilised formulation.


• Treatment Groups:Group HRV vaccine liquid formulation Lot A

Group HRV vaccine liquid formulation Lot B

Group HRV vaccine liquid formulation Lot C

Group HRV vaccine lyophilised formulation

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• Blinding: Double blind for three lots of the liquid formulation of GSK Biologicals�HRV vaccine, and open label for liquid formulation versus the lyophilisedformulation.

• Vaccination schedule: Two-dose immunisation at 3 and 4 months of age in healthyinfants aged between 10 and 17 weeks (70 - 125 days) at the time of the first doseand previously uninfected with HRV. (Amendment 1: 06 October 2006)

• During the study, routine childhood vaccines (Infanrix hexa�) will be administeredat 3, 4, 5 months of age. The first two doses of Infanrix hexa will be coadministeredwith each dose of HRV vaccine. All routine vaccinations administered from birth upto Visit 3 should be recorded in the eCRF. Subjects will receive a booster dose ofInfanrix hexa according to the approved prescribing information outside the scope ofthis study.


• Three study visits and one contact for extended safety follow-up:Visit 1 (Day 0): Pre-vaccination blood sample, Dose 1 of HRV vaccine and Dose 1 ofroutine childhood vaccines (Infanrix hexa).

Visit 2 (Month 1): Dose 2 of HRV vaccine, Dose 2 of routine childhood vaccines(Infanrix hexa), return reactogenicity diary cards, follow-up for safety (solicitedsymptoms, unsolicited AEs and SAEs), record any GE and collection of GE stoolsamples.

Visit 3 (Month 2): Post-vaccination blood sample, return reactogenicity diary cards,follow-up for safety (solicited symptoms, unsolicited AEs and SAEs), record any GE,collection of GE stool samples and study conclusion.

Extended safety contact (at 6 months after Dose 2 of HRV vaccine or Dose 1 of HRVvaccine in case Dose 2 not administered): Record SAEs since previous visit andconclusion of extended safety follow-up.

• Blood samples will be collected from all subjects at Visits 1 and 3 to measure serumanti-rotavirus IgA antibody concentrations using ELISA. The assay cut-off is 20U/ml.

• Solicited symptoms occurring between the day of each HRV vaccine dose and thefollowing 7 days (Day 0 to Day 7) will be recorded daily using diary cards for allsubjects.

• Unsolicited symptoms occurring within 31 days (Day 0 to Day 30) after each HRVvaccine dose will be recorded for all subjects.

• SAEs will be recorded from Dose 1 of HRV vaccine up to 6 months after the lastdose of HRV vaccine.

• Any GE episodes occurring from Dose 1 of HRV vaccine up to Visit 3 should berecorded in the diary card. Parents/guardians should be instructed to collect stoolsample(s) if the subject develops GE during the period from Dose 1 of HRV vaccineup to Visit 3. Refer to the glossary of terms for definition of GE. A stool sample

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should be collected as soon as possible after illness begins and preferably not laterthan 7 days after the start of diarrhoea. A stool sample should be collected for eachseparate diarrhoea episode. A second stool sample should be collected if the firstsample was insufficient. Two occurrences of diarrhoea should be classified asseparate episodes if there are 5 or more diarrhoea-free days between the episodes.


• Data collection: By Remote Data Entry (RDE) using individual electronic CaseReport Forms (eCRF).

• Duration of the study: The intended duration of the study, per subject will beapproximately 7 months including the 6-month safety follow-up period after Dose 2of HRV vaccine.

4. STUDY COHORT

4.1. Number of subjects / centers

Target enrolment will be 1200 subjects (300 subjects in each HRV vaccine liquidformulation group and 300 subjects in the HRV vaccine lyophilised formulation group) toobtain 960 evaluable subjects (240 subjects in each HRV vaccine liquid formulationgroup and 240 subjects in the HRV vaccine lyophilised formulation group) for theevaluation of the primary objectives. Refer to Section 10.3 for a detailed description ofthe criteria used in the estimation of sample size.

All subjects will be enrolled in multiple sites in Finland.

Enrolment will be terminated when 1200 eligible subjects have been enrolled.

Refer to Appendix C for a summary of the recruitment plan.

4.2. Inclusion criteria

All subjects must satisfy the following criteria at study entry:

• Subjects who the investigator believes that their parents/guardians can and willcomply with the requirements of the protocol (e.g., completion of the diary cards,return for follow-up visits) should be enrolled in the study.

• A male or female between, and including, 10-17 weeks (70 - 125 days) of age at thetime of the first vaccination. (Amendment 1: 06 October 2006)

• Written informed consent obtained from the parent or guardian of the subject.

• Healthy subjects as established by medical history and clinical examination beforeentering into the study.

• Birth weight >2000g.

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4.3. Exclusion criteria for enrolment


The following criteria should be checked at the time of study entry. If any apply, thesubject must not be included in the study:

• Use of any investigational or non-registered product (drug or vaccine) within 30 dayspreceding the first dose of any of the study vaccines, or planned use during the studyperiod.

• Chronic administration (defined as more than 14 days) of immunosuppressants orother immune-modifying drugs within six months prior to the first vaccine dose. (Forcorticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaledand topical steroids are allowed.).

• Planned administration/administration of a vaccine not foreseen by the studyprotocol within 30 days of the first dose of vaccine.

• Concurrently participating in another clinical study, at any time during the studyperiod, in which the subject has been or will be exposed to an investigational or anon-investigational product (pharmaceutical product or device).

• Previous vaccination against RV.

• Previous vaccination against diphtheria, tetanus, pertussis, polio or Hib.

• Previous confirmed occurrence of RV GE.

• History of diphtheria, tetanus, pertussis, hepatitis B, polio and/ or Hib disease.

• Any confirmed or suspected immunosuppressive or immunodeficient condition,based on medical history and physical examination (no laboratory testing required).

• A family history of congenital or hereditary immunodeficiency.

• History of allergic disease or reactions likely to be exacerbated by any component ofthe vaccine(s).

• Major congenital defects or serious chronic illness.

• Uncorrected congenital malformation (such as Meckel�s diverticulum) of thegastrointestinal tract that would predispose for IS.

• Acute disease at time of enrolment. (Acute disease is defined as the presence ofmoderate or severe illness with or without fever i.e. temperature ≥ 37.5°C asmeasured by an axillary thermometer or ≥ 38.0°C as measured by a rectalthermometer). Temperature greater than or equal to these cut-offs warrants deferralof the vaccination pending recovery of the subject.

• GE within 7 days preceding the study vaccine administration (warrants deferral ofthe vaccination).

• Administration of immunoglobulins and/or any blood products since birth or plannedadministration during the study period.

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4.4. Elimination criteria during the study

The following criteria should be checked at each visit subsequent to the first visit. If anybecome applicable during the study, it will not require withdrawal of the subject from thestudy but may determine a subject�s evaluability in the ATP analysis. See Section 10.4for definition of study cohorts to be evaluated.

• Use of any investigational or non-registered product (drug or vaccine) other than theinvestigational vaccine (HRV vaccine) during the study period.

• Chronic administration (defined as more than 14 days) of immunosuppressantsduring the study period. (Inhaled and topical steroids are allowed.) (Amendment 1:06 October 2006)

• Administration of a vaccine not foreseen by the study protocol during the studyperiod.

• Administration of immunoglobulins and/or any blood products during the studyperiod.

• Any confirmed or suspected immunosuppressive or immunodeficient conditionbased on medical history and physical examination (no laboratory testing isrequired).

4.5. Contraindications to subsequent vaccination

GSK Biologicals� HRV vaccine

The following AEs constitute absolute contraindications to further administration of theHRV vaccine; if any of these AEs occur during the study, the subject must not receiveadditional doses of vaccine but may continue other study procedures at the discretion ofthe investigator (see Section 9). The subject must be followed until resolution of theevent, as with any AE (see Section 8.7):

• Known hypersensitivity after previous administration of HRV vaccine or to anycomponent of the vaccine.

• Uncorrected congenital malformation (such as Meckel�s diverticulum) of thegastrointestinal tract that would predispose for IS.

The following AEs constitute precautions to administration of the HRV vaccine at thatpoint in time; if any one of these AEs occurs at the time scheduled for vaccination, thesubject may be vaccinated at a later date, within the time window specified in theprotocol (see Section 5.5), or withdrawn at the discretion of the investigator (see Section9). The subject must be followed until resolution of the event, as with any AE (seeSection 8.7).

• Acute severe febrile illness.

• Diarrhoea or vomiting.

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5. CONDUCT OF STUDY

5.1. Ethics and regulatory considerations

The study will be conducted according to Good Clinical Practice (GCP), the 1996Declaration of Helsinki (Protocol Appendix A) and local rules and regulations of thecountry.

Submission of the protocol and any protocol amendments to regulatory agencies willoccur in accordance with local regulatory requirements. For some countries, submissionto the local regulatory authority may not be required. When submission to the localregulatory authority is required, the timing of the submission relative to IEC/IRBsubmission or approval and whether or not the authority will provide their approval of orfavourable opinion on the protocol or amendment before it can be implemented willdepend on local regulatory requirements.

5.1.1. Institutional Review Board/Independent Ethics Committee(IRB/IEC)

The IRB/IEC must be constituted according to the local laws/customs of eachparticipating country. The ICH Harmonised Tripartite Guideline for Good ClinicalPractice recommends that the IRB/IEC should include:

a. At least five members.

b. At least one member whose primary area of interest is in a non-scientific area.

c. At least one member who is independent of the institution/ study site.

Only those IRB/IEC members who are independent of the investigator and the sponsor ofthe study should provide opinion on a study-related matter.

A list of IRB/IEC members and their qualifications should be obtained by theinvestigator.

This protocol and any other documents that the IRB/IEC may need to fulfil itsresponsibilities, including subject recruitment procedures and information aboutpayments and compensation available to subjects, will be submitted to the IRB/IEC bythe investigator. Written and dated unconditional approval/favourable opinion from theIRB/IEC of the protocol and amendment (if any and applicable), written informedconsent form, consent form updates (if any), subject recruitment procedure(s) (e.g.advertisements), and any other written information to be provided to subjects must be inthe possession of the investigator and GSK before commencement of the study. Thisapproval/favourable opinion must refer to the study by study title and number with exactprotocol version and date, and should identify the documents reviewed and state the dateof review. Relevant GSK Biologicals� data will be supplied by the investigator to thehospital/ university/ independent IRB/IEC for review and approval of the protocol.Verification of the unconditional approval/favourable opinion of the IRB/IEC will be

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transmitted by the investigator to GSK Biologicals� Study Monitor prior to shipment ofvaccine supplies and CRFs to the site.

No deviations from, or changes to, the protocol should be initiated without prior writtensponsor and IRB/IEC approval/ favourable opinion of an appropriate amendment, exceptwhen necessary to eliminate immediate hazards to the subjects or where permitted by allapplicable regulatory requirements or when the change(s) involves only logistical oradministrative aspects of the study (e.g., change of monitor[s], telephonenumber[s].)Approvals/ verifications must be transmitted in writing to GSK Biologicals�Study Monitor by the investigator.

The IRB/IEC must be informed by the investigator of:

• all subsequent protocol amendments, informed consent changes or revisions of otherdocuments originally submitted for review,

• serious and/or unexpected adverse events occurring during the study, where required,

• all subsequent protocol administrative changes (for information, except for USstudies),

• new information that may affect adversely the safety of the subjects or the conduct ofthe study,

• an annual update and/or request for re-approval, where required,

• when the study has been completed, where required.If a trial is prematurely terminated or suspended for reasons including, but not limited to,safety or ethical issues or severe non-compliance, the sponsor will promptly inform theregulatory authorities of the termination or suspension and the reason(s) for thetermination or suspension. If required by applicable regulations, the investigator mustinform the IEC/IRB promptly and provide the reason for the suspension or termination(see Appendix B for further details).

5.1.2. Informed consent

In obtaining and documenting informed consent, the investigator should comply with theapplicable regulatory requirement(s), and should adhere to GCP and to the ethicalprinciples that have their origin in the 1996 Declaration of Helsinki. Prior to thebeginning of the trial, the investigator should have the IRB/IEC�s writtenapproval/favourable opinion of the written informed consent form and any other writteninformation to be provided to the subjects� parents/guardians.

Freely given informed consent should be obtained from every subject�s parents/guardiansprior to clinical trial participation.

Information should be given in both oral and written form whenever possible and asdeemed appropriate by the IRB/IEC.

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An investigator or designate will describe the protocol to potential subjects�parents/guardians face to face. The Informed Consent Form may be read to the subjects�parents/guardians, but, in any event, the investigator or designate shall give the subjects�parents/guardians ample opportunity to inquire about details of the study and ask anyquestions before dating and signing the Informed Consent Form.

While informed consent information can be presented to groups at an initial informationsession, each subject�s parents/guardians must be given the opportunity to individuallypose questions to the investigator or designate prior to the subject�s parents/ guardiansdating and signing the Informed Consent Form.

Informed Consent Form must be in a language fully comprehensible to the prospectivesubjects� parents/guardians. Informed consent shall be documented by the use of awritten consent form approved by the IRB/IEC and signed and dated by theparents/guardians and by the person who conducted the informed consent discussion. Thesignature confirms the consent is based on information that has been understood. Allilliterate individuals will have the study, the Informed Consent Form explained to thempoint by point by the interviewer in the presence of an impartial witness. The witness willpersonally sign and date the consent form. Oral witnessed consent will replace writtenconsent only in countries where the local custom is contrary or if the subject�sparents�/guardians� incapacity precludes this and provided that the local legal obligationsare fulfilled.

Each subject's signed informed consent form must be kept on file by the investigator forpossible inspection by Regulatory Authorities and/or GSK Biologicals� professional andRegulatory Compliance persons. The parents/guardians should receive a copy of thesigned and dated written informed consent form and any other written informationprovided to the subjects� parents/guardians, and should receive copies of any signed anddated consent form updates. Any amendments to the written information will be providedto subjects� parents/guardians.

Both the informed consent discussion and the written informed consent form and anyother written information to be provided to the subjects� parents/guardians should includeexplanations of the following:

a. That the trial involves research.

b. The purpose of the trial.

c. The trial treatment(s) and the probability for random assignment to each treatment.

d. The trial procedures to be followed, including all invasive procedures.

e. The subject�s parents�/guardians� responsibilities.

f. Those aspects of the trial that are experimental.

g. The reasonably foreseeable risks or inconveniences to the subjects and, whenapplicable, to an embryo, fetus or nursing infant.

h. The reasonable expected benefits. When there is no intended clinical benefit tosubjects, the subjects� parents/guardians should be made aware of this.

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i. The alternative procedure(s) or course(s) of treatment/ methods of prevention thatmay be available to subjects, and their important potential benefits and risks.

j. The compensation and/or treatment available to subjects in the event of trial-relatedinjury.

k. The anticipated prorated payment, if any, to subjects� parents/guardians forparticipating in the trial.

l. The anticipated expenses, if any, to subjects� parents/guardians for participating inthe trial.

m. That the subjects� participation in the trial is voluntary and subjects�parents/guardians may refuse to participate or withdraw from the trial, at any time,without penalty or loss of benefits to which subjects are otherwise entitled.

n. That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies)will be granted direct access to the subject�s original medical records for verificationof clinical trial procedures and/or data, without violating the confidentiality ofsubjects, to the extent permitted by the applicable laws and regulations and that, bysigning a written informed consent, the subject�s parents/guardians is authorizingsuch access.

o. That records identifying subjects will be kept confidential and, to the extentpermitted by the applicable laws and/or regulations, will not be made publiclyavailable. If the results of the trial are published, subjects� identity will remainconfidential.

p. That the subjects� parents/guardians will be informed in a timely manner ifinformation becomes available that may be relevant to the subjects�parents/guardians willingness for continued participation in the trial.

q. The person(s) to contact for further information regarding the trial and the rights oftrial subjects, and who to contact in the event of trial-related injury.

r. The foreseeable circumstances and/or reasons under which a subject�s participationin the trial may be terminated.

s. The expected duration of a subject�s participation in the trial.

t. The approximate number of subjects involved in the trial.

GSK Biologicals will prepare a model Informed Consent Form which will embody all theelements described above. While it is strongly recommended that this model document befollowed as closely as possible, the informed consent requirements given in thisdocument are not intended to pre-empt any local regulations which require additionalinformation to be disclosed for informed consent to be legally effective. Clinicaljudgement, local regulations and requirements should guide the final structure andcontent of the document.

The investigator has the final responsibility for the final presentation of InformedConsent Form, respecting the mandatory requirements of local regulations. The consentform generated by the investigator with the assistance of the sponsor�s representative,must be approved (along with the protocol, and any other necessary documentation) bythe IRB/IEC and be acceptable to GSK Biologicals.

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5.2. Independent Data Monitoring Committee

An IDMC consisting of clinical experts and a biostatistician has been charged withmonitoring the safety aspects of the HRV vaccine clinical development: i.e. each SAEcase is reviewed by this committee.

5.3. General study aspects

Administration of all routine childhood vaccinations since birth should be documented inthe eCRF.

During the study, routine childhood vaccines (Infanrix hexa�) will be administered at 3,4, 5 months of age. The first two doses of Infanrix hexa will be coadministered with eachdose of HRV vaccine. All routine vaccinations administered from birth up to Visit 3should be recorded in the eCRF. Subjects will receive a booster dose of Infanrix hexaaccording to the approved prescribing information outside the scope of this study.

The parents/guardians will be instructed to contact the investigator and his staffimmediately should the subject manifest any signs or symptoms they perceive as serious.

There will be no restrictions on feeding the infants before or after study vaccines�administration.

Parents/guardians should be instructed to collect stool sample(s) if the subject developsGE during the period from Dose 1 of HRV vaccine up to Visit 3. Refer to the glossary ofterms for definition of GE. A stool sample should be collected as soon as possible afterillness begins and preferably not later than 7 days after the start of diarrhoea. A stoolsample should be collected for each separate diarrhoea episode. A second stool sampleshould be collected if the first sample was insufficient. Two occurrences of diarrhoeashould be classified as separate episodes if there are 5 or more diarrhoea-free daysbetween the episodes.

At Visits 1 and 2, diary cards will be provided to the parents/guardians of all subjects todaily record information on solicited symptoms (loss of appetite, fussiness/irritability,fever, diarrhoea, vomiting, cough/runny nose) occurring between the day of each HRVvaccine dose and the following 7 days, on any medications and unsolicited adverse eventsoccurring within 31 days after each dose of HRV vaccine as well as on GE occurringuntil the next visit.

A safety follow-up contact by telephone call or any other convenient procedure will takeplace at 6 months after the last dose of HRV vaccine to collect information on SAEs thatoccurred after Visit 3 or the last visit in case Visit 3 not done.

5.4. Subject identification

Subject numbers will be assigned sequentially to subjects consenting to participate in thestudy, according to the range of subject numbers allocated to each study centre.

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5.5. Outline of study procedures(Amendment 1:06 October 2006)

Table 1 List of study proceduresAge 10 - 17 weeks

(70 - 125 days)4 months 5 months 10 months

Visit VISIT 1 VISIT 2 VISIT 3 CONTACTTiming Day 0 Month 1 Month 2 Month 7

Sampling time point Pre Post-vacc 2Informed consent •Check inclusion criteria •Check exclusion criteria •Check elimination criteria • •Check contraindications • •Medical history •Physical examination • •� •�Pre-vaccination body temperature • •Measure/record height and weight •Randomisation •Blood sampling:for antibody determination (2.0 ml) • •Study vaccination • •Routine vaccination (Infanrix hexa)� • • •Recording of oral vaccine intakecharacteristics (tick box*)

• •

Daily post-vaccination recording of solicitedsymptoms (Days 0�7 after each HRVvaccine dose) by subjects� parents/guardians

• •

Recording of non-serious adverse eventswithin 31 days post-vaccination, byinvestigator

• • •

Recording of GE • • •Collection of stool samples if the childdevelops GE

• • •

Return of diary cards • •Diary card transcription • •Record any concomitantmedication/vaccination§

• • • •

Reporting of Serious Adverse Events • • • •Study Conclusion •Contact for safety follow-up •Safety follow-up conclusion •

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Note: The triple-line border following Month 2 indicates the final analysis of immunogenicity, reactogenicity, unsolicitedAEs and SAEs up to Visit 3 to be performed on all data up to Visit 3, as soon as all the data are available and cleaned.The safety results after Visit 3 up to the safety contact will be reported in an annex report.• is used to indicate a study procedure that requires documentation in the individual eCRF� Physical examination at this visit can take place in case of request from the nurse or parents/guardians, and can belimited appropriate with local requirements for routine physical examination for a child at this age and appropriate forintervention that is to follow (blood draw etc.)�During the study, routine childhood vaccines (Infanrix hexa) will be administered at 3, 4, 5 months of age. The firsttwo doses of Infanrix hexa will be coadministered with each dose of HRV vaccine. All routine vaccinations administeredfrom birth up to Visit 3 should be recorded in the eCRF. Subjects will receive a booster dose of Infanrix hexa accordingto the approved prescribing information outside the scope of this study.*: See tick box in eCRF: smooth vaccine intake, vaccine intake interrupted due to coughing or choking, regurgitationafter vaccine intake, vomiting after vaccine intake.§Recording of medications/vaccinations at each visit/contact will be according to the guidelines in Section 6.9.

It is the investigator�s responsibility to ensure that the intervals between visits/contactsare strictly followed.

Follow-up for the occurrence of SAEs will continue from Dose 1 of HRV vaccine up to 6months after the last dose of HRV vaccine.


Interval Length of interval1 (Visit 1→ Visit 2) 30 � 48 days2 (Visit 2→ Visit 3) 30 - 48 days

Contact� 168-202 days after the lastdose of HRV vaccine

�A safety follow-up contact (by telephone call or any other convenient procedure) to collect information on SAEs sincethe last visit

5.6. Detailed description of study visits/contacts

When materials are provided by GSK Biologicals, it is MANDATORY that all clinicalsamples (including serum samples) will be collected and stored using exclusively thosematerials in the appropriate manner. The use of other materials could result in theexclusion of the subject from the ATP analysis (See Section 10.4 for definition of studycohorts to be evaluated). The investigator must ensure that his/her personnel and thelaboratory(ies) under his/her supervision comply with this requirement. However, whenGSK Biologicals does not provide material for collecting and storing clinical samples,then appropriate materials from the investigator�s site are to be used. Refer to AppendixD and Appendix E.

The detailed description of procedures to be performed during each study visit ispresented below:

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5.6.1. Detailed description of study visits

Visit 1 (Day 0): Dose 1 of the study vaccine (at 10 - 17 weeks or 70 - 125days of age) (Amendment 1: 06 October 2006)

• Written informed consent obtained from the parents/guardians of the subject.

• Physical examination and medical history recording in the eCRF.

• Checking inclusion/exclusion criteria.

• Checking of contraindications to vaccination.

• Recording of pre-vaccination body temperature (measured by a rectal or axillarythermometer) in the eCRF.

• Measure and record subject�s height and weight in the eCRF.

• Randomisation of the subjects into one of the four study groups. See Section 6.4.

• Collection of blood sample for serology prior to vaccination from all subjects: aminimum of 2.0 ml of whole blood according to instructions in Appendix D.

• Recording of any prior/concomitant medication or vaccination administered, in theeCRF according to the guidelines in Section 6.9.

• Study Vaccination: Dose 1 of the HRV vaccine according to the guidelines set out inSection 6.2.

The vaccinees will be observed closely for at least 30 minutes, with appropriate medicaltreatment readily available in case of a rare anaphylactic reaction following theadministration of vaccine dose.

• Recording (in eCRF) of oral vaccine intake characteristics (smooth vaccine intake,vaccine intake interrupted due to coughing or choking, regurgitation after vaccineintake, vomiting after vaccine intake) by the infant. If regurgitation or vomitingoccurs after vaccination, do not give another dose at this visit.

• Routine childhood vaccines (Infanrix hexa) will be coadministered with the HRVvaccine dose. Administration of the routine childhood vaccines should be recorded inthe eCRF.

• Diary cards will be provided to the parents/guardians of all subjects to daily recordinformation on solicited symptoms (loss of appetite, fussiness/irritability, fever,diarrhoea, vomiting, cough/runny nose) occurring between the day of Dose 1 and thefollowing 7 days, on any medications and unsolicited AE occurring within 31 daysafter Dose 1 as well as on any GE occurring until Visit 2. The parents/guardiansshould be instructed to return the completed diary card to the investigator at Visit 2.

• The subjects� parents/guardians will be instructed to contact the investigatorimmediately should the subject manifest any signs or symptoms they perceive asserious.

• Parents/guardians should be instructed to collect stool sample(s) if the subjectdevelops GE (diarrhoea with or without vomiting) at any time until the next visit. A

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stool sample should be collected as soon as possible after illness begins andpreferably not later than 7 days after the start of diarrhoea. A stool sample should becollected for each separate diarrhoea episode. A second stool sample should becollected if the first sample was insufficient. Two occurrences of diarrhoea should beclassified as separate episodes if there are 5 or more diarrhoea-free days between theepisodes.

Visit 2 (Month 1): Dose 2 of the study vaccine (at 30 � 48 days after Visit1)

• Physical examination (Physical examination at this visit can take place in case ofrequest from the nurse or parents/guardians, and can be limited appropriate withlocal requirements for routine physical examination for a child at this age andappropriate for intervention that is to follow (blood draw etc.).

• Checking elimination criteria.

• Checking of contraindications to vaccination.

• Recording of pre-vaccination body temperature (measured by a rectal or axillarythermometer) in the eCRF.

• Recording of any concomitant medication or vaccination administered, in the eCRFaccording to the guidelines in Section 6.9.

• Collection and verification of diary card containing information onmedication/adverse experiences/GE occurring from Visit 1 till Visit 2. Theinvestigator will verify the diary card and transcribe the information into theappropriate sections of the eCRF, in English. The study monitor may help in thistranslation.

• Reporting of SAEs.

• Collection of any GE stool samples.

• Study Vaccination: Dose 2 of the HRV vaccine according to the guidelines set out inSection 6.2.

The vaccinees will be observed closely for at least 30 minutes, with appropriate medicaltreatment readily available in case of a rare anaphylactic reaction following theadministration of vaccine dose.

• Recording (in eCRF) of oral vaccine intake characteristics (smooth vaccine intake,vaccine intake interrupted due to coughing or choking, regurgitation after vaccineintake, vomiting after vaccine intake) by the infant. If regurgitation or vomitingoccurs after vaccination, do not give another dose at this visit.

• Routine childhood vaccines (Infanrix hexa) will be coadministered with the HRVvaccine dose. Administration of the routine childhood vaccines should be recorded inthe eCRF.

• Diary cards will be provided to the parents/guardians of all subjects to daily recordinformation on solicited symptoms (loss of appetite, fussiness/irritability, fever,diarrhoea, vomiting, cough/runny nose) occurring between the day of Dose 2 and the

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following 7 days, on any medications and unsolicited AE occurring within 31 daysafter Dose 2, as well as on any GE occurring until Visit 3. The parents/guardiansshould be instructed to return the completed diary card to the investigator at Visit 3.

• The subjects� parents/guardians will be instructed to contact the investigatorimmediately should the subject manifest any signs or symptoms they perceive asserious.

• Parents/guardians should be instructed to collect stool sample(s) if the subjectdevelops GE (diarrhoea with or without vomiting) at any time until the next visit. Astool sample should be collected as soon as possible after illness begins andpreferably not later than 7 days after the start of diarrhoea. A stool sample should becollected for each separate diarrhoea episode. A second stool sample should becollected if the first sample was insufficient. Two occurrences of diarrhoea should beclassified as separate episodes if there are 5 or more diarrhoea-free days between theepisodes.

Visit 3 (Month 2): Follow-up (at 30 � 48 days after Visit 2)

• Physical examination (Physical examination at this visit can take place in case ofrequest from the nurse or parents/guardians, and can be limited appropriate withlocal requirements for routine physical examination for a child at this age andappropriate for intervention that is to follow (blood draw etc.).

• Check of the appropriate elimination criteria.

• Recording of any concomitant medication/vaccination administered.

• Routine childhood vaccines (Infanrix hexa) will be administered. Administration ofthe routine childhood vaccines should be recorded in the eCRF.

• Collection of any GE stool samples.

• Collection of blood sample for serology from all subjects: a minimum of 2.0 ml ofwhole blood according to instructions in Appendix D.

• Collection and verification of diary card containing information on medication/adverse experiences/ GE occurring from Visit 2 till Visit 3. The investigator willverify the diary card and transcribe the information into the appropriate sections ofthe case report form, in English. The study monitor may help in this translation.

• Reporting of SAEs.

• Study conclusion.

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Extended safety follow-up contact at 168-202 days after the last dose ofHRV vaccine

• Study personnel will contact the parents/guardians of all subjects (by telephone callor any other convenient procedure) and use a script to record any SAEs that thesubject may have experienced since the last visit.

• Recording of SAEs.

• Recording of any investigational concomitant medication/vaccination administeredsince the previous visit according to the guidelines in Section 6.9.

• Study conclusion of extended safety follow-up.

5.7. Sample handling and analysis

5.7.1. Treatment and storage of biological samples

See Appendix D of the protocol for details of treatment and storage of biologicalsamples.

See Appendix E for instructions for shipment of biological samples.

5.7.2. Laboratory assays

GE Stool analysis

Stool samples collected during each GE episode from Visit 1 until Visit 3 will be tested atGSK Biologicals or a laboratory designated by GSK Biologicals using ELISA to detectRV. If RV positive, the sample will be tested by PCR to determine the G and P type. Ifany G1 RV is detected, vaccine virus will be differentiated from the wild type serotypeby sequence analysis or an equivalent approach (refer Appendix F).

Serum analysis

Serum obtained from whole blood samples collected from subjects at Visit 1 and Visit 3will be tested by ELISA at GSK Biologicals' designated laboratory to measure serumanti-rotavirus IgA antibody concentrations (refer to Appendix F). The assay cut-off is 20U/ml.

A seronegative subject for anti-rotavirus IgA antibodies is defined as a subject who hasantibody concentration below the assay cut-off value. A seropositive subject for anti-rotavirus IgA antibodies is defined as a subject who has antibody concentration greaterthan or equal to the assay cut-off value.

Table 3 Laboratory Assays

Antibody Assaymethod

Test Kit/Manufacturer

Assayunit

Assaycut-off

CoreLaboratory

Rotavirus IgA ELISA In-house U/ml 20 GSK

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The GSK Biologicals� laboratory at Rixensart has established Quality Control Proceduresand an established Quality System. Both are audited regularly for quality assessment byan internal (sponsor-dependent) but laboratory-independent Quality Department todocument the competency of the facility to perform the required tests and support thereliability of the results. Methods and equipment are validated, where required.

5.7.3. Immunological read-outs

Table 4 presents the sampling time points for serology and stools.

Table 4 Immunological read-outs

Timing Month Visit no. Antigen Antigen priority rank No. subjectsBlood sampling time point

Pre Day 0 1 HRV None AllPost-vacc 2 Month 2 3 HRV None All

Stool sampling time pointGE stools from Visit 1 to Visit 3 HRV None All

Any additional testing on biological samples will be performed if deemed necessary byGSK Biologicals if any findings in the present study necessitate further investigation ofthe vaccine.

5.7.4. Endpoints for suboptimal response

Not applicable.

6. INVESTIGATIONAL PRODUCT AND ADMINISTRATION

6.1. Study vaccines

The HRV vaccines tested in this study have been developed and manufactured by GSKBiologicals. The Quality Control Standards and Requirements for the candidate vaccinesare described in separate release protocols and the required approvals have been obtained.

The lyophilised formulation of the HRV vaccine will be supplied in monodose glassvials. The diluent to be used to reconstitute the lyophilised HRV vaccine will be suppliedseparately in pre-filled syringes.

The liquid formulation of the HRV vaccine will be supplied in pre-filled syringes.

Table 5 presents the composition of the liquid formulation and lyophilised formulation ofthe HRV vaccine.

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Table 5 Composition of GSK Biologicals’ HRV vaccine

Ingredient QuantityLiquid formulation of HRV vaccineActive substanceHuman Rotavirus, Live Attenuated,RIX4414 strain

At least 106.0 CCID50 perdose (1.5 ml)

ExcipientsSucrose 55% w/wDi-sodium adipate 132.74 mgDMEM 2.26 mgWater for Injection q.s. ad 1.5 mlLyophilised formulation of HRV vaccine (after reconstitution)Active substanceHuman Rotavirus, Live Attenuated,RIX4414 strain

At least 106.0 CCID50 perdose (1.0 ml)

ExcipientsLyophilised with active substance:Sucrose 9 mgDextran 18 mgSorbitol 13.5 mgAmino acids 9 mgDMEM 2.25 mgIn liquid diluent:Calcium carbonate 60 mgXanthan 2.5 mgWater for Injection q.s. ad 1 ml

CCID50 = median Cell Culture Infective Dose (quantity of virus causing infection in 50% of exposed cells)DMEM = Dulbecco's Modified Eagle Medium

Refer to Appendix G for details of vaccine supplies.

6.2. Dosage and administration

Liquid formulation of HRV vaccine

The pre-filled glass syringe is shaken well before use. The product (vaccine) should thenbe administered smoothly as a single oral dose.

In order to allow swallowing of the entire volume of the single oral dose, theadministration should occur in a quiet environment. Sufficient time should be allowed forthe baby to swallow the liquid vaccine solution, to avoid regurgitation or vomiting.Should the subject regurgitate or vomit after study vaccine administration, no new studyvaccine dose should be administered at that visit. The subject may continue to participateto the study and will be excluded from the planned ATP analysis of immunogenicity. Theoral vaccine intake characteristics (smooth vaccine intake, vaccine intake interrupted dueto coughing or choking, regurgitation after vaccine intake, vomiting after vaccine intake)should be recorded in the eCRF.

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Lyophilised formulation of HRV vaccine

To prepare the vaccine for administration, the entire content of one pre-filled syringecontaining the calcium carbonate buffer should be injected into the vial of the lyophilisedproduct (vaccine) using the provided transfer device. The vial should be shaken well toresuspend the vaccine. The entire volume of the resuspended product should bewithdrawn into the same syringe, the transfer device should be discarded and theresuspended product should then be administered smoothly as a single oral dose. Shouldthe subject regurgitate or vomit after the HRV vaccine administration, no new HRVvaccine dose should be administered at that visit. The subject may continue to participateto the study and will be excluded from the planned ATP analysis of immunogenicity. Theoral vaccine intake characteristics (smooth vaccine intake, vaccine intake interrupted dueto coughing or choking, regurgitation after vaccine intake, vomiting after vaccine intake)should be recorded in the eCRF.

The vaccinees will be observed closely for at least 30 minutes following theadministration of vaccines, with appropriate medical treatment readily available in caseof a rare anaphylactic reaction.

The vaccination regimen is summarised in Table 6.

Table 6 Dosage and Administration

Visit Vaccination Dose Vaccine Route Site

1, 2 Rotavirus 1 HRV Oral not applicable

During the study, routine childhood vaccines (Infanrix hexa) will be administered at 3, 4,5 months of age. The first two doses of Infanrix hexa will be coadministered with eachdose of HRV vaccine. All routine vaccinations should be recorded in the eCRF accordingto the guidelines in Section 6.9. Subjects will receive a booster dose of Infanrix hexaaccording to the approved prescribing information outside the scope of this study.

6.3. Storage

All vaccines must be stored in a safe and locked place with no access for unauthorisedpersonnel.

Vaccines will be stored at the defined range of temperature (i.e. +2°C to +8°C/ 36°F to46°F).

The storage temperature of vaccines will be monitored and recorded daily during workingdays, preferably at the same time of the day (e.g. at the beginning of the day).

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At a minimum, a calibrated/validated min/max thermometer will be placed close to thevaccines and will be used to monitor and record the daily temperature (actual, min andmax temperatures will be logged). Additionally, a continuous temperature recordingsystem (e.g. 75 days Ryan EZT) will be used as a back up device and it will be opened incase of temperature deviation (temperature outside the defined range, i.e. +2°C to +8°C/36°F to 46°F) during weekends or holidays. Alternatively, the temperature monitoringsystem of the storage facility can be used (as a replacement of the GSK continuoustemperature recording system), if:

• proper functioning was demonstrated during the monitor�s site evaluation,

• if the system continues to work in case of a power failure, and

• if the system is maintained regularly (e.g. once/year) as documented in the site files.

It is also permitted to monitor the storage temperature using a validated temperaturecontinuous recording device, provided it can read the daily actual and min/maxtemperatures, and that it keeps working when after the alarm is activated.

It is also required to place a validated freezing point indicator (e.g. Freeze Tag) close tothe vaccines as a back up device.

Any temperature deviation, i.e. temperature outside the defined range (i.e. +2°C to +8°C/36°F to 46°F), must be reported within 24 hours to the Sponsor (i.e. Study Monitor/ GSKLocal Contact).

Following exposure to a temperature deviation, vaccines will not be used until writtenapproval is given by the sponsor.

Storage conditions for transport of vaccines from country medical department or dispatchcentre to study sites or between sites are described in Appendix G.

6.4. Treatment allocation and randomisation

Target enrolment will be 1200 eligible subjects (300 subjects in each group) to berandomly assigned to four study groups in a 1:1:1:1 ratio.

6.4.1. Randomisation of supplies

A randomisation list will be generated at GSK Biologicals, Rixensart, using a standardSAS (Statistical Analysis System) program and will be used to number the vaccines. Arandomisation blocking scheme (1:1:1:1 ratio) will be used to ensure that balancebetween treatments is maintained: a treatment number will identify uniquely the vaccinedoses to be administered to the same subject.

To allow GSK Biologicals to take advantage of greater rates of recruitment thananticipated at individual centers in this multicentre study and to thus reduce the overallstudy recruitment period, an over-randomisation of supplies will be prepared.

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The vaccine doses will be distributed to each study centre, respecting the randomisationblock size.

6.4.2. Randomisation of subjects

The treatment allocation at the investigator site will be performed using a centralrandomisation system on Internet (SBIR). The randomisation algorithm will use aminimisation procedure accounting for centre.

After having checked that a subject is eligible, the person in charge of the vaccinationwill access the randomisation system on Internet. Upon providing a subject number forthe subject, the randomisation system will use the minimisation algorithm to determinethe treatment number to be used for the subject.

The actual treatment number used for first vaccination of the subject must be recorded bythe investigator in the eCRF (Rando/Treatment Allocation Section).

6.5. Method of blinding and breaking the study blind

The study will be conducted in a double-blind manner with respect to the three lots ofHRV vaccine liquid formulation. The parents/guardians of the subjects and the studypersonnel will be unaware of the administered lot of the HRV vaccine liquid formulation.However, the study personnel, and in certain circumstances the parents/guardians, will beaware if the subject received lyophilised or liquid formulation, since blinding between thetwo different formulations is technically not possible. The study will thus be open labelfor liquid formulation versus the lyophilised formulation.

The investigator, or person designated by the investigator, should contact GSKBiologicals� Central Safety physician directly or via the local safety contact (see StudyContact for Emergency Code Break in Sponsor Information page) to discuss the need foremergency unblinding. No set of individual codes will be held at the local GSKBiologicals� Safety Office or GSK Biologicals� Central Safety Office. The GSKBiologicals� Central Safety Office will be allowed to access the individual randomisationcode. The code will be broken by the GSK Biologicals� Central Safety physician (StudyContact for Emergency Code Break in Sponsor Information page) only in the case ofmedical events that the investigator/physician in charge of the subject feels cannot betreated without knowing the identity of the study vaccine(s).

GSK Biologicals� policy (incorporating ICH E2A guidance, EU Clinical Trial Directiveand Federal Regulations) is to unblind any serious adverse event (SAE) report associatedwith the use of the investigational product, which is unexpected andattributable/suspected, prior to regulatory reporting. The Clinical Safety physician isresponsible for unblinding the treatment assignment in accordance with specified timeframes for expedited reporting of SAEs (Refer to Section 8.9).

The IDMC will have access to the individual codes and may at its discretion identify theproduct administered to any subject to evaluate whether enrolment in the study should behalted.

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6.6. Replacement of unusable vaccine doses

Additional vaccine doses will be provided to replace those that are unusable (seeAppendix G for details of supplies).

In addition to the vaccine doses provided for the planned number of subjects, at least 5%additional doses will be supplied. In case a vaccine dose is broken or unusable, theinvestigator should replace it with a replacement vaccine dose. Although the sponsorneed not be notified immediately in these cases (except in the case of cold-chain failure),documentation of the use of the replacement vaccine must be recorded by the investigatoron the vaccine administration page of the eCRF and on the vaccine accountability form.

The investigator will use the central randomisation system (SBIR) to obtain thereplacement vial number. The system will ensure, in a blinded manner, that thereplacement vial is of the same (formulation/lot as applicable) as the randomised vaccine.

6.7. Packaging

See Appendix G.

6.8. Vaccine accountability

See Appendix G.

6.9. Concomitant medication/treatment

At each study visit/contact, the investigator should question the subject's parents/guardianabout any medication(s) given.

All concomitant medication, with the exception of vitamins and/or dietary supplements,administered at ANY time during the period starting with administration of each dose ofstudy vaccine and ending 30 days after each dose of study vaccine are to be recorded withgeneric name of the medication (trade names are allowed for combination drugs, i.e.multi-component drugs), medical indication, total daily dose, route of administration,start and end dates of treatment.

Any treatments and/or medications specifically contraindicated, e.g., anyimmunoglobulins, other blood products and any immune modifying drugs administeredsince birth or at any time up to Visit 3 are to be recorded with generic name of themedication (trade names are allowed for combination drugs only), medical indication,total daily dose, route of administration, start and end dates of treatment. Refer toSections 4.3 and 4.4.

All routine/planned vaccines and any vaccine not foreseen in the study protocoladministered since birth or at any time up to Visit 3 are to be recorded with trade name,route of administration and date(s) of administration. Refer to Sections 4.3 and 4.4

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A prophylactic medication is a medication administered in the absence of ANY symptomand in anticipation of a reaction to the vaccination (e.g. an anti-pyretic is considered to beprophylactic when it is given in the absence of fever [rectal temperature < 38 °C] and anyother symptom, to prevent fever from occurring). Any concomitant medicationadministered prophylactically in anticipation of reaction to the vaccination must berecorded in the eCRF with generic name of the medication (trade names are allowed forcombination drugs only), total daily dose, route of administration, start and end dates oftreatment and coded as �Prophylactic�.

Concomitant medication administered for the treatment of an AE or SAE within thefollow-up period for adverse events must be recorded in the eCRF with generic name ofthe medication (trade names are allowed for combination drugs only), medical indication(including which AE/SAE), total daily dose, route of administration, start and end datesof treatment. Similarly, concomitant medication administered for the treatment of a SAE,at any time, must be recorded on the on the SAE screens in the eCRF (or the SAE ReportForm if back-up reporting system is used). Refer to Section 8.2 for definition of SAE.

Any investigational medication or vaccine administered from Dose 1 of HRV vaccine upto the extended safety contact must be recorded in the eCRF.

7. HEALTH ECONOMICS

Not applicable.

8. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS

The investigator is responsible for the detection and documentation of events meeting thecriteria and definition of an AE or SAE as provided in this protocol. During the study,when there is a safety evaluation, the investigator or site staff will be responsible fordetecting AEs and SAEs, as detailed in this section of the protocol.

Each subject�s parents/guardians will be instructed to contact the investigatorimmediately should the subject manifest any signs or symptoms they perceive as serious.

8.1. Definition of an adverse event

An AE is any untoward medical occurrence in a clinical investigation subject, temporallyassociated with the use of a medicinal product, whether or not considered related to themedicinal product.

An AE can therefore be any unfavourable and unintended sign (including an abnormallaboratory finding), symptom, or disease (new or exacerbated) temporally associated withthe use of a medicinal product. For marketed medicinal products, this also includesfailure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

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Examples of an AE include:

• Exacerbation of a chronic or intermittent pre-existing condition including either anincrease in frequency and/or intensity of the condition.

• New conditions detected or diagnosed after investigational product administrationeven though it may have been present prior to the start of the study.

• Signs, symptoms, or the clinical sequelae of a suspected interaction.

• Signs, symptoms, or the clinical sequelae of a suspected overdose of eitherinvestigational product or a concurrent medication (overdose per se should not bereported as an AE/SAE).

• Signs, symptoms temporally associated with vaccine administration

Examples of an AE DO NOT include:

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition thatleads to the procedure is an AE.

• Situations where an untoward medical occurrence did not occur (social and/orconvenience admission to a hospital).

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) presentor detected at the start of the study that do not worsen.

AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e. invasive procedures, modification of subject�s previoustherapeutic regimen).

N.B. AEs to be recorded as endpoints (solicited events) are described in Section 8.5.1.All other AEs will be recorded as UNSOLICITED AES.

Example of events to be recorded in the medical history section of the CRF:

• Pre-existing conditions or signs and/or symptoms present in a subject prior to thestart of the study (i.e. prior to the first study vaccination).

8.2. Definition of a serious adverse event

A serious adverse event (SAE) is any untoward medical occurrence that:

a. results in death,

b. is life-threatening,

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in whichthe subject was at risk of death at the time of the event. It does not refer to an event,which hypothetically might have caused death, if it were more severe.

c. requires hospitalisation or prolongation of existing hospitalisation,

NOTE: In general, hospitalisation signifies that the subject has been detained (usuallyinvolving at least an overnight stay) at the hospital or emergency ward for observation

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and/or treatment that would not have been appropriate in the physician�s office or out-patient setting. Complications that occur during hospitalisation are AEs. If acomplication prolongs hospitalisation or fulfils any other serious criteria, the event isserious. When in doubt as to whether �hospitalisation� occurred or was necessary, theAE should be considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen frombaseline is not considered an AE.

d. results in disability/incapacity, or

NOTE: The term disability means a substantial disruption of a person�s ability to conductnormal life functions. This definition is not intended to include experiences of relativelyminor medical significance such as uncomplicated headache, nausea, vomiting,diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere orprevent everyday life functions but do not constitute a substantial disruption.

e. is a congenital anomaly/birth defect in the offspring of a study subject.

f. Medical or scientific judgement should be exercised in deciding whether reporting isappropriate in other situations, such as important medical events that may not beimmediately life-threatening or result in death or hospitalisation but may jeopardizethe subject or may require medical or surgical intervention to prevent one of theother outcomes listed in the above definition. These should also be consideredserious. Examples of such events are invasive or malignant cancers, intensivetreatment in an emergency room or at home for allergic bronchospasm, blooddyscrasias or convulsions that do not result in hospitalisation.

8.2.1. Disease-related events or outcomes not qualifying as seriousadverse events

Not applicable.

8.3. Lack of efficacy

�Lack of efficacy� per se will not be reported as an AE. The signs and symptoms orclinical sequelae resulting from lack of efficacy will be reported if they fulfil the AE orSAE definition (including clarifications).

8.4. Clinical laboratory parameters and other abnormalassessments qualifying as adverse events and seriousadverse events

Abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or otherabnormal assessments (e.g., ECGs, X-rays, vital signs, ultrasound etc) that are judged bythe investigator to be clinically significant will be recorded as AEs or SAEs if they meetthe definition of an AE, as defined in Section 8.1 or SAE, as defined in Section 8.2.Clinically significant abnormal laboratory findings or other abnormal assessments that

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are detected during the study or are present at baseline and significantly worsen followingthe start of the study will be reported as AEs or SAEs.

The investigator will exercise his or her medical and scientific judgement in decidingwhether an abnormal laboratory finding or other abnormal assessment is clinicallysignificant.

8.5. Time period, frequency, and method of detecting adverseevents and serious adverse events

All AEs occurring within one month (minimum 30 days) following administration ofeach dose of HRV vaccine as well as all diarrhoea occurring from Visit 1 to Visit 3 mustbe recorded on the Adverse Event form in the subject's CRF, irrespective of intensity orwhether or not they are considered vaccination-related.

The standard time period for collecting and recording SAEs will begin at randomisationor the first receipt of HRV vaccine and will end at the last contact foreseen for the subject(from Dose 1 of HRV vaccine up to 6 months after the last dose of HRV vaccine).Section 8.8 for instructions for reporting and recording SAEs.

Additionally, in order to fulfil international reporting obligations, SAEs that are related tostudy participation (e.g. procedures, invasive tests, a change from existing therapy) or arerelated to a concurrent medication will be collected and recorded from the time thesubject consents to participate in the study until she/he is discharged.

The investigator will inquire about the occurrence of AEs/SAEs at every visit during thestudy.

All AEs either observed by the investigator or one of his clinical collaborators or reportedby the subject�s parent/guardian spontaneously or in response to a direct question will beevaluated by the investigator. AEs not previously documented in the study will berecorded in the Adverse Event form within the subject's CRF. The nature of each event,date and time (where appropriate) of onset, outcome, intensity and relationship tovaccination should be established. Details of any corrective treatment should be recordedon the appropriate page of the CRF. Refer to Section 6.9.

As a consistent method of soliciting AEs, the subject�s parent/guardian should be asked anon-leading question such as:

"Has your child acted differently or felt different in any way since receiving the vaccineor since the last visit?"

N.B. The investigator should record only those AEs having occurred within the timeframe defined above.

AEs already documented in the CRF, i.e. at a previous assessment, and designated as �notrecovered/not resolved� or �recovering/resolving� should be reviewed at subsequentvisits, as necessary. If these have resolved, the documentation in the CRF should becompleted.

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When an AE/SAE occurs, it is the responsibility of the investigator to review alldocumentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relativeto the event. The investigator or designate will record all relevant information regardingan AE on the Adverse Event form within the subject's eCRF. The investigator ordesignate will also record all relevant information regarding the SAE on the SAE screensin the eCRF.

The electronic system using SAE screens in the eCRF will be the primary mode forreporting SAEs to GSK Biologicals during the study period. In case this electronicsystem for reporting SAEs does not work or after clinical database freezing, paper SAEReport Forms and the facsimile (Fax) system should be used to report SAEs.

The investigator will attempt to establish a diagnosis of the event based on signs,symptoms, and/or other clinical information. In such cases, the diagnosis should bedocumented as the AE/SAE and not the individual signs/symptoms.

8.5.1. Solicited adverse events

Solicited adverse events will be evaluated during the 8-day follow-up period (Day 0 toDay 7) after each HRV vaccine dose. Diary cards will be provided to the parents/guardian�s of the subject to daily record the specific solicited symptoms observedbetween the day of each HRV vaccine dose and the following 7 days (Day 0 to Day 7).

The following adverse events will be solicited:

Table 7 Solicited general adverse events

FeverIrritability/ FussinessDiarrhoeaVomitingLoss of appetiteCough/ runny nose

N.B. Temperature will be recorded in the evening. Should additional temperaturemeasurements be performed at other times of day, the highest temperature will berecorded.

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8.6. Evaluating adverse events and serious adverse events

8.6.1. Assessment of intensity

Table 8 Intensity scales for solicited symptoms

Adverse Event Intensity grade ParameterFever* Record temperature in °CIrritability/Fussiness 0 Behaviour as usual

1 Crying more than usual/ no effect on normal activity2 Crying more than usual/ interferes with normal activity3 Crying that cannot be comforted/ prevents normal activity

Diarrhoea¶ Record the number of looser than normal stools /dayVomiting§ Record the number of vomiting episodes/dayCough/runny nose 0 Normal

1 Cough/runny nose which is easily tolerated2 Cough/runny nose which interferes with daily activity3 Cough/runny nose which prevents daily activity

Loss of appetite 0 Appetite as usual1 Eating less than usual/ no effect on normal activity2 Eating less than usual/ interferes with normal activity3 Not eating at all

*Fever is defined as: rectal temperature ≥ 38 °C (/ axillary temperature ≥ 37.5 °C).¶Diarrhoea is defined as passage of three or more looser than normal stools within a day.§Vomiting is defined as one or more episodes of forceful emptying of partially digested stomach contents ≥ 1 hour afterfeeding within a day.

The maximum intensity of diarrhoea, fever and vomiting occurring during the solicitedfollow-up period will be scored at GSK Biologicals as described in Table 8.

Table 9 Intensity scales for diarrhoea, vomiting and fever reported duringthe solicited follow-up period

Adverse Experience Intensitygrade

Parameter

Diarrhoea 0 Normal (0 � 2 looser than normal stools/day)1 3 looser than normal stools/day2 4 � 5 looser than normal stools/day3 ≥ 6 looser than normal stools/day

Vomiting 0 Normal (no emesis)1 1 episode of vomiting/day2 2 episodes of vomiting/day3 ≥ 3 episodes of vomiting/day

Fever 0 Rectal temperature < 38.0°C or axillary temperature < 37.5°C1 Rectal temperature ≥ 38.0 � < 38.5°C or axillary temperature ≥

37.5 � ≤ 38.0°C2 Rectal temperature > 38.5 � < 39.5°C or axillary temperature >

38.0 � ≤ 39.0°C3 Rectal temperature > 39.5°C or axillary temperature > 39.0°C

The investigator will make an assessment of the maximum intensity that occurred overthe duration of the event for all other AEs, i.e. unsolicited symptoms, including SAEsreported during the study. The assessment will be based on the investigator�s clinical

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judgement. The intensity of each AE and SAE recorded in the Adverse Event form withinthe subject's eCRF, SAE screens in the eCRF or SAE Report Form (if back-up reportingsystem is used) should be assigned to one of the following categories:

1 (mild) = An AE which is easily tolerated by the subject, causingminimal discomfort and not interfering with everydayactivities.

2 (moderate) = An AE which is sufficiently discomforting to interfere withnormal everyday activities.

3 (severe) = An AE which prevents normal, everyday activities. (In ayoung child, such an AE would, for example, preventattendance at school/ kindergarten/ a day-care centre andwould cause the parents/ guardians to seek medical advice).

An AE that is assessed as Grade 3 (severe) should not be confused with a SAE.Grade 3 is a category utilised for rating the intensity of an event; and both AEsand SAEs can be assessed as Grade 3. An event is defined as �serious� when itmeets one of the pre-defined outcomes as described in Section 8.2.

8.6.2. Assessment of causality

The investigator is obligated to assess the relationship between investigational productand the occurrence of each AE/SAE. The investigator will use clinical judgement todetermine the relationship. Alternative causes, such as natural history of the underlyingdiseases, concomitant therapy, other risk factors and the temporal relationship of theevent to the investigational product will be considered and investigated. The investigatorwill also consult the Investigator Brochure and/or Product Information, for marketedproducts, in the determination of his/her assessment.

There may be situations when a SAE has occurred and the investigator has minimalinformation to include in the initial report to GSK Biologicals. However, it is veryimportant that the investigator always makes an assessment of causality for every eventprior to completion and data submission of the SAE screens in eCRF (or transmission ofthe SAE Report Form to GSK Biologicals if back-up reporting system is used). Theinvestigator may change his/her opinion of causality in light of follow-up information,amending the SAE screens in eCRF (or SAE Report Form if back-up reporting system isused). The causality assessment is one of the criteria used when determining regulatoryreporting requirements.

In case of concomitant administration of multiple vaccines, it may not be possible todetermine the causal relationship of general AEs to the individual vaccines administered.The investigator should, therefore, assess whether the AE could be causally related tovaccination rather than to the individual vaccines.

Causality of all AEs should be assessed by the investigator using the following question:

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Is there a reasonable possibility that the AE may have been caused by the investigationalproduct?

NO : The AE is not causally related to administration of the studyvaccine(s). There are other, more likely causes and administrationof the study vaccine(s) is not suspected to have contributed to theAE.

YES : There is a reasonable possibility that the vaccine(s) contributed tothe AE.

Non-serious and serious AEs will be evaluated as two distinct events. If an event meetsthe criteria to be determined �serious� (see Section 8.2 for definition of serious adverseevent), it will be examined by the investigator to the extent to be able to determine ALLcontributing factors applicable to each serious adverse event.

Other possible contributors include:

• Medical history

• Other medication

• Protocol required procedure

• Other procedure not required by the protocol

• Lack of efficacy of the vaccine(s), if applicable

• Erroneous administration

• Other cause (specify).

8.6.3. Medically attended visits

For each solicited and unsolicited symptom the subject experiences, the subject�sparents/guardians will be asked if they received medical attention defined ashospitalisation, an emergency room visit or a visit to or from medical personnel (medicaldoctor) for any reason and this information will be recorded in the CRF.

8.7. Follow-up of adverse events and serious adverse eventsand assessment of outcome

After the initial AE/SAE report, the investigator is required to proactively follow eachsubject and provide further information to GSK Biologicals on the subject�s condition.

All AEs and SAEs documented at a previous visit/contact and designated as notrecovered/not resolved or recovering/resolving will be reviewed at subsequentvisits/contacts.

Investigators will follow-up subjects:

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• with SAEs or subjects withdrawn from the study as a result of an AE, until the eventhas resolved, subsided, stabilised, disappeared, the event is otherwise explained, orthe subject is lost to follow-up;

• or, in the case of other non-serious AEs, until they complete the study or they are lostto follow-up.

Clinically significant laboratory abnormalities will be followed up until they havereturned to normal, or a satisfactory explanation has been provided. Additionalinformation (including but not limited to laboratory results) relative to the subsequentcourse of such an abnormality noted for any subject must be made available to the StudyMonitor.

GSK Biologicals may request that the investigator perform or arrange for the conduct ofsupplemental measurements and/or evaluations to elucidate as fully as possible the natureand/or causality of the AE or SAE. The investigator is obliged to assist. If a subject diesduring participation in the study or during a recognised follow-up period, GSKBiologicals will be provided with a copy of any available post-mortem findings,including histopathology.

New or updated information will be recorded on the originally completed SAE screens ineCRF. The update and submission of SAE screens in eCRF should be done within 24hours of receipt of the follow-up information as outlined in Section 8.8.1.

When paper SAE Report Form is used as back-up system during the study period, ifelectronic SAE reporting system does not work, the investigator or designate shouldupdate the SAE screens in eCRF once the electronic system is working again beforeusing it to report additional information.

When paper SAE Report Form is used as back-up system (after clinical databasefreezing), new or updated information is to be recorded on the originally completed SAEReport Form, with all changes signed and dated by the investigator. The updated SAEReport Form should be resent to GSK Biologicals within 24 hours of receipt of thefollow-up information as outlined in Section 8.8.1. In case paper SAE Report Forms areused, it is not acceptable for the investigator to send photocopies of the subject�s medicalrecords to GSK Biologicals in lieu of the appropriate completed AE/SAE pages.However, there may be instances when copies of medical records for certain cases arerequested by GSK Biologicals. In this instance, all subject identifiers will be blinded onthe copies of the medical records prior to submission to GSK Biologicals.

Outcome of any non-serious AE occurring within 30 days post-vaccination (i.e.unsolicited AE) or any SAE reported during the entire study will be assessed as:

• Recovered/resolved

• Not recovered/not resolved

• Recovering/resolving

• Recovered with sequelae/resolved with sequelae

• Fatal (SAEs only).

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8.8. Prompt reporting of serious adverse events to GSKBiologicals

The electronic system using SAE screens in the eCRF will be the primary mode forreporting SAEs to GSK Biologicals during the study period. In case this electronicsystem for reporting SAEs does not work or after clinical database freezing, paper SAEReport Forms and the facsimile (Fax) system should be used to report SAEs.

8.8.1. Time frames for submitting serious adverse event reports to GSKBiologicals

SAEs will be reported promptly to GSK once the investigator determines that the eventmeets the protocol definition of an SAE.

The investigator or designate will encode and submit relevant information on the SAEs inthe SAE screens in eCRF WITHIN 24 HOURS OF HIS/HER BECOMING AWARE OF THESEEVENTS. Additional or follow-up information relating to the initial SAE report is also tobe encoded and submitted in the SAE screens in eCRF within 24 hours of receipt of suchinformation.

When paper SAE Report Form is used as back-up system (if electronic SAE reportingsystem does not work or after clinical database freezing), the investigator or designatewill fax the SAE reports to GSK Biologicals� Central Safety for Serious Adverse EventReporting. Additional or follow-up information relating to the initial SAE report is also tobe reported to the GSK Biologicals� Central Safety for Serious Adverse Event Reportingwithin 24 hours of receipt of such information.

8.8.2. Completion and transmission of serious adverse event reports toGSK Biologicals

Once an investigator becomes aware that a SAE has occurred in a study subject, theinvestigator or designate will encode and submit the information in the SAE screens ineCRF within 24 hours as outlined in Section 8.8.1. The SAE screens in eCRF will alwaysbe completed as thoroughly as possible with all available details of the event andsubmitted by the investigator or designate. If the investigator or designate does not haveall information regarding an SAE, he/she will not wait to receive additional informationbefore notifying GSK of the event and completing the SAE screens in eCRF. The SAEscreens in eCRF should be updated when additional information is received WITHIN 24HOURS as outlined in Section 8.8.1.

When paper SAE Report Form is used as back-up system (if electronic SAE reportingsystem does not work or after clinical database freezing), the investigator or designatewill report relevant information on SAEs to GSK within the 24 hours as outlined inSection 8.8.1. The SAE Report Form will always be completed as thoroughly as possiblewith all available details of the event, signed by the investigator or designate, andforwarded to GSK within the designated time frames. If the investigator or designate doesnot have all information regarding an SAE, he/she will not wait to receive additionalinformation before notifying GSK of the event and completing the form. When additional

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information is received on a SAE reported to GSK using the back-up paper SAE ReportForm during the study period, the electronic system should be used to report theadditional information WITHIN 24 HOURS if the electronic system is working again andonly after updating the SAE screens in eCRF once the electronic system was workingagain. When additional information is received on a SAE after clinical database freezing,the paper SAE Report Form should be updated and forwarded to GSK WITHIN 24 HOURSas outlined in Section 8.8.1.

The investigator will always provide an assessment of causality at the time of the initialreport as described in Section 8.6.2.

In rare circumstances, if the electronic system for reporting SAEs does not work and inthe absence of facsimile equipment, notification by telephone is acceptable, with a copyof the SAE Report Form sent by email or by mail. Initial notification via the telephonedoes not replace the need for the investigator or designate to complete and submit SAEscreens in the eCRF (or complete and sign the SAE Report Form if back-up system needto be used) as outlined in Section 8.8.1.

In the event of a death determined by the investigator to be related to vaccination,completion of SAE screens in the eCRF / sending of the fax (if electronic SAE reportingsystem does not work or after clinical database freezing) must be accompanied bytelephone call to the Study Contact for Reporting SAEs.

Study Contact for Reporting SAEsName, address: GlaxoSmithKlinePO Box 24 (Piispansilta 9A), 02231 Espoo, FinlandTel: Tel Mobile: Fax: (Backup: email:

Back-up Study Contact for Reporting SAEsGSK Biologicals Clinical Safety PhysicianTel:

Fax: or Mobile phones for 7/7 day availability:

Back-up mobile phone contact:

8.9. Regulatory reporting requirements for serious adverseevents

The investigator will promptly report all SAEs to GSK in accordance with the proceduresdetailed in Section 8.8. GSK Biologicals has a legal responsibility to promptly notify, asappropriate, both the local regulatory authority and other regulatory agencies about the

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safety of a product under clinical investigation. Prompt notification of SAEs by theinvestigator to the Study Contact for Reporting SAEs is essential so that legal obligationsand ethical responsibilities towards the safety of other subjects are met.

The investigator, or responsible person according to local requirements, will comply withthe applicable local regulatory requirements related to the reporting of SAEs to theIRB/IEC and, if required, to the applicable government authority.

Investigator safety reports are prepared according to the current GSK policy and areforwarded to investigators as necessary. An investigator safety report is prepared for aSAE(s) that is both attributable to investigational product and unexpected. The purposeof the report is to fulfil specific regulatory and Good Clinical Practice (GCP)requirements, regarding the product under investigation.

An investigator who receives an investigator safety report describing a SAE(s) or otherspecific safety information (e.g., summary or listing of SAEs) from GSK Biologicals willfile it with the Investigator Brochure or other appropriate study documentation and willnotify the IRB or IEC, if appropriate according to local requirements.

8.10. Post-study adverse events and serious adverse events

A post-study AE/SAE is defined as any event that occurs outside of the AE/SAEdetection period defined in Section 8.5. Investigators are not obligated to actively seekAEs or SAEs in former study participants.

However, if the investigator learns of any SAE, including a death, at any time after asubject has been discharged from the study, and he/she considers the event reasonablyrelated to the investigational product, the investigator will promptly notify the StudyContact for Reporting SAEs.

After clinical database freezing, if SAE follow-ups or new SAEs have to be reported, theinvestigators or designate should use paper SAE Report Forms and the facsimile (Fax)system.

8.10.1. Extended safety follow-up

At 6 months (168-202 days) after the last dose of HRV vaccine, study personnel willcontact the parents/guardians of all subjects (by telephone call or any other convenientprocedure) and use a script to record any SAEs that the subject may have experiencedsince the last visit. Also, any investigational medication or vaccine administered since thelast visit will be recorded.

8.11. Treatment of adverse events

Treatment of any adverse event is at the sole discretion of the investigator and accordingto current good medical practice. Any medication administered for the treatment of anAE should be recorded in the subject�s CRF. Refer to Section 6.9.

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9. SUBJECT COMPLETION AND WITHDRAWAL

9.1. Subject completion

A subject who returns for the concluding visit (Visit 3) foreseen in the protocol isconsidered to have completed the study. A subject who can be contacted for theconcluding contact foreseen in the protocol is considered to have completed the extendedsafety follow-up.

9.2. Subject withdrawal

Subjects who are withdrawn because of SAE/AEs must be clearly distinguished fromsubjects who are withdrawn for other reasons. Investigators will follow subjects who arewithdrawn as result of a SAE/AE until resolution of the event (see Section 8.7).

Withdrawals will not be replaced.

9.2.1. Subject withdrawal from the study

From an analysis perspective, a �withdrawal� from the study is any subject who did notcome back for the concluding visit (Visit 3) foreseen in the protocol.

A subject qualifies as a �withdrawal� from the study when no study procedure hasoccurred, no follow-up has been performed and no further information has been collectedfor this subject from the date of withdrawal/last contact.

Investigators will make an attempt to contact those subjects who do not return forscheduled visits or follow-up.

Information relative to the withdrawal will be documented on the Study Conclusion pageof the eCRF. The investigator will document whether the decision to withdraw from thestudy was made by the subject�s parent or guardian or the investigator and which of thefollowing possible reasons was responsible for withdrawal:

• SAE

• non-serious AE

• protocol violation (specify)

• consent withdrawal, not due to an AE

• moved from the study area

• lost to follow-up

• other (specify).

9.2.2. Subject withdrawal from investigational product

A �withdrawal� from the investigational product is any subject who does not receive thecomplete treatment, i.e. when no further planned dose is administered from the date ofwithdrawal. A subject withdrawn from the investigational product may not necessarily be

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withdrawn from the study as further study procedures or follow-up may be performed(safety or immunogenicity) if planned in the study protocol.

Information relative to premature discontinuation of the investigational product will bedocumented on the Vaccine Administration page of the eCRF. The investigator willdocument whether the decision to discontinue further vaccination was made by thesubject�s parent or guardian or the investigator and which of the following possiblereasons was responsible for withdrawal:

• SAE,

• non-serious AE,

• other (specify).

10. DATA EVALUATION: CRITERIA FOR EVALUATION OFOBJECTIVES

10.1. Co-primary endpoints

• Serum anti-rotavirus IgA antibody concentration at Visit 3.


Seroconversion is defined as appearance of anti-rotavirus IgA antibody concentration ≥20 units (U)/millilitre (ml) in subjects initially (i.e. prior to the first dose of HRV vaccine)seronegative (i.e. with anti-rotavirus IgA antibody concentration< 20 U/ml)

10.2. Secondary endpoints

• Serum anti-rotavirus IgA antibody concentration at Visit 3 in the HRV vaccinelyophilised formulation group.

• Occurrence of each type of solicited symptom within the 8-day solicited follow-upperiod (Day 0 to Day 7) after each dose of HRV vaccine.

• Occurrence of unsolicited AEs within 31 days (Day 0 � Day 30) after any dose ofHRV vaccine, according to the Medical Dictionary for Regulatory Activities(MedDRA) classification.

• Occurrence of SAEs from Dose 1 of HRV vaccine up to 6 months after the last doseof HRV vaccine.

• Presence of RV in GE stools collected from Dose 1 of HRV vaccine up to Visit 3.

10.3. Estimated sample size

Target enrolment will be 1200 subjects (300 subjects in each of the liquid formulation ofHRV vaccine group and 300 subjects in the lyophilised formulation of HRV vaccinegroup) to obtain 960 evaluable subjects (240 subjects in each of the liquid formulation of

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HRV vaccine group and 240 subjects in the lyophilised formulation of HRV vaccinegroup) for the evaluation of the primary objectives.

This sample size will provide respectively 96% and 94% power to demonstrate the firstand the second co-primary objective, leading to a global power of 90% to demonstratethe 2 co-primary objectives (Bonferroni adjustment of beta).

The first co-primary objective is to demonstrate the lot-to-lot consistency of threeconsecutive production lots of the liquid formulation HRV vaccine in terms ofimmunogenicity as measured by serum anti-rotavirus IgA antibody levels one monthafter Dose 2.

Consistency will be reached if, for all pairs of lots, the two-sided 95% CIs for the ratio ofanti-rotavirus IgA antibody GMCs one month after Dose 2 are within the [0.5; 2] clinicallimit interval.

Table 10 presents the power to demonstrate consistency one month after Dose 2considering 240 evaluable subjects by vaccine lot.

Table 10 Power to rule out the null hypothesis that at least two of the threelots differ by more than 2-fold with respect to GMC after Dose 2(N=240 evaluable subjects per lot, two-sided test, Bonferroniadjustment of beta for 3 lot-to-lot comparisons, alpha = 2.5%, powerunder equal variance for both lots, PASS 2005 equivalence inmeans)

Endpoint Standard deviation[Log10 (titer)]

Power

Anti-rotavirus IgA antibody concentration 0.730* 96%0.750 95%0.800 90%

*anticipated value (reference study: ROTA-036)

The second co-primary objective is to demonstrate non-inferiority of the liquidformulation of GSK Biologicals' HRV vaccine to that of lyophilised formulation of GSKBiologicals� HRV vaccine in terms of seroconversion rates one month after Dose 2.

Non-inferiority, in terms of seroconversion rates, will be reached if the upper limit of thetwo-sided asymptotic standardised 95% CI for the difference in seroconversion ratebetween the lyophilised formulation of HRV vaccine and (minus) the liquid formulationof HRV vaccine is less than or equal to 10%.

Table 11 presents the power to demonstrate non-inferiority of the liquid formulation ofGSK Biologicals' HRV vaccine compared to the lyophilised formulation of GSKBiologicals� HRV vaccine, for a range of seroconversion rates.

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Table 11 Power to rule out that the seroconversion rate to anti-rotavirus IgAantibodies under the liquid formulation of HRV vaccine is decreasedby more than 10% as compared to the lyophilised formulation ofHRV vaccine (one-sided test, alpha = 2.5%, N=720 subjects in theliquid formulation of HRV vaccine and 240 subjects in thelyophilised formulation of HRV vaccine, PASS 2005)

Seroconversion rateLyophilised formulation of

HRV vaccineLiquid formulation of

HRV vaccinePower

80* 80* 94%75 75 89%70 70 85%

*anticipated rate (reference study: ROTA-036)

A secondary objective is to demonstrate non-inferiority of the liquid formulation of GSKBiologicals' HRV vaccine to that of lyophilised formulation of GSK Biologicals� HRVvaccine in terms of serum anti-rotavirus IgA antibody levels one month after Dose 2.

Non-inferiority, in terms of serum anti-rotavirus IgA antibody levels, will be reached ifthe upper limit of the two-sided 95% CI for the ratio of anti-rotavirus IgA antibodyGMCs one month after Dose 2 between the lyophilised formulation of HRV vaccine and(over) the liquid formulation of HRV vaccine is less than or equal to 2.

Table 12 presents the power to demonstrate non-inferiority of the liquid formulation ofGSK Biologicals' HRV vaccine compared to the lyophilised formulation of GSKBiologicals� HRV vaccine, for a range of standard deviation.

Table 12 Power to rule out the null hypothesis that the GMC after Dose 2under the lyophilised formulation of HRV vaccine is more than 2-foldgreater than under the liquid formulation of HRV vaccine (one-sidedtest, alpha = 2.5%, N=720 subjects in the liquid formulation of HRVvaccine and 240 subjects in the lyophilised formulation of HRVvaccine, power under equal variance for both formulations, PASS2005)

Endpoint Standard deviation[Log10 (titer)]

Power

Anti-rotavirus IgA antibody concentration 0.730* 99%0.750 99%0.800 99%

*anticipated value (reference study rota-036)

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10.4. Study cohorts to be evaluated

Total Vaccinated cohort

The total vaccinated cohort will include all subjects with at least one study vaccineadministration documented:

• a safety analysis based on the total vaccinated cohort will include all vaccinatedsubjects,

• an immunogenicity analysis based on the total vaccinated cohort will include allvaccinated subjects for whom immunogenicity data are available.

According-To-Protocol (ATP) cohort for analysis of safety

The ATP cohort for safety will include all subjects from the Total Vaccinated cohort

• who have received at least one dose of study vaccine according to their randomassignment,

• for whom the HRV vaccine liquid or lyophilised formulation was administeredaccording to protocol

• who have not received a vaccine forbidden by or not specified in the protocol.

• who were seronegative for serum anti-rotavirus IgA antibodies on the day of Dose 1.

According To Protocol (ATP) cohort for analysis of immunogenicity

The ATP immunogenicity cohort will include all subjects from the ATP safety cohort:

• who have not received medication forbidden by the protocol,

• whose underlying medical condition was not forbidden by the protocol,

• with no protocol violation of demographics (unknown age at study entry or outsideprotocol defined age-interval),

• who comply with vaccination schedule for HRV vaccine liquid or lyophilisedformulation,

• who comply with blood sampling schedule,

• for whom immunogenicity data are available at post-sampling time point.

• who have no RV other than vaccine strain in GE stool samples collected up toVisit 3.

• who have no concomitant infection unrelated to the vaccine which may influence theimmune response.

The total vaccinated cohort will be used for the primary analysis of safety. The analysison the ATP cohort for safety will only be performed if more than 5% of the vaccinatedsubjects are excluded from the ATP safety cohort.

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The ATP immunogenicity cohort will be used for the primary analysis ofimmunogenicity. An analysis of immunogenicity based on the total vaccinated cohortwill only be performed if more than 5% of the vaccinated subjects with immunologicalresults available are excluded from the ATP immunogenicity cohort. In such a case, thetotal vaccinated cohort analyses will evaluate whether exclusion from the ATP cohorthave biased the results.

10.5. Derived and transformed data

Demography

For a given subject and a given demographic variable, missing measurement will not bereplaced. Therefore, analysis of demography excluded subjects with missingmeasurements.

Immunogenicity

The cut-off value of anti-rotavirus IgA antibody is defined by the laboratory before theanalysis and is described in Section 5.7.2.

A seronegative subject is a subject whose antibody concentration is below the cut-offvalue.

A seropositive subject is a subject whose antibody concentration is greater than or equalto the cut-off value.

Seroconversion is defined as the appearance of anti-rotavirus IgA antibody concentration≥ 20 units (U)/millilitre (ml) in subjects initially (i.e. prior to the first dose of HRVvaccine) seronegative (i.e. with anti-rotavirus IgA antibody concentration< 20 U/ml).

The GMC calculations are performed by taking the anti-log of the mean of the logconcentration transformations. Antibody concentrations below the cut-off of the assaywill be given an arbitrary value of half the cut-off for the purpose of GMC calculation.

For a given subject and a given immunogenicity measurement, missing or non-evaluablemeasurements will not be replaced. Therefore, an analysis on immunogenicity willexclude subjects with missing or non-evaluable measurements.

Reactogenicity and safety

Subjects who missed reporting symptoms (solicited/unsolicited or concomitantmedications) will be treated as subjects without symptoms (solicited/unsolicited orconcomitant medications, respectively).

Additional analysis based on the total vaccinated cohort including only subjects/doseswith documented safety data (i.e. symptom screen completed) will also be performed.

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10.6. Final analyses

Final analysis of immunogenicity, reactogenicity, unsolicited AEs and SAEs up to Visit 3will be performed on all data up to Visit 3, as soon as all the data are available andcleaned. The safety results after Visit 3 up to the safety contact will be reported in anannex report.

10.6.1. Analysis of demographics

The distribution of subjects enrolled across the study centers will be tabulated as a wholeand by group.

The mean, range and standard deviation of height in cm, weight in kg and of age inweeks will be calculated by group. The racial and gender composition by group will alsobe presented.

10.6.2. Analysis of immunogenicity

For each HRV vaccine group and for pooled HRV liquid formulation groups,

• Seroconversion/seropositivity rates at Visit 3 and their exact 95% CI will becalculated.

• GMCs at Visit 3 and their 95% CI will be calculated.

The distribution of anti-rotavirus IgA antibody concentrations at Visit 3 will be displayedusing reverse cumulative curves.

The 95% CI for the ratio of anti-rotavirus IgA antibody GMCs at Visit 3 between anypair of the three lots of the liquid formulation of HRV vaccine will be computed.

The 95% CI for the ratio of anti-rotavirus IgA antibody GMCs at Visit 3 between theHRV lyophilised formulation group and (over) the HRV liquid formulation group will becomputed. This will be done using the group contrast between the HRV lyophilisedformulation group and the average of the HRV liquid formulation groups: (1, -1/3, -1/3, -1/3), in a one-way ANOVA model on the logarithm10 transformation of the titres.

The asymptotic standardised 95% CI for the difference in percentage of subjects whoseroconverted at Visit 3 between each pair of lot of the liquid formulation of HRVvaccine will be computed.

The asymptotic standardised 95% CI for the difference in percentage of subjects whoseroconverted at Visit 3 between the HRV lyophilised formulation group and (minus) thepooled HRV liquid formulation groups will be computed.

Interpretation of the primary objectives:

• The three HRV lots of the liquid formulation will be considered consistent at Visit 3if, for all pairs of lots, the two-sided 95% CIs for the ratio of anti-rotavirus IgAantibody GMCs one month after Dose 2 are within the [0.5; 2] clinical limit interval.

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• Non-inferiority, in terms of seroconversion rates, of the liquid formulation of GSKBiologicals' HRV vaccine to that of lyophilised formulation of GSK Biologicals�HRV vaccine will be reached if the upper limit of the two-sided asymptoticstandardised 95% CI for the difference in seroconversion rate at Visit 3 between theHRV lyophilised formulation group and (minus) the pooled HRV liquid formulationgroups is less than or equal to 10%.

Interpretation of the secondary objective:

Non-inferiority, in terms of serum anti-rotavirus IgA antibody levels, of the liquidformulation of GSK Biologicals' HRV vaccine to that of lyophilised formulation of GSKBiologicals� HRV vaccine will be reached if the upper limit of the two-sided 95% CI forthe ratio of anti-rotavirus IgA antibody GMCs one month after Dose 2 between thelyophilised formulation of HRV vaccine and (over) the liquid formulation of HRVvaccine is less than or equal to 2.

10.6.3. Analysis of safety

For each HRV vaccine group and for pooled HRV liquid formulation groups:

The overall incidence, with exact 95% CI, of any adverse events (solicited or unsolicited)during the solicited follow-up period will be tabulated for each dose, for overall dosesand per subject.

The incidence, with exact 95% CI, of each individual solicited general symptom, will betabulated over the solicited follow-up period, after each dose, for all doses and persubject. The same calculations will be done for each individual solicited generalsymptoms rated as grade �3� and for each individual solicited general symptom related tovaccination.

The verbatim reports of unsolicited adverse events will be reviewed by a physician andthe signs and symptoms will be coded according to MedDRA. Every verbatim term willbe matched with the appropriate Preferred Term. The percentage of subjects withunsolicited adverse events occurring within 31 days after any dose with its exact 95% CIwill be tabulated by preferred term. Similar tabulation will be done for unsolicitedadverse events rated as grade �3� and for unsolicited adverse events with causalrelationship to vaccination.

Difference in the incidence of specific symptoms between the HRV liquid formulationgroups and between the pooled HRV liquid formulation groups and the HRV lyophilisedformulation will be explored using two-sided Fisher Exact test. Statistically significantdifferences (p-value <0.05) should be interpreted cautiously, because of the number ofendpoints, the differences observed in this study are likely to occur by chance alone.

The percentage of subjects with GE and RV GE episodes reported during the studyperiod will be tabulated.

Serious adverse events reported during the study period will be described in detail.

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The percentages of subjects who received at least one concomitant medication during thesolicited follow-up period (Day 0�Day 7 after vaccination) will be tabulated by type ofmedication.

10.7. Planned interim analysis

No interim analysis is planned.

11. ADMINISTRATIVE MATTERS

To comply with Good Clinical Practice important administrative obligations relating toinvestigator responsibilities, monitoring, archiving data, audits, confidentiality andpublications must be fulfilled. See Appendix B for details.

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12. REFERENCES

Bernstein DI, Sack DA, Reisinger K, Rothstein E, Ward RL. Second year follow-upevaluation of live attenuated human rotavirus vaccine 89-12 in healthy infants. J InfectDis. 2002:1487-9.

Bernstein DI, Sack DA, Rothstein E, Reisinger K, Ward RL. Efficacy of live attenuatedhuman rotavirus vaccine 89-12 in infants. Lancet. 1999:287-90.

Bernstein DI, Smith VE, Sherwood JR, et al. Safety and immunogenicity of liveattenuated human rotavirus vaccine 89-12. Vaccine. 1998:381-7.

Dennehy PH, Brady RC, Scott H, et al. Comparative evaluation of safety andimmunogenicity of two doses of an oral live attenuated human rotavirus vaccine. PediatrInfect Dis J. 2005:481-8.

Glass RI, Kilgore PE, Holman RC, et al. The epidemiology of rotavirus in the UnitedStates: surveillance and estimation of disease burden. J Infect Dis. 1996:S5.

Parashar UD, et al. Global illness and deaths caused by rotavirus disease in children.Emerg Infect Dis. 2003:565-72.

Parashar UD, Gibson CJ, Bresee JS, Glass RI. Rotavirus and severe childhood diarrhoea.Emerg Infect Dis. 2006;12:304-6.

Ruiz-Palacios GM, Perez-Schael I, Linhares AC, et al. Safety and efficacy of anattenuated vaccine against severe rotavirus gastroenteritis. NEJM. 2006;354:11-22.

Ruuska T, Vesikari T. Rotavirus disease in Finnish children: use of numerical scores forseverity of diarrhoeal episodes. Scand J Infect Dis. 1990:259-67.

Salinas B, Perez-Schael I, Linhares AC, et al. Evaluation of safety, immunogenicity andefficacy of an attenuated rotavirus vaccine RIX4414: a randomized, placebo-controlledtrial in Latin American infants. Pediatr Infect Dis J. 2005:807-16.

Soriano-Gabarro M, Murkowicz J, Vesikari T, Verstraten T. Burden of rotavirus diseasein European Union countries. Pediatr Infect Dis J. 2006:S7-11.

Tucker AW, Haddix AC, Bresee JS, et al. Cost-effectiveness analysis of a rotavirusimmunization program in the United States. JAMA. 1998:371-6.

Vesikari T, Karvonen A, Puustinen L, et al. Efficacy of RIX4414 live attenuated humanrotavirus vaccine in Finnish infants. Pediatr Infect Dis J. 2004:937-43.

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Appendix A World Medical Association Declaration of Helsinki

Recommendations guiding physiciansin biomedical research involving human subjects

Adopted by the 18th World Medical AssemblyHelsinki, Finland, June 1964

and amended by the29th World Medical AssemblyTokyo, Japan, October 197535th World Medical AssemblyVenice, Italy, October 1983

41st World Medical AssemblyHong Kong, September 1989

and the48th General Assembly

Somerset West, Republic of South Africa, October 1996

INTRODUCTION

It is the mission of the physician to safeguard the health of the people. His or herknowledge and conscience are dedicated to the fulfilment of this mission.

The Declaration of Geneva of the World Medical Association binds the physician withthe words, "The health of my patient will be my first consideration," and the InternationalCode of Medical Ethics declares that, "A physician shall act only in the patient's interestwhen providing medical care which might have the effect of weakening the physical andmental condition of the patient."

The purpose of biomedical research involving human subjects must be to improvediagnostic, therapeutic and prophylactic procedures and the understanding of the etiologyand pathogenesis of disease.

In current medical practice most diagnostic, therapeutic or prophylactic proceduresinvolve hazards. This applies especially to biomedical research.

Medical progress is based on research which ultimately must rest in part onexperimentation involving human subjects.

In the field of biomedical research a fundamental distinction must be recognised betweenmedical research in which the aim is essentially diagnostic or therapeutic for a patient,and medical research, the essential object of which is purely scientific and withoutimplying direct diagnostic or therapeutic value to the person subjected to the research.

Special caution must be exercised in the conduct of research which may affect theenvironment, and the welfare of animals used for research must be respected.

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Because it is essential that the results of laboratory experiments be applied to humanbeings to further scientific knowledge and to help suffering humanity, the World MedicalAssociation has prepared the following recommendations as a guide to every physician inbiomedical research involving human subjects. They should be kept under review in thefuture. It must be stressed that the standards as drafted are only a guide to physicians allover the world. Physicians are not relieved from criminal, civil and ethicalresponsibilities under the laws of their own countries.

I. BASIC PRINCIPLES

1. Biomedical research involving human subjects must conform to generally acceptedscientific principles and should be based on adequately performed laboratory andanimal experimentation and on a thorough knowledge of the scientific literature.

2. The design and performance of each experimental procedure involving humansubjects should be clearly formulated in an experimental protocol which should betransmitted for consideration, comment and guidance to a specially appointedcommittee independent of the investigator and the sponsor provided that thisindependent committee is in conformity with the laws and regulations of the countryin which the research experiment is performed.

3. Biomedical research involving human subjects should be conducted only byscientifically qualified persons and under the supervision of a clinically competentmedical person. The responsibility for the human subject must always rest with amedically qualified person and never rest on the subject of research, even though thesubject has given his or her consent.

4. Biomedical research involving human subjects cannot legitimately be carried outunless the importance of the objective is in proportion to the inherent risk to thesubject.

5. Every biomedical research project involving human subjects should be preceded bycareful assessment of predictable risks in comparison with foreseeable benefits to thesubject or to others. Concern for the interests of the subject must always prevail overthe interests of science and society.

6. The right of the research subject to safeguard his or her integrity must always berespected. Every precaution should be taken to respect the privacy of the subject andto minimize the impact of the study on the subject's physical and mental integrity andon the personality of the subject.

7. Physicians should abstain from engaging in research projects involving humansubjects unless they are satisfied that the hazards involved are believed to bepredictable. Physicians should cease any investigation if the hazards are found tooutweigh the potential benefits.

8. In publication of the results of his or her research, the physician is obliged topreserve the accuracy of the results. Reports of experimentation not in accordancewith the principles laid down in this Declaration should not be accepted forpublication.

9. In any research on human beings, each potential subject must be adequatelyinformed of the aims, methods, anticipated benefits and potential hazards of the

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study and the discomfort it may entail. He or she should be informed that he or she isat liberty to abstain from participation in the study and that he or she is free towithdraw his or her consent to participation at any time. The physician should thenobtain the subject's freely-given informed consent, preferably in writing.

10. When obtaining informed consent for the research project the physician should beparticularly cautious if the subject is in a dependent relationship to him or her or mayconsent under duress. In that case the informed consent should be obtained by aphysician who is not engaged in the investigation and who is completely independentof this official relationship.

11. In case of legal incompetence, informed consent should be obtained from the legalguardian in accordance with national legislation. Where physical or mentalincapacity makes it impossible to obtain informed consent, or when the subject is aminor, permission from the responsible relative replaces that of the subject inaccordance with national legislation.Whenever the minor child is in fact able to give a consent, the minor's consent mustbe obtained in addition to the consent of the minor's legal guardian.

12. The research protocol should always contain a statement of the ethical considerationsinvolved and should indicate that the principles enunciated in the present Declarationare complied with.

II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE(Clinical research)

1. In the treatment of the sick person, the physician must be free to use a newdiagnostic and therapeutic measure, if in his or her judgement it offers hope ofsaving life, re-establishing health or alleviating suffering.

2. The potential benefits, hazards and discomfort of a new method should be weighedagainst the advantages of the best current diagnostic and therapeutic methods.

3. In any medical study, every patient - including those of a control group, if any -should be assured of the best proven diagnostic and therapeutic method. This doesnot exclude the use of inert placebo in studies where no proven diagnostic ortherapeutic method exists.

4. The refusal of the patient to participate in a study must never interfere with thephysician�patient relationship.

5. If the physician considers it essential not to obtain informed consent, the specificreasons for this proposal should be stated in the experimental protocol fortransmission to the independent committee (I, 2).

6. The Physician can combine medical research with professional care, the objectivebeing the acquisition of new medical knowledge, only to the extent that medicalresearch is justified by its potential diagnostic or therapeutic value for the patient.

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III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMANSUBJECTS (Non-clinical biomedical research)

1. In the purely scientific application of medical research carried out on a human being,it is the duty of the physician to remain the protector of the life and health of thatperson on whom biomedical research is being carried out.

2. The subjects should be volunteers - either healthy persons or patients for whom theexperimental design is not related to the patient's illness.

3. The investigator or the investigating team should discontinue the research if inhis/her or their judgement it may, if continued, be harmful to the individual.

In research on man, the interest of science and society should never take precedence overconsiderations related to the well being of the subject.

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Appendix B Administrative Matters

I. Responsibilities of the Investigator

• To ensure that he/she has sufficient time to conduct and complete the study and hasadequate staff and appropriate facilities and equipment which are available for theduration of the study and to ensure that other studies do not divert essential subjectsor facilities away from the study at hand.

• To submit an up-to-date curriculum vitae or Investigator Biography and othercredentials (e.g., medical license number in the United States) to GSK and�whererequired�to relevant authorities. It is recommended that this documentationindicates any previous clinical research experience and history of training in GCP.

• To acquire the reference ranges for laboratory tests performed locally and, if requiredby local regulations, obtain the laboratory�s current certification or QualityAssurance procedure manual.

• To ensure that no clinical samples (including serum samples) are retained on site orelsewhere without the approval of GSK Biologicals and the express written informedconsent of the subject and/or the subject�s legally authorised representative.

• To perform no other biological assays at the investigator site except those describedin the protocol or its amendment(s).

• To prepare and maintain adequate subject source data or raw data designed to recordobservations, and other data pertinent to the study.

• To conduct the study in compliance with the protocol any amendment and �GoodClinical Practice� (GCP) and all applicable regulatory requirements.

• To co-operate with a representative of GSK Biologicals in the monitoring process ofthe study and in resolution of queries about the data.

• To permit drug regulatory agencies and GSK audits.

II. Protocol Amendments and Administrative changes

• No changes to the study protocol will be allowed unless discussed in detail with theGSK Biologicals' Clinical Development Manager/Medical Monitor and filed as anamendment/administrative change to this protocol.

• Any amendment/administrative change to the protocol will be adhered to by theparticipating centre(s) and will apply to all subjects. Written IRB/IEC approval ofprotocol amendments is required prior to implementation, except where permitted byall applicable regulatory requirements; administrative changes and amendments notsubmitted for approval are submitted to IRBs/IECs for information only. Submissionof protocol amendments to regulatory agencies will occur in accordance with localregulatory requirements. For some countries, submission to the local regulatoryauthority may not be required. When submission to the local regulatory authority isrequired, the timing of the submission relative to IEC/IRB submission or approvaland whether or not the authority will provide their approval of or favourable opinion

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on the amendment before it can be implemented will depend on local regulatoryrequirements.

III. Sponsor�s Termination of Study

GSK Biologicals reserves the right to temporarily suspend or prematurely discontinuethis study either at a single site or at all sites at any time for reasons including, but notlimited to, safety or ethical issues or severe non-compliance. Reasons for suspension orearly termination will be documented in the study file at GSK Biologicals.

If GSK Biologicals determines that suspension or early termination is needed, GSKBiologicals will discuss this with the Investigator (including the reasons for taking suchaction). When feasible, GSK Biologicals will provide advance notification to theinvestigator of the impending action prior to it taking effect.

GSK Biologicals will promptly inform, via written communication, all investigatorsand/or institutions conducting the study, if the study is suspended or terminated for safetyreasons, and will also inform the regulatory authorities of the suspension or terminationof the study and the reason(s) for the action. If required by applicable regulations, theinvestigator must inform the IEC/IRB promptly and provide the reason for the suspensionor termination.

If the study is prematurely discontinued, all study data must be returned to GSK. Inaddition, arrangements will be made for all unused investigational product(s) inaccordance with the applicable GSK procedures for the study. Financial compensation toinvestigators and/or institutions will be in accordance with the agreement establishedbetween the investigator and/or institutions and GSK.

IV. Remote Data Entry Instructions

Remote Data Entry (RDE) will be used as the method for data collection, which meansthat subject information will be entered into a computer at the investigational site. Thesite will be capable of modifying the data to assure accuracy with source documentation.All new/updated information will be reviewed and verified by a GSK Biologicals'representative. This information will finally be stored in a central database maintained byGSK Biologicals. At the conclusion of the study, GSK Biologicals will archive the studydata in accordance with internal procedures. In addition, the investigator will be providedwith a CD-ROM of the final version of the data generated at the investigational site.

Specific instructions for use of RDE will be included in the training material provided tothe investigational site.

V. Monitoring by GSK Biologicals

To ensure compliance with the protocol, monitoring visits by a professionalrepresentative of the sponsor will be scheduled to take place early in the study, during thestudy at appropriate intervals and after the last subject has completed the study. It isanticipated that monitoring visits will occur at a frequency defined and communicated tothe investigator before study start.

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These visits are for the purpose of confirming that GSK Biologicals� sponsored studiesare being conducted in accordance with the ethical principles that have their origins in theDeclaration of Helsinki and that are consistent with Good Clinical practice (GCP) and theapplicable regulatory requirement(s) (verifying continuing compliance with the protocol,amendment(s), reviewing the investigational product accountability records, verifyingthat the site staff and facilities continue to be adequate to conduct the study. Direct accessto all study-related site and source data/ documents is mandatory for the purpose ofmonitoring review. The monitor will perform an eCRF review and a Source Documentverification (verifying eCRF/ RDE entries by comparing them with the sourcedata/documents that will be made available by the investigator for this purpose: any dataitem for which the eCRF will serve as the source must be identified, agreed anddocumented. Data to be recorded directly into the eCRF pages/RDE screens will bespecified in writing preferably in the source documentation agreement form that iscontained in both the monitor�s and investigator�s study file. For RDE, the monitor willmark completed and approved screens at each visit. The investigator must ensureprovision of reasonable time, space and adequate qualified personnel for monitoringvisits. Source data verification (SDV) must be conducted using a GSK standard SDVsampling strategy (as defined at the study start in the study specific monitoringguidelines) in which monitors will perform partial SDV for all subjects and full SDV forselected subjects.

VI. Archiving of Data

Following closure of the study, the investigator must maintain all site study records in asafe and secure location. The records must be maintained to allow easy and timelyretrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow anysubsequent review of data in conjunction with assessment of the facility, supportingsystems, and staff. Where permitted by applicable laws/regulations or institutionalpolicy, some or all of these records can be maintained in a validated format other thanhard copy (e.g., microfiche, scanned, electronic for studies with an eCRF, for example);however, caution needs to be exercised before such action is taken. The investigator mustassure that all reproductions are legible and are a true and accurate copy of the originaland meet accessibility and retrieval standards, including re-generating a hard copy, ifrequired. Furthermore, the investigator must ensure there is an acceptable back-up ofthese reproductions and that an acceptable quality control process exists for making thesereproductions.

GSK will inform the investigator/ institution of the time period for retaining these recordsto comply with all applicable regulatory requirements. However, the investigator/institution should seek the written approval of the sponsor before proceeding with thedisposal of these records. The minimum retention time will meet the strictest standardapplicable to that site for the study, as dictated by ICH GCP E6 Section 4.9, anyinstitutional requirements or applicable laws or regulations, or GSKstandards/procedures; otherwise, the minimum retention period will default to 15 years.

The investigator/ institution must notify GSK of any changes in the archivalarrangements, including, but not limited to, the following: archival at an off-site facility,transfer of ownership of the records in the event the investigator leaves the site.

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VII. Audits

For the purpose of compliance with Good Clinical Practice and Regulatory AgencyGuidelines it may be necessary for GSK or a Drug Regulatory Agency to conduct a siteaudit. This may occur at any time from start to after conclusion of the study.

When an investigator signs the protocol, he agrees to permit drug regulatory agencies andGSK audits, providing direct access to source data/ documents. Furthermore, if aninvestigator refuses an inspection, his data will not be accepted in support of a New DrugRegistration and/or Application, Biologics Licensing Application.

Having the highest quality data and studies are essential aspects of vaccine development.GSK has a Regulatory Compliance staff who audit investigational sites. RegulatoryCompliance assesses the quality of data with regard to accuracy, adequacy andconsistency. In addition, Regulatory Compliance assures that GSK Biologicals�sponsored studies are in accordance with GCP and that relevant regulations/guidelinesare being followed.

To accomplish these functions, Regulatory Compliance selects investigational sites toaudit. These audits usually take 1 to 2 days. GSK�s audits entail review of sourcedocuments supporting the adequacy and accuracy of CRFs, review of documentationrequired to be maintained, and checks on vaccine accountability. GSK�s audit thereforehelps prepare an investigator for a possible regulatory agency inspection as well asassuring GSK Biologicals of the validity of the database across investigational sites.

The Inspector will be especially interested in the following items:

• Log of visits from the sponsor�s representatives

• Study personnel

• Study file

• Safety reporting

• IRB/IEC and regulatory authority approvals

• Facilities

• monitoring

• Vaccine accountability

• Approved study protocol and amendments and investigator brochure

• Informed consent of the subjects (written consent [or witnessed oral if applicable] )

• Medical records and other source documents supportive of eCRF data

• Reports to the IRB/IEC and the sponsor

• Record retention.GSK Biologicals will gladly help investigators prepare for an inspection.

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VIII. Ownership, Confidentiality and Publication

Ownership:All information provided by GSK and all data and information generated by the site aspart of the study (other than a subject�s medical records) are the sole property of GSK.

All rights, title, and interests in any inventions, know-how or other intellectual orindustrial property rights which are conceived or reduced to practice by site staff duringthe course of or as a result of the study are the sole property of GSK, and are herebyassigned to GSK.

If a written contract for the conduct of the study which includes ownership provisionsinconsistent with this statement is executed between GSK and the study site, thatcontract�s ownership provisions shall apply rather than this statement.

Confidentiality:Documented evidence that a potential investigator is aware and agrees to the confidentialnature of the information related to the study must be obtained by means of aconfidentiality agreement.

All information provided by GSK and all data and information generated by the site aspart of the study (other than a subject�s medical records) will be kept confidential by theinvestigator and other site staff. This information and data will not be used by theinvestigator or other site personnel for any purpose other than conducting the study.These restrictions do not apply to: (1) information which becomes publicly availablethrough no fault of the investigator or site staff; (2) information which it is necessary todisclose in confidence to an IEC or IRB solely for the evaluation of the study; (3)information which it is necessary to disclose in order to provide appropriate medical careto a study subject; or (4) study results which may be published as described in the nextparagraph. If a written contract for the conduct of the study which includesconfidentiality provisions inconsistent with this statement is executed, that contract�sconfidentiality provisions shall apply rather than this statement.

Publication:For multicentre studies, the first publication or disclosure of study results shall be acomplete, joint multicentre publication or disclosure coordinated by GSK. Thereafter,any secondary publications will reference the original publication(s).

Prior to submitting for publication, presentation, use for instructional purposes, orotherwise disclosing the study results generated by the site (collectively, a �Publication�),the investigator shall provide GSK with a copy of the proposed Publication and allowGSK a period to review the proposed Publication (at least 21 (twenty-one) days [or atleast 15 (fifteen) working days for abstracts/posters/presentations]. ProposedPublications shall not include either GSK confidential information other than the studyresults or personal data on any subject, such as name or initials.

At GSK�s request, the submission or other disclosure of a proposed Publication will bedelayed a sufficient time to allow GSK to seek patent or similar protection of any

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inventions, know-how or other intellectual or industrial property rights disclosed in theproposed Publication.

If a written contract for the conduct of the study, which includes publication provisionsinconsistent with this statement is executed, that contract�s publication provisions shallapply rather than this statement.

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Appendix C Overview of the Recruitment Plan

• All subjects will be enrolled at multiple sites in Finland.

• Target enrolment will be 1200 eligible subjects (300 subjects per group).

• Enrolment will be terminated when 1200 eligible subjects have been enrolled.

• All subjects will be enrolled within a period of 2 months.

• The intended duration of the study, per subject will be approximately 7 monthsincluding the 6-month safety follow-up period after Dose 2 of HRV vaccine.

• The recruitment will be monitored by the site monitor(s).

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Appendix D Handling of Biological Samples Collected by theInvestigator

Instructions for Handling of Serum Samples

When materials are provided by GSK Biologicals, it is MANDATORY that all clinicalsamples (including serum samples) will be collected and stored using exclusively thosematerials in the appropriate manner. The use of other materials could result in theexclusion of the subject from the ATP analysis. The investigator must ensure that his/herpersonnel and the laboratory(ies) under his/her supervision comply with this requirement.However, when GSK Biologicals does not provide material for collecting and storingclinical samples, then appropriate materials from the investigator�s site are to be used.

1. Collection

The whole blood (by capillary or venous route) should be collected observing appropriateaseptic conditions. It is recommended that Vacutainer tubes WITH integrated serumseparator (e.g. Becton-Dickinson Vacutainer SST or Corvac Sherwood Medical) beused to minimize the risk of haemolysis and to avoid blood cell contamination of theserum when transferring to standard serum tubes.

2. Serum separation

These guidelines aim to ensure high quality serum by minimizing the risk of haemolysis,blood cell contamination of the serum or serum adverse cell toxicity at testing.

• For separation of serum using Vacutainer® tubes, the instructions provided by themanufacturer should be followed. Often the manufacturer�s instruction states that therelative centrifugal acceleration known also as �G� must be �between 1000 and 1300G� with tubes spinning for ten minutes. Error in calculation of centrifuge speed canoccur when laboratory personnel confuse �G� acceleration with �RPM� (revolutionsper minute). The speed of centrifugation must be calculated using the �G� rateprovided in the manufacturer�s instructions and the radius of the centrifuge head.After measuring the radius of the centrifuge machine, a speed/accelerationnomograph must be employed to determine the centrifuge speed in �RPM�.

• Following separation, the serum should be aseptically transferred to the appropriatestandard tubes using a sterile disposable pipette. The serum should be transferred asgently as possible to avoid blood cell contamination.

• The tube should not be overfilled (max. 3/4 of the total volume) to allow room forexpansion upon freezing.

• The tube should be identified by the appropriate label provided by GSK Biologicals(see point 3).

3. Labelling

• The standard labels provided by GSK Biologicals should be used to label each serumsample.

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• If necessary, any hand-written additions to the labels should be made using indelibleink.

• The label should be attached to the tube as follows (see diagram):

• first attach the paper part of the label to the tube

• then wrap the label around the tube so that the transparent, plastic part of thelabel overlaps with the label text and bar code and shields them.

This will ensure optimal label attachment.

Plastic, transparent part

Paper, text part

Bar code

Study N°.........

Subject N° ......

POST VACC. I STUDY MTH 1For GlaxoSmithKline

Biologicals

• Labels should not be attached to caps.4. Sorting and storage

• Tubes should be placed in the GSK Biologicals� cardboard boxes in numerical orderfrom left to right, starting from the lower left hand corner, beginning with the pre-vaccination samples series, then with the post-vaccination sample series.

• The tubes of serum should be stored in a vertical position at approximately -20°C(alternatively at approximately -70°/80°C is also acceptable) until shipment to GSKBiologicals. The storage temperature should be checked regularly and documented.Wherever possible, a backup facility for storage of serum samples should beavailable.

• A standard Biological Specimen Sample listing form, specifying the samples beingshipped for individual subjects at each timepoint, should be prepared for eachshipment. A copy of this list should be retained at the study site, while the originalshould be sealed in a plastic envelope and shipped with the serum samples.

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• Once shipment details are known, a standard Specimen Transfer Form must becompleted and faxed to GSK Biologicals to the number provided below. A copy ofthe Specimen Transfer Form must be in the parcel.1

GLAXOSMITHKLINE BIOLOGICALS

Attention Biospecimen ReceptionClinical Immunology

R & D Department/Building 44Rue de l'Institut, 89

B-1330 Rixensart � BelgiumTelephone: or

or or Fax:

E-mail:

Instructions for Handling of Stool Samples

When materials are provided by GSK Biologicals, it is mandatory that all clinicalsamples be collected and stored using exclusively those materials in the appropriatemanner. The use of other materials could result in the exclusion of the subject fromanalysis. The investigator must ensure that his/her personnel and the laboratory(ies) underhis/her supervision comply with this requirement.

1. Collection

Containers/ 8 ml tubes/ ziplock bags and fridge envelopes will be provided toparents/guardians for collection of stool samples during any GE episodes.Parents/guardians will be asked to preferably use the containers to collect stool samples.If this is not possible, soiled diapers should be individually placed in the ziplock bags andsealed.

Fresh stool samples are to be temporarily stored at a preferable fridge temperature (+2° Cto +8° C) until collection and transfer to laboratory (parents should be advised to keep thestool containers into the fridge envelopes containing the blue ice pack maintained at +2°C to +8° C). In case of non-availability of fridge storage, samples can be kept at ambienttemperature. Samples should first be transferred rapidly to the Investigators laboratory(within 0 � 3 days of collection). At the laboratory, stool samples should only be stored at+2° C to +8° C and should be processed within 24 hours.

2. Labelling

• The parents/guardians/study personnel should complete the label provided on thecontainer/ 8 ml tubes/ ziplock bag label with a black ink or ballpoint pen and return

1 The Biological Specimen Sample listing form and the Specimen Transfer Form are standard documents

used in GSK Biologicals� clinical trials. These documents are provided by GSK Biologicals� ClinicalTrials� monitor at study initiation.

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the collected stool samples to the study personnel. Subject number will be used forstool sample identification.

• If necessary, any hand-written additions to the labels by the study personnel shouldbe made using indelible ink.

3. Sorting and storage

• The stool 8 ml tubes should be stored at a temperature between -20°C and -70°Cuntil shipment to GSK Biologicals. Wherever possible, a backup facility for storageof stool samples should be available

• A standard Biological Specimen Sample listing form, specifying the samples beingshipped for individual subjects at each time point, should be prepared for eachshipment. A copy of this list should be retained at the study site, while the originalshould be sealed in a plastic envelope and shipped with the stool samples.

• Once flight details are known, a standard Specimen Transfer Form must becompleted and faxed to GSK Biologicals to the number provided below. A copy ofthe Specimen Transfer Form must be in the parcel.

GLAXOSMITHKLINE BIOLOGICALS

Biospecimen receptionClinical Immunology

R & D Department/Building 44Rue de l'Institut, 89

B-1330 Rixensart � BelgiumTelephone:

Fax:

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Appendix E Shipment of Biological Samples

Instructions for Shipment of Serum and Stool Samples

Serum samples should be sent to GSK Biologicals at regular intervals. The frequency ofshipment of samples should be decided upon by the Site Monitor, Central StudyCoordinator and the investigator prior to the study start.

Serum samples should always be sent by air, preferably on a Monday, Tuesday orWednesday, unless otherwise requested by the sponsor.

Serum samples must be placed with dry ice (maximum -20°C) in a container complyingwith International Air Transport Association (IATA) requirements. The completedstandard Biological Specimen Sample listing form should always accompany theshipment.

The container must be clearly identified with the labels provided by GSK Biologicalsspecifying the shipment address and the storage temperature (-20°C).

The airway bill should contain the instruction for storage of samples at maximum -20°C.

A "proforma" invoice, stating a value for customs purposes only, should be prepared andattached to the container. This document should contain the instruction for storage ofsamples at maximum -20°C.

Details of the shipment, including: * number of samples* airway bill* flight number* flight departure and arrival times

should be sent by fax or by e-mail, two days before shipment, to:

GLAXOSMITHKLINE BIOLOGICALSAttention Biospecimen Reception

Clinical ImmunologyR & D Department/Building 44

Rue de l'Institut, 89B-1330 Rixensart � Belgium

Telephone: or or or

Fax:E-mail:

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Appendix F Laboratory Assays

Description of Clinical Immunological Assays

Measurement of IgA Antibodies by ELISA

This assay allows the detection of rotavirus IgA in human serum and was initiallydesigned by (1, 2) and has been adapted by GSK Biologicals. It will be used formeasuring the immune response after vaccination and/or infection. Samples will beanalyzed at GSK Biologicals, Rixensart, Belgium (or designated laboratory).

Description of the ELISA Assay

96-well plates are coated by overnight incubation with anti-rotavirus antibody dilutions.The wells are washed and a lysate of cells either infected with vaccine strain (positivewells) or either uninfected (negative wells) is added. Following incubation on a rotatingplatform, the plates are washed and the dilutions of serum samples or standard serum areincubated in both kinds of wells (positive and negative). The use of negative wellsallows the assessment of non-specific IgA binding.

The plates are washed and bound human IgA is detected by addition of biotinylatedrabbit anti-human IgA (30 minutes under agitation). After washing the plates, peroxidase-conjugated avidin-biotin at an optimal concentration is added to each well and incubated(30 minutes, RT under agitation). Plates are again washed and orthophenylenediamine(OPD) is added. The plates are then incubated (30 minutes, room temperature (RT) indarkness) before the reaction is stopped with 2N H2SO4.

Optical absorption is measured at 490/620 nm. Specific optical densities are calculatedfor each sample / standard by measuring the difference between positive and negativewells. Concentrations of the samples are determined by using the four-parameter logisticfunction generated by the standard curve. The most accurate part of the standard curve(working range) for the calculation of the results is determined. Antibody concentrationsin units per millilitre (U/mL) are calculated relative to the standard (concentration =1000U/mL) by averaging the values for each unknown that fall within the working rangeof the standard curve and then corrected for the dilution factor. Each experiment includesnegative and positive controls.

For all reagents optimal concentration are pre-determined.

References

1. Bernstein DI, Smith VE, Sherwood JR et al. Safety and immunogenicity of a liveattenuated human rotavirus 89-12 vaccine. Vaccine 1998;16:381-7.

2. Bernstein DI, Sack DA, Rothstein E, Reisinger K et al. Efficacy of live attenuatedhuman rotavirus vaccine 89-12 in infants: a randomised placebo-controlled trial. Lancet1999;354:287-90.

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Stool assays

1. Antigen Detection in Stool Samples

Rotavirus antigen in stool samples collected during gastroenteritis episodes will bedetected by ELISA at Central Lab (GSK or designated laboratory).

2. RV strain typing

Targeted RV gene will be amplified by Reverse Transcriptase Polymerase Reactions(RT-PCR) to generate RV cDNA fragments. The genotype will be confirmed byhybridization using serotype-specific DNA probes and/or by direct sequencing of theamplified RV cDNA product.

This serotyping analysis can be completed with the determination of the P-serotypewhich is related to the VP4 gene. In that case, the typing approaches will be based on themethods such as described for the G typing.

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Appendix G Vaccine supplies, packaging and accountability

1. Vaccine and/or other suppliesGSK Biologicals will supply the following study vaccines, sufficient number of doses toadminister to all subjects as described in the present protocol.

• GSK Biologicals’ HRV lyophilised vaccine in monodose vials.GSK Biologicals’calcium carbonate buffer in a pre-filled syringe.GSK Biologicals’ HRV liquidvaccine in pre-filled syringes.GSK Biologicals will also provide sufficient number of

Infanrix hexa doses to administer to all subjects as described in the present protocol.

At least an additional 5% of their respective amounts will be supplied for replacement incase of breakage, bad storage conditions or any other reason that would make the vaccineunusable (i.e. given by mistake to another subject).

All monodose vials/pre-filled syringes must be accounted for on the form provided.

Labels for sample identification:The investigator will receive labels from GSK Biologicals to identify samples taken fromeach subject at each timepoint. Each label will contain the following information: studynumber, identification number for the subject , sampling timepoint

, and timing .

Other supplies provided by GSK Biologicals:In addition to the vaccines, the study documentation and the sample labels, theinvestigator will receive the following supplies:• materials for collection of stool samples,

• tubes with screw caps for serum samples,

• racks and cardboard boxes for the tubes of serum.The investigator or pharmacist must sign a statement that he/she has received the clinicalsupplies for the study.

It is NOT permitted to use any of the supplies provided by GSK Biologicals for purposesother than those specified in the protocol.

2. Vaccine packagingThe vaccines will be packed in labelled boxes. The box label will contain, as a minimum,the following information: study number, treatment number, lot number (or numbers,when double-blind), instructions for vaccine administration and any other relevantregulatory requirements.

3. Vaccine shipment from GSK Biologicals Rixensart to local country medicaldepartment, dispatching centre or investigational site from local countrymedical department to investigational site

On arrival of vaccine shipment, the cold-chain monitoring device should be removedfrom the vaccine boxes and checked. The temperature recording chart (chart from Ryan

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EZT or print-out data of the electronic device) should be obtained from the temperaturerecording device.

The following documents should be completed and returned to GSK Biologicals onreception of vaccine shipment:

Notification of vaccine delivery/temperature controlTemperature recording (chart).

These documents should then be returned to:

Attention of Clinical Trials Supply UnitClinical Operations LogisticsGSK Biologicals RixensartFax: E-mail:

In case of any temperature deviation, the official written approval for the use of vaccinemust be obtained from GSK.

4. Vaccine accountabilityAt all times the figures on supplied, used and remaining vaccine doses should match. Atthe end of the study, it must be possible to reconcile delivery records with those of usedand unused stocks. An explanation must be given of any discrepancies.

After approval from GSK Biologicals and in accordance with GSK SOP WWD-1102,used and unused vaccine vials/syringes should be destroyed at the study site using locallyapproved biosafety procedures and documentation unless otherwise described in theprotocol. If no adequate biosafety procedures are available at the study site, the used andunused vaccine vials/syringes are to be returned to an appropriate GSK Biologicals sitefor destruction, also in accordance with current GSK SOP WWD-1102.

5. Transfers of clinical vaccines or products from country medical departmentor dispatch centre to study sites or between sites

Storage temperatures must be maintained during transport and deviations must bereported to GSK for guidance. All transfers of clinical vaccines or products must bedocumented using the Clinical Supply Transfer Form.

All packaging and shipment procedures for transfer of clinical vaccines or products mustfollow procedures approved by the sponsor.

Clinical vaccines or products should always be sent by contract courier designated by thesponsor, unless otherwise requested by the sponsor.

Appendix H Amendments and Administrative Changes to theProtocol

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GlaxoSmithKline BiologicalsClinical Research & DevelopmentProtocol Amendment Approval


107876 (rota-061)


Date of approval 05 July 2006 – Final Protocol

Date of approval forsubstantial amendment1

06 October 2006

Detailed Title


A phase III, randomised study to evaluate the clinicalconsistency in terms of immunogenicity and reactogenicityof three production lots of the liquid formulation ofGlaxoSmithKline (GSK) Biologicals’ oral live attenuatedhuman rotavirus (HRV) vaccine and to evaluate the liquidformulation as compared to the lyophilised formulation ofthe HRV vaccine in terms of immunogenicity, reactogenicityand safety when administered as a two-dose primaryvaccination in healthy infants previously uninfected withHRV.

Co-ordinating author: Scientific Writer

Rationale/background for changes: This amendment was done to implement specificchanges requested by the investigator, to align the exclusion criteria with the currentapproved version of the SPC and to implement changes to the GSK Biologicals’standard protocol template.

Amended text has been indicated in bold italics in the following sections:

Cover page

Study vaccine number 444563 (lyophilised formulation of the HRV vaccine) andGSK357941A (liquid formulation of the HRV vaccine)


Detailed Title

Title A study in infants to test two preparations (freeze-dried orliquid) of the rotavirus vaccine (HRV vaccine).

Throughout the protocol

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Detailed Title



Synopsis (study design) and Section 3

• Vaccination schedule: Two-dose immunisation at 3 and 4 months of age in healthyinfants aged between 11 10 and 17 weeks (70 - 125 days) at the time of the first doseand previously uninfected with HRV.

Section 3 Ra ndo mizatio n

(1 :1 :1 :1)







Fo llow -up v is it

Extended sa fe ty contac t† Safe ty follow -up conc lus io n



Section 4.2

• A male or female between, and including, 11 10-17 weeks (70 - 125 days) of age atthe time of the first vaccination.

Section 4.3

• History of any neurologic disorders or seizures.

Section 4.4

• Chronic administration (defined as more than 14 days) of immunosuppressantsduring the study period. (Inhaled and topical steroids are allowed.)

Section 5.5


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Age 1110-17 weeks(70 - 125 days)

Section 5.6.1

Visit 1 (Day 0): Dose 1 of the study vaccine (at 11 10 - 17 weeks or 70 -125 days of age)

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107876 (rota-061)




06 October 2006

Detailed Title


A phase III, randomised study to evaluate the clinicalconsistency in terms of immunogenicity and reactogenicityof three production lots of the liquid formulation ofGlaxoSmithKline (GSK) Biologicals’ oral live attenuatedhuman rotavirus (HRV) vaccine and to evaluate the liquidformulation as compared to the lyophilised formulation ofthe HRV vaccine in terms of immunogenicity,reactogenicity and safety when administered as a two-doseprimary vaccination in healthy infants previouslyuninfected with HRV.

Approved by:Director

dd-mm-yyyy

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107876 (rota-061)




06 October 2006

Detailed Title


A phase III, randomised study to evaluate the clinicalconsistency in terms of immunogenicity and reactogenicityof three production lots of the liquid formulation ofGlaxoSmithKline (GSK) Biologicals’ oral live attenuatedhuman rotavirus (HRV) vaccine and to evaluate the liquidformulation as compared to the lyophilised formulation ofthe HRV vaccine in terms of immunogenicity,reactogenicity and safety when administered as a two-doseprimary vaccination in healthy infants previouslyuninfected with HRV.

Agreed by:Investigator:

Investigator signature:

Date:

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Final: 20 Mar 2008 9522c706dcefcccf0626d23382919e3345

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107876 (rota-061)




06 October 2006

Detailed Title


A phase III, randomised study to evaluate the clinicalconsistency in terms of immunogenicity and reactogenicityof three production lots of the liquid formulation ofGlaxoSmithKline (GSK) Biologicals’ oral live attenuatedhuman rotavirus (HRV) vaccine and to evaluate the liquidformulation as compared to the lyophilised formulation ofthe HRV vaccine in terms of immunogenicity, reactogenicityand safety when administered as a two-dose primaryvaccination in healthy infants previously uninfected withHRV.

Co-ordinating author: Scientific Writer

Rationale/background for changes: This amendment was done to implement specificchanges requested by the investigator, to align the exclusion criteria with the currentapproved version of the SPC and to implement changes to the GSK Biologicals’standard protocol template.

Amended text has been indicated in bold italics in the following sections:

Cover page

Study vaccine number 444563 (lyophilised formulation of the HRV vaccine) andGSK357941A (liquid formulation of the HRV vaccine)


Detailed Title

Title A study in infants to test two preparations (freeze-dried orliquid) of the rotavirus vaccine (HRV vaccine).

Throughout the protocol

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Detailed Title



Synopsis (study design) and Section 3

• Vaccination schedule: Two-dose immunisation at 3 and 4 months of age in healthyinfants aged between 11 10 and 17 weeks (70 - 125 days) at the time of the first doseand previously uninfected with HRV.

Section 3 Ra ndo mizatio n

(1 :1 :1 :1)







Fo llow -up v is it

Extended sa fe ty contac t† Safe ty follow -up conc lus io n



Section 4.2

• A male or female between, and including, 11 10-17 weeks (70 - 125 days) of age atthe time of the first vaccination.

Section 4.3

• History of any neurologic disorders or seizures.

Section 4.4

• Chronic administration (defined as more than 14 days) of immunosuppressantsduring the study period. (Inhaled and topical steroids are allowed.)

Section 5.5


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Age 1110-17 weeks(70 - 125 days)

Section 5.6.1

Visit 1 (Day 0): Dose 1 of the study vaccine (at 11 10 - 17 weeks or 70 -125 days of age)

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Sample Case Report Form

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Final: 20 Mar 2008 1ad9377725abd3f8405e62a2e160ec6c6

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Final: 20 Mar 2008 2241bb476cd975045b78ff3e932e384ca83

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Confidential - CRF version 12.2 - December 6, 2006

GlaxoSmithKline Biologicals Rue de l’Institut 89, B – 1330 Rixensart, Belgium Tel: Fax

Centre number Subject number

|__|__|__|__|__|__| |__|__|__|__|__|__| Treatment number

|__|__|__|__|__|

Protocol 107876 (Rota-061)

WORKBOOK 1

A phase III, randomised study to evaluate the clinical consistency in terms of immunogenicity and reactogenicity of three production lots of the liquid formulation of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus (HRV) vaccine and to evaluate the liquid formulation as compared to the lyophilised formulation of the HRV vaccine in terms of immunogenicity, reactogenicity and safety when administered as a two-dose primary vaccination in healthy infants previously uninfected with HRV.

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Final: 20 Mar 2008 251104b8ed8cf9543673de4d253aaa340

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GENERAL INSTRUCTIONS

ABBREVIATIONS: Abbreviations for medical conditions, clinical events or drug names should not be used. Units and route of administration of medication may be abbreviated. NA: not applicable.

DATES

Use the following three-letter abbreviations for each month:

January = JAN February = FEB March = MAR April = APR May = MAY June = JUN July = JUL August = AUG September = SEP October = OCT November = NOV December = DEC Example: |__|__| |__|__|__| |__|__|__|__|= 1st January 2005

day month year

The Medication, the Concomitant Vaccination and the Non-Serious Adverse Events sections as well as possible Serious Adverse Event section(s) must be checked for final assessment at the end of the study. For all subjects enrolled, please complete the Study Conclusion form.

0 1 J A N 2 0 0 5

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ADVERSE EVENT DEFINITIONS

INTENSITY FOR SOLICITED SYMPTOMS

Cough/runny nose 0: Normal 1: Cough/runny nose which is easily tolerated 2: Cough/runny nose which interferes with daily activity 3: Cough/runny nose which prevents daily activity

Irritability/Fussiness 0: Behavior as usual 1: Crying more than usual / no effect on normal activity 2: Crying more than usual / interferes with normal activity 3: Crying that cannot be comforted / prevents normal activity

Loss of appetite 0: Appetite as usual 1: Eating less than usual / no effect on normal activity 2: Eating less than usual / interferes with normal activity 3: Not eating at all

Vomiting

One or more episodes of forceful emptying of partially digested stomach contents � 1 hour after feeding within a day.

Diarrhea A passage of three or more looser than normal stools within a day.

GASTROENTERITIS EPISODES Diarrhea with or without vomiting.

INTENSITY FOR NON-SOLICITED SYMPTOMS 1: Mild: An adverse event which is easily tolerated by the subject, causing minimal discomfort and not

interfering with everyday activities. 2: Moderate: An adverse event which is sufficiently discomforting to interfere with normal everyday

activities. 3: Severe: An adverse event which prevents normal, everyday activities

(In a young child, such an adverse event would, for example, prevent attendance at school/kindergarten/a day-care center and would cause the parents/guardians to seek medical advice).

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CAUSALITY / RELATIONSHIP TO INVESTIGATIONAL PRODUCTS Is there a reasonable possibility that the AE may have been caused by the investigational product? NO: The adverse event is not causally related to administration of the study vaccine(s) / placebo. There are other, more likely causes and administration of the study vaccine(s) / placebo is not suspected to have contributed to the adverse event. YES: There is a reasonable possibility that the vaccine / placebo contributed to the adverse event.

OUTCOME 1: Recovered / Resolved 2: Recovering / Resolving: Subject is recovering at the time she/he completes the study or at the time

she/he withdraws from study. 3: Not recovered / Not resolved: AE is ongoing at the time the subject completes the study or becomes lost

to follow-up; in case of death AEs that are not the cause of death. 4: Recovered with sequelae / Resolved with sequelae 5: Fatal: AE is the cause of death (only applicable for SAE section)

SERIOUS ADVERSE EVENT A serious adverse event is any untoward medical occurrence that: • results in death • is life threatening • results in persistent or significant disability / incapacity • requires in-patient hospitalization • prolongation of existing hospitalization • is a congenital anomaly / birth defect in the offspring of a study subject • In addition, important medical events that may jeopardize the subject or may require intervention to

prevent one of the other outcomes listed above should be considered serious. (Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)

For each serious adverse event the investigator becomes aware of, please complete and submit the Serious Adverse Event (SAE) section within 24 hours.

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107876 (Rota-061)

FLOW SHEET

Age 10 - 17 weeks (70 - 125 days)


Visit VISIT 1 VISIT 2 VISIT 3 CONTACT Timing Day 0 Month 1 Month 2 Month 7

Sampling time point Pre Post-vacc 2 Informed consent • Check inclusion criteria • Check exclusion criteria • Check elimination criteria • • Check contraindications • • Medical history • Physical examination • •‡ •‡ Pre-vaccination body temperature • • Measure/record height and weight • Randomisation • Blood sampling: for antibody determination (2.0 ml) • • Study vaccination • • Routine vaccination (Infanrix hexa)† • • • Recording of oral vaccine intake characteristics (tick box*)

• •

Daily post-vaccination recording of solicited symptoms (Days 0–7 after each HRV vaccine dose) by subjects’ parents/guardians

• •

Recording of non-serious adverse events within 31 days post-vaccination, by investigator

• • •

Recording of GE • • • Collection of stool samples if the child develops GE

• • •

Return of diary cards • • Diary card transcription • • Record any concomitant medication/vaccination§

• • • •

Reporting of Serious Adverse Events • • • • Study Conclusion • Contact for safety follow-up • Safety follow-up conclusion • Note: The triple-line border following Month 2 indicates the final analysis of immunogenicity, reactogenicity, unsolicited AEs and SAEs up to Visit 3 to be performed on all data up to Visit 3, as soon as all the data are available and cleaned. The safety results after Visit 3 up to the safety contact will be reported in an annex report. • is used to indicate a study procedure that requires documentation in the individual eCRF ‡ Physical examination at this visit can take place in case of request from the nurse or parents/guardians, and can be limited appropriate with local requirements for routine physical examination for a child at this age and appropriate for intervention that is to follow (blood draw etc.) †During the study, routine childhood vaccines (Infanrix hexa) will be administered at 3, 4, 5 months of age. The first two doses of Infanrix hexa will be coadministered with each dose of HRV vaccine. All routine vaccinations administered from birth up to Visit 3 should be recorded in the eCRF. Subjects will receive a booster dose of Infanrix hexa according to the approved prescribing information outside the scope of this study. *: See tick box in eCRF: smooth vaccine intake, vaccine intake interrupted due to coughing or choking, regurgitation after vaccine intake, vomiting after vaccine intake. §Recording of medications/vaccinations at each visit/contact will be according to the protocol.

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107876 (Rota-061)

FLOW SHEET

It is the investigator’s responsibility to ensure that the intervals between visits/contacts are strictly followed. These intervals determine each subject’s evaluability in the according-to-protocol analyses.

Intervals between study visits

Interval Length of interval 1 (Visit 1→ Visit 2) 30 – 48 days 2 (Visit 2→ Visit 3) 30 - 48 days

Contact‡ 168-202 days after the last dose of HRV vaccine

‡A safety follow-up contact (by telephone call or any other convenient procedure) to collect information on SAEs since the last visit

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VISIT 1

DAY 0

DOSE 1

Informed Consent has to be obtained prior to any study procedure

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107876 (Rota-061)

ELIMINATION CRITERIA DURING THE STUDY The following criteria should be checked at each visit subsequent to the first visit. If any become applicable during the study, it will not require withdrawal of the subject from the study but may determine a subject’s evaluability in the ATP analysis.

[ A ] Use of any investigational or non-registered product (drug or vaccine) other than the investigational vaccine (HRV vaccine) during the study period.

[ B ] Chronic administration (defined as more than 14 days) of immunosuppressants during the study period. (Inhaled and topical steroids are allowed.)

[ C ] Administration of a vaccine not foreseen by the study protocol during the study period.

[ D ] Administration of immunoglobulins and/or any blood products during the study period.

[ E ] Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination (no laboratory testing is required).

CONTRAINDICATIONS TO SUBSEQUENT VACCINATION The following AEs constitute absolute contraindications to further administration of the HRV vaccine; if any of these AEs occur during the study, the subject must not receive additional doses of vaccine but may continue other study procedures at the discretion of the investigator. The subject must be followed until resolution of the event, as with any AE:

[ A ] Known hypersensitivity after previous administration of HRV vaccine or to any component of the vaccine.

[ B ] Uncorrected congenital malformation (such as Meckel’s diverticulum) of the gastrointestinal tract that would predispose for IS.

The following AEs constitute precautions to administration of the HRV vaccine at that point in time; if any one of these AEs occurs at the time scheduled for vaccination, the subject may be vaccinated at a later date, within the time window specified in the protocol, or withdrawn at the discretion of the investigator. The subject must be followed until resolution of the event, as with any AE.

[ C ] Acute severe febrile illness.

[ D ] Diarrhoea or vomiting.

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107876 (Rota-061)Protocol Visit Date of visit Subject Number

107876 1 VISIT 1 |__|__| |__|__|__| |__|__|__|__| day month year

|__|__|__|__|__|__|

INFORMED CONSENT I certify that Informed Consent has been obtained prior to any study procedure.

Informed Consent Date: |__|__| |__|__|__| |__|__|__|__| day month year

DEMOGRAPHICS

Center number: |__|__|__|__|__|__| Date of Birth: |__|__| |__|__|__| |__|__|__|__| day month year Gender: [M] Male

[F] Female Ethnicity: [1] American Hispanic or Latino

[2] Not American Hispanic or Latino Race: [1] African Heritage / African American

[2] American Indian or Alaskan Native

[3] Asian - Central/South Asian Heritage

[4] Asian - East Asian Heritage

[5] Asian - Japanese Heritage

[6] Asian - South East Asian Heritage

[7] Native Hawaiian or Other Pacific Islander

[8] White - Arabic / North African Heritage

[9] White - Caucasian / European Heritage

[99] Other, specify: ________________________

Height:� |__|__|__| cm

Weight: |__|__|__| . |__| kg

1.

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107876 (Rota-061) Protocol Visit Subject Number

107876 1

VISIT 1 |__|__|__|__|__|__|

ELIGIBILITY CHECK

Did the subject meet all the entry criteria?

Yes No � If No, tick (�) all boxes corresponding to violations of any inclusion/exclusion criteria.

Do not enter the subject into the study if he/she failed any inclusion or exclusion criteria below.

INCLUSION CRITERIA

Tick (�) the boxes corresponding to any of the inclusion criteria the subject failed

[ 1 ] � Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits) should be enrolled in the study.

[ 2 ] � A male or female between, and including, 10 – 17 weeks (70 - 125 days) of age at the time of the first vaccination.

[ 3 ] � Written informed consent obtained from the parent or guardian of the subject.

[ 4 ] � Healthy subjects as established by medical history and clinical examination before entering into the study.

[ 5 ] � Birth weight >2000g

EXCLUSION CRITERIA Tick (�) the box corresponding to any of the exclusion criteria that disqualified the subject from entry.

[ 6 ] � Use of any investigational or non-registered product (drug or vaccine) within 30 days preceding the first dose of any of the study vaccines, or planned use during the study period.

[ 7 ] � Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose. (For corticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topical steroids are allowed.).

[ 8 ] � Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days of the first dose of vaccine.

[ 9 ] � Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).

2

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107876 1

VISIT 1 |__|__|__|__|__|__|

ELIGIBILITY CHECK (continued)

EXCLUSION CRITERIA Tick (�) the box corresponding to any of the exclusion criteria that disqualified the subject from entry.

[ 10 ] � Previous vaccination against RV.

[ 11 ] � Previous vaccination against diphtheria, tetanus, pertussis, polio or Hib.

[ 12 ] � Previous confirmed occurrence of RV GE.

[ 13 ] � History of diphtheria, tetanus, pertussis, hepatitis B, polio and/ or Hib disease.

[ 14 ] � Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).

[ 15 ] � A family history of congenital or hereditary immunodeficiency.

[ 16 ] � History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s).

[ 17 ] � Major congenital defects or serious chronic illness.

[ 18 ] � Uncorrected congenital malformation (such as Meckel’s diverticulum) of the gastrointestinal tract that would predispose for IS.

[ 19 ] � Not applicable.

[ 20 ] � Acute disease at time of enrolment. (Acute disease is defined as the presence of moderate or severe illness with or without fever i.e. temperature ≥ 37.5°C as measured by an axillary thermometer or ≥ 38.0°C as measured by a rectal thermometer). Temperature greater than or equal to these cut-offs warrants deferral of the vaccination pending recovery of the subject.

[ 21 ] � GE within 7 days preceding the study vaccine administration (warrants deferral of the vaccination).

[ 22 ] � Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period.

RANDOMISATION / TREATMENT ALLOCATION Record treatment number: |__|__|__|__|__|

3.

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107876 1 VISIT 1 |__|__|__|__|__|__|

GENERAL MEDICAL HISTORY / PHYSICAL EXAMINATION

Are you aware of any pre-existing conditions, signs or symptoms present prior to the start of the study?

No Yes � Please give diagnosis and tick (�) appropriate Past/Current box(es).

MedDRA System Organ Class DIAGNOSIS PAST CURRENT

[1] Skin and subcutaneous tissue _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[2] Musculoskeletal and connective tissue

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[3] Cardiac _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[4] Vascular _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[5] Respiratory, thoracic and mediastinal

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[6] Gastrointestinal _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[7] Hepatobiliary _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[8] Renal and urinary _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[9] Nervous system _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[10] Eye _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[11] Ear and labyrinth _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[12] Endocrine _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[13] Metabolism and nutrition _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[14] Blood and lymphatic system _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[15] Immune system (incl allergies, autoimmune disorders)

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[16] Infections and infestations _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [17] Neoplasms benign, malignant

and unspecified (incl cysts, polyps) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[18] Surgical and medical procedures

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

[99] Other _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Please report medication(s) as specified in the protocol and fill in the Medication section. 4.

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107876 1 VISIT 1 |__|__|__|__|__|__|

LABORATORY TESTS

BLOOD SAMPLE (2 ml)

Has a blood sample been taken ?

Yes � Date if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year

No

5.

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107876 1 VISIT 1 DOSE 1 |__|__|__|__|__|__|

VACCINE ADMINISTRATION Date (fill in only if different from visit date): |__|__| |__|__|__| |__|__|__|__| day month year

Pre-Vaccination temperature: |__|__|. |__|°C � Route: [A] Axillary [O] Oral [R] Rectal [X] Tympanic (oral conversion) [Y] Tympanic (rectal conversion)

VACCINE ADMINISTRATION (only one box must be ticked by vaccine)

Route

[S] HRV Vaccine (liquid or lyophilized formulation) [R] Replacement vial �|__|__|__|__|__|

[W] Wrong vial number �|__|__|__|__|__|

[N] Not administered � Please complete below (*)

Oral

Oral vaccine intake characteristics (tick only one box):

Smooth vaccine intake Vaccine intake interrupted due to coughing or choking

Regurgitation after vaccine intake(**) Vomiting after vaccine intake(**)

(**) If regurgigation or vomiting occurs after vaccination, do not give another dose at this visit

(*) Why not administered?

� Please tick the major reason for non administration

[SAE] Serious adverse event: � Please complete and submit SAE section

� Please specify SAE No. |__|__|

[AEX] Non-Serious adverse event: � Please complete Non-serious Adverse Event section

� Please specify AE No. |__|__|

[OTH] Other, please specify: ________________________________________________________ (e.g.: consent withdrawal, Protocol violation, …)

� Please tick who made the decision: � [I] � Investigator [P] � Parents/Guardians 6.

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107876 1

VISIT 1

|__|__|__|__|__|__|

VACCINE ADMINISTRATION (continued)

IMMEDIATE POST-VACCINATION OBSERVATION If any adverse events occurred during the immediate post-vaccination time (30 minutes) please fill in the Solicited Adverse Events section, the Non-Serious Adverse Event section or a Serious Adverse Event section. If any prophylactic medication has been administered in anticipation of study vaccine reaction, please complete the Medication section and tick prophylactic box.

PROTOCOL REQUIRED CONCOMITANT VACCINATION Has the following protocol required concomitant vaccine been administered ?

Infanrix Hexa vaccine

Yes � Please complete only if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year

No

If Yes is ticked, the above vaccines are not to be reported again in the Concomitant Vaccination section at the end of the CRF.

Any other vaccines administered during the study period are to be recorded in the Concomitant Vaccination section at the end of the CRF

7.

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107876 1 VISIT 1 |__|__|__|__|__|__|

SOLICITED ADVERSE EVENTS - GENERAL SYMPTOMS Has the subject experienced any of the following signs/symptoms during the solicited period? [U] Information not available [NA] No Vaccine administered [N] No [Y] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

GENERAL SYMPTOMS

Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Ongoing

after day 7?

Date of last day of symptoms

day month year

Causa-lity?

Medically attended visit

Fever [FE] � No � Yes � ° C:

[A] � Axillary [O] � Oral [[R] � Rectal [X] � Tympanic

oral [Y] � Tympanic

rectal

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

� No � Yes�

|__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Cough/runny nose [CO] � No � Yes � intensity: |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Irritability/ Fussiness [ I R ] � No � Yes � intensity: |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Loss of appetite [ L O ] � No � Yes � intensity: |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Vomiting [ V O ] � No � Yes � number: |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Diarrhea [DA] (*) � No � Yes � Number of looser than normal stools: |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

(*) Stool sample should be collected in case of diarrhea. Please report the stool collection date in the gastroenteritis stools collection section.

Intensity: 0 / 1 / 2 / 3 (see Adverse Events definitions)

Fever: Axillary > 37.5°C Oral > 37.5°C Rectal > 38° C Tympanic (oral conversion) > 37.5°C Tympanic (rectal conversion) > 38° C

Medically attended visit: HO: Hospitalization ER: Emergency Room MD: Medical Personnel (see protocol for full definition)

If any of these adverse events meets the protocol definition of serious, please complete a Serious Adverse Event section and fax to GSK Biologicals Study Contact for SAE reporting within 24 hours.

8.

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107876 1 VISIT 1 |__|__|__|__|__|__|

UNSOLICITED ADVERSE EVENTS Has the subject experienced any serious or non-serious unsolicited adverse events within one month (minimum 30 days) post-vaccination?

[ U ] Information not available

[ N A ] No vaccine administered

[ N ] No

[ Y ] Yes � Fill in the Non-Serious Adverse Event section or Serious Adverse Event section as necessary.

9.

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VISIT 2

MONTH 1

30 - 48 days after visit 1

DOSE 2

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REMINDERS

ELIMINATION CRITERIA

Please check all appropriate criteria before continuing the visit.

ADVERSE EVENTS

Please report adverse events as specified in the Protocol and fill in the Non-Serious Adverse Events section or complete and submit the Serious Adverse Event (SAE) section within 24 hours from the time you become aware of the SAE.

MEDICATION / CONCOMITANT VACCINATION

Please report medication as specified in the Protocol and fill in the Medication section. Please report concomitant vaccination in the Concomitant Vaccination section.

CONTRAINDICATIONS

Before any vaccine administration, please review the Contraindications as specified in the Protocol.

STOOLS COLLECTION

Please fill the gastroenteritis stools collection section if any stools have been collected in case of diarrhea (defined as three or more looser than normal stools within a day.)

PHYSICAL EXAMINATION

Physical examination at this visit can take place in case of request from the nurse or parents/guardians, and can be limited appropriate with local requirements for routine physical examination for a child at this age and appropriate for intervention that is to follow (blood draw etc).

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107876 1 VISIT 2 |__|__|__|__|__|__|

CHECK FOR STUDY CONTINUATION Did the subject return for visit 2?

Yes � Please complete the next pages

No � Please tick the ONE most appropriate reason and skip the following pages of this visit.

[SAE] Serious adverse event � Please complete and submit SAE section


[AEX] Non-Serious adverse event � Please complete Non-serious Adverse Event section

� Please specify AE No. |__|__| or solicited AE code |__|__|

[OTH] Other, please specify: _______________________________________ (e.g.: consent withdrawal, Protocol violation, …)

� Please tick who made the decision: [I] � Investigator [P] � Parents/Guardians

10.

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107876 (Rota-061) Protocol Visit Date of visit Subject Number

107876 1 VISIT 2

|__|__| |__|__|__| |__|__|__|__| day month year

|__|__|__|__|__|__|

GASTROENTERITIS EPISODES Did the subject present diarrhea (with or without vomiting) during the period starting 8 days after dose 1 until visit 2 ?

No

Yes, …If yes � please fill the Non serious Adverse Events section � please collect a stool sample as soon as possible after diarrhea begins and

preferably not later than 7 days after the start of the diarrhea and report the stool collection date in the Gastroenteritis stool collection section.

11.

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107876 1 VISIT 2 DOSE 2 |__|__|__|__|__|__|

VACCINE ADMINISTRATION Date (fill in only if different from visit date): |__|__| |__|__|__| |__|__|__|__| day month year

Pre-Vaccination temperature: |__|__|. |__|°C � Route: [A] Axillary [O] Oral [R] Rectal [X] Tympanic (oral conversion) [Y] Tympanic (rectal conversion)

VACCINE ADMINISTRATION (only one box must be ticked by vaccine)

Route

[S] HRV Vaccine (liquid or lyophilized formulation) [R] Replacement vial �|__|__|__|__|__|

[W] Wrong vial number �|__|__|__|__|__|

[N] Not administered � Please complete below (*)

Oral

Oral vaccine intake characteristics (tick only one box):

Smooth vaccine intake Vaccine intake interrupted due to coughing or choking

Regurgitation after vaccine intake(**) Vomiting after vaccine intake(**)

(**) If regurgigation or vomiting occurs after vaccination, do not give another dose at this visit

(*) Why not administered?

� Please tick the major reason for non administration

[SAE] Serious adverse event: � Please complete and submit SAE section


[AEX] Non-Serious adverse event: � Please complete Non-serious Adverse Event section


[OTH] Other, please specify: ________________________________________________________ (e.g.: consent withdrawal, Protocol violation, …)

� Please tick who made the decision: � [I] � Investigator [P] � Parents/Guardians 12.

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107876 1

VISIT 2

|__|__|__|__|__|__|

VACCINE ADMINISTRATION (continued)

IMMEDIATE POST-VACCINATION OBSERVATION If any adverse events occurred during the immediate post-vaccination time (30 minutes) please fill in the Solicited Adverse Events section, the Non-Serious Adverse Event section or a Serious Adverse Event section. If any prophylactic medication has been administered in anticipation of study vaccine reaction, please complete the Medication section and tick prophylactic box.

PROTOCOL REQUIRED CONCOMITANT VACCINATION Has the following protocol required concomitant vaccine been administered ?



No


Any other vaccines administered during the study period are to be recorded in the Concomitant Vaccination section at the end of the CRF.

13.

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107876 1 VISIT 2 |__|__|__|__|__|__|

SOLICITED ADVERSE EVENTS - GENERAL SYMPTOMS Has the subject experienced any of the following signs/symptoms during the solicited period? [U] Information not available [NA] No Vaccine administered [N] No [Y] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

GENERAL SYMPTOMS

Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Ongoing

after day 7?

Date of last day of symptoms

day month year

Causa-lity?

Medically attended visit

Fever [FE] � No � Yes � ° C:

[A] � Axillary [O] � Oral [[R] � Rectal [X] � Tympanic

oral [Y] � Tympanic

rectal

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

_ . _

� not

taken

� No � Yes�

|__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Cough/runny nose [CO] � No � Yes � intensity: |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Irritability/ Fussiness [ I R ] � No � Yes � intensity: |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Loss of appetite [ L O ] � No � Yes � intensity: |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Vomiting [ V O ] � No � Yes � number : |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

Diarrhea [DA] (*) � No � Yes � Number of looser than normal stools: |___| |___| |___| |___| |___| |___| |___| |___|

� No � Yes� |__|__| |__|__|__| |__|__|__|__|

� No � Yes

� No � Yes �

HO/ER/MD

|__|__|

(*) Stool sample should be collected in case of diarrhea. Please report the stool collection date in the gastroenteritis stools collection section.

Intensity: 0 / 1 / 2 / 3 (see Adverse Events definitions)

Fever: Axillary > 37.5°C Oral > 37.5°C Rectal > 38° C Tympanic (oral conversion) > 37.5°C Tympanic (rectal conversion) > 38° C

Medically attended visit: HO: Hospitalization ER: Emergency Room MD: Medical Personnel (see protocol for full definition)

If any of these adverse events meets the protocol definition of serious, please complete a Serious Adverse Event section and fax to GSK Biologicals Study Contact for SAE reporting within 24 hours.

14.

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107876 1 VISIT 2 |__|__|__|__|__|__|

UNSOLICITED ADVERSE EVENTS Has the subject experienced any serious or non-serious unsolicited adverse events within one month (minimum 30 days) post-vaccination?

[ U ] Information not available

[ N A ] No vaccine administered

[ N ] No

[ Y ] Yes � Fill in the Non-Serious Adverse Event section or Serious Adverse Event section as necessary.

15.

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VISIT 3

MONTH 2

30 – 48 days after visit 2

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REMINDERS


Please check all appropriate criteria before continuing the visit.

ADVERSE EVENTS

Please report adverse events as specified in the Protocol and fill in the Non-Serious Adverse Events section or complete and submit the Serious Adverse Event (SAE) section within 24 hours from the time you become aware of the SAE.

MEDICATION / CONCOMITANT VACCINATION

Please report medication as specified in the Protocol and fill in the Medication section. Please report concomitant vaccination in the Concomitant Vaccination section.

CONTRAINDICATIONS

Before any vaccine administration, please review the Contraindications as specified in the Protocol.

STOOLS COLLECTION

Please fill the gastroenteritis stools collection section if any stools have been collected in case of diarrhea (defined as three or more looser than normal stools within a day.)

PHYSICAL EXAMINATION

Physical examination at this visit can take place in case of request from the nurse or parents/guardians, and can be limited appropriate with local requirements for routine physical examination for a child at this age and appropriate for intervention that is to follow (blood draw etc).

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107876 (Rota-061) Protocol Book Visit Subject Number

107876 1 VISIT 3 |__|__|__|__|__|__|

CHECK FOR STUDY CONTINUATION Did the subject return for visit 3?

Yes � Please complete the next pages

No � Please complete below and skip the following pages of this visit.

Same reason and decision as previous visit.

OR

� Please tick the ONE most appropriate reason and skip the following pages of this visit.





[OTH] Other, please specify: _____________________________________ (e.g.: consent withdrawal, Protocol violation, …)

� Please tick who made the decision: [I] � Investigator [P] � Parents/Guardians

16.

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107876 (Rota-061) Protocol Book Visit Date of visit Subject Number

107876 1 VISIT 3 |__|__| |__|__|__| |__|__|__|__| day month year

|__|__|__|__|__|__|

LABORATORY TESTS

BLOOD SAMPLE (2 ml)

Has a blood sample been taken ?

Yes � Date if different from visit date: |__|__| |__|__|__| |__|__|__|__| day month year

No

GASTROENTERITIS EPISODES Did the subject present diarrhea (with or without vomiting) during the period starting 8 days after dose 2 until visit 3 ?

No

Yes, …If yes � please fill the Non serious Adverse Events section � please collect a stool sample as soon as possible after diarrhea begins and

preferably not later than 7 days after the start of the diarrhea and report the stool collection date in the Gastroenteritis stool collection section.

17.

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107876 1 VISIT 3 |__|__|__|__|__|__|

PROTOCOL REQUIRED VACCINATION Has the following protocol required vaccine been administered?



No


Any other vaccines administered during the study period are to be recorded in the Concomitant Vaccination section at the end of the CRF.

18.

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GASTROENTERITIS

STOOL

COLLECTION

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ludol

107876 (Rota-061) Protocol Subject Number

107876 1 |__|__|__|__|__|__|

ONLY record the stool samples collected in case of gastroenteritis.

STOOLS 1 STOOLS 2 STOOLS 3 Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

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GASTROENTERITIS STOOLS COLLECTION

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ludol


107876 1 |__|__|__|__|__|__|

ONLY record the stool samples collected in case of gastroenteritis.


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min


|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

Date:

|__|__| |__|__|__| |__|__|__|__| day month year

Time: |__|__|: |__|__|

hour min

20.

GASTROENTERITIS STOOLS COLLECTION (continued)

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NON-SERIOUS ADVERSE EVENTS

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107876 1 |__|__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS (Please report all serious adverse events only on the Serious Adverse Event (SAE) section).

Has any non-serious adverse events occurred within one month (minimum 30 days) post-vaccination, or has any diarrhea occurred from visit 1 to visit 3 excluding those recorded on the solicited adverse event page ?

No Yes, please complete the following table.

AE No. 1 2 Description:

_______________________

_______________________

_______________________

_______________________

_______________________

_______________________ For GSK

Date Started: |__|__| |__|__|__| |__|__|__|__| day month year

during immediate post-vaccination period (30 minutes)

|__|__| |__|__|__| |__|__|__|__| day month year


Date Stopped: |__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

Maximum Intensity: [1] Mild [2] Moderate [3] Severe

[1] Mild [2] Moderate [3] Severe

Relationship to investigational products: Is there a reasonable possibility that the AE may have been caused by the investigational product?

[N] No [Y] Yes

[N] No [Y] Yes

Outcome: [1] Recovered / resolved [2] Recovering / resolving [3] Not recovered / not

resolved [4] Recovered with sequelae /

resolved with sequelae

[1] Recovered / resolved [2] Recovering / resolving [3] Not recovered / not


resolved with sequelae Medically attended visit: (Refer to protocol for full definition.) If yes please specify type:

HO: Hospitalisation ER: Emergency Room MD: Medical Personnel

[N] No

[Y] Yes � type: |__|__|

[N] No

[Y] Yes � type: |__|__|

21.

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107876 1 |__|__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS (continued)

AE No. 3 4

Description:

_______________________

_______________________

_______________________

_______________________

_______________________

_______________________ For GSK

Date Started: |__|__| |__|__|__| |__|__|__|__| day month year


|__|__| |__|__|__| |__|__|__|__| day month year


Date Stopped: |__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

Maximum Intensity: [1] Mild [2] Moderate [3] Severe

[1] Mild [2] Moderate [3] Severe

Relationship to investigational products: Is there a reasonable possibility that the AE may have been caused by the investigational product?

[N] No [Y] Yes

[N] No [Y] Yes

Outcome: [1] Recovered / resolved [2] Recovering / resolving [3] Not recovered / not


resolved with sequelae

[1] Recovered / resolved [2] Recovering / resolving [3] Not recovered / not


resolved with sequelae Medically attended visit: (Refer to protocol for full definition.) If yes please specify type:

HO: Hospitalisation ER: Emergency Room MD: Medical Personnel

[N] No

[Y] Yes � type: |__|__|

[N] No

[Y] Yes � type: |__|__|

22.

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CONCOMITANT

VACCINATION

Any vaccine not foreseen in the study protocol administered since birth or at any time up to Visit 3 are to be recorded with trade name, route of administration and date(s) of administration. Any protocol required concomitant vaccination i.e. Infanrix hexa™ administered at visit 1, visit 2 and visit 3 are not to be reported again in the concomitant vaccination section.

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107876 1 |__|__|__|__|__|__|

CONCOMITANT VACCINATION Has any vaccine other than the study vaccine(s) been administered during the timeframe as specified in the Protocol (except Infanrix hexa™ given at visit 1, visit 2 and visit 3)?

No Yes, please record concomitant vaccination with trade name and / or generic name, route and

vaccine administration date.

Trade / (Generic) Name Route Administration date day month year

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

|__|__| |__|__|__| |__|__|__|__|

For GSK

ID = Intradermal PE = Parenteral IH = Inhalation PO = Oral IM = Intramuscular SC = Subcutaneous IV = Intravenous SL = Sublingual NA = Intranasal TD = Transdermal

OTH = Other UNK = Unknown 23.

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MEDICATION

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Medication route. Please use below defined codes.

CODE LABEL

EXT External ID Intradermal IH Inhalation IM Intramuscular IR Intraarticular IT Intrathecal IV Intravenous NA Intranasal OTH Other PE Parenteral PO Oral PR Rectal SC Subcutaneous SL Sublingual TD Transdermal TO Topical UNK Unknown VA Vaginal

All concomitant medication, with the exception of vitamins and/or dietary supplements, administered at ANY time during the period starting with administration of each dose of study vaccine and ending 30 days after each dose of study vaccine are to be recorded with generic name of the medication (trade names are allowed for combination drugs, i.e. multi-component drugs), medical indication, total daily dose, route of administration, start and end dates of treatment. Any treatments and/or medications specifically contraindicated, e.g., any immunoglobulins, other blood products and any immune modifying drugs administered since birth or at any time up to Visit 3 are to be recorded with generic name of the medication (trade names are allowed for combination drugs only), medical indication, total daily dose, route of administration, start and end dates of treatment. A prophylactic medication is a medication administered in the absence of ANY symptom and in anticipation of a reaction to the vaccination (e.g. an anti-pyretic is considered to be prophylactic when it is given in the absence of fever [rectal temperature < 38 °C] and any other symptom, to prevent fever from occurring). Any concomitant medication administered prophylactically in anticipation of reaction to the vaccination must be recorded in the eCRF with generic name of the medication (trade names are allowed for combination drugs only), total daily dose, route of administration, start and end dates of treatment and coded as ‘Prophylactic’. Concomitant medication administered for the treatment of an AE or SAE within the follow-up period for adverse events must be recorded in the eCRF with generic name of the medication (trade names are allowed for combination drugs only), medical indication (including which AE/SAE), total daily dose, route of administration, start and end dates of treatment. Similarly, concomitant medication administered for the treatment of a SAE, at any time, must be recorded on the on the SAE screens in the eCRF (or the SAE section Form if back-up reporting system is used). Any investigational medication or vaccine administered from Dose 1 of HRV vaccine up to the extended safety contact must be recorded in the eCRF.

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107876 1 |__|__|__|__|__|__|

MEDICATION Have any medications/treatments been administered during study period?

No Yes, please complete the following table.

Trade / Generic Name Medical Indication Total daily dose Route

Start and end date or tick box if continuing at end of study

day month year

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|

For GSK

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STUDY CONCLUSION

AT VISIT 3

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107876 1 |__|__|__|__|__|__|

SUBJECT STATUS AT VISIT 3 OCCURRENCE OF SERIOUS ADVERSE EVENT

Did the subject experience any Serious Adverse Event up to visit 3?

No Yes � Specify total number of SAE's: |__|__|

STATUS OF TREATMENT BLIND

Was the treatment blind broken up to visit 3?

No Yes � Complete date and tick one reason below.

|__|__| |__|__|__| |__|__|__|__| day month year

[1] Medical emergency requiring identification of investigational product for further treatments

[9] Other, specify: _________________________________

� Complete Non-Serious Adverse Event section or a Serious Adverse Event section as appropriate.


Did any elimination criteria become applicable up to visit 3 ?

No Yes � Specify: _________________________________

25.

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107876 (Rota-061) Protocol Book Subject Number

107876 1 |__|__|__|__|__|__|

SUBJECT STATUS AT VISIT 3 (continued) Is the subject withdrawn at visit 3? (A subject is withdrawn at visit 3 if he/she did not come for the visit 3.)

No

Yes � Major reason for withdrawal (tick one box only).





[PTV] Protocol violation, please specify: ______________________________________

[CWS] Consent withdrawal, not due to an adverse event.

[MIG] Migrated / moved from the study area

[LFU] Lost to follow-up.

[OTH] Other, please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

� Who made the decision: [I] � Investigator [P] � Parents/Guardians

� Date of last contact: |__|__| |__|__|__| |__|__|__|__| day month year

� Was the subject in good condition at date of last contact?

No � Please give details in Adverse Events section. Yes

INVESTIGATOR'S SIGNATURE

I confirm that I have reviewed the data in this Case Report Form for this subject. All information entered by myself or my colleagues is, to the best of my knowledge, complete and accurate, as of the date below.

Investigator's signature: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: |__|__| |__|__|__| |__|__|__|__|

Printed Investigator's name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

day month year

26.

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Confidential - CRF version 12.2 -August 29, 2006

GlaxoSmithKline Biologicals Rue de l’Institut 89, B – 1330 Rixensart, Belgium Tel Fax:

Centre number Subject number

|__|__|__|__|__|__| |__|__|__|__|__|__| Treatment number

|__|__|__|__|__|

Protocol 107876 (Rota-061)

Extended Safety Follow-up

WORKBOOK 2

A phase III, randomised study to evaluate the clinical consistency in terms of immunogenicity and reactogenicity of three production lots of the liquid formulation of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus (HRV) vaccine and to evaluate the liquid formulation as compared to the lyophilised formulation of the HRV vaccine in terms of immunogenicity, reactogenicity and safety when administered as a two-dose primary vaccination in healthy infants previously uninfected with HRV.

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Final: 20 Mar 2008 4602748834c7630b371e350e538b41d145

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GENERAL INSTRUCTIONS

ABBREVIATIONS: Abbreviations for medical conditions, clinical events or drug names should not be used. Units and route of administration of medication may be abbreviated. NA: not applicable.

DATES

Use the following three-letter abbreviations for each month:

January = JAN February = FEB March = MAR April = APR May = MAY June = JUN July = JUL August = AUG September = SEP October = OCT November = NOV December = DEC Example: |__|__| |__|__|__| |__|__|__|__|= 1st January 2005

day month year

0 1 J A N 2 0 0 5

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INTENSITY FOR NON-SOLICITED SYMPTOMS 1: Mild: An adverse event which is easily tolerated by the subject, causing minimal discomfort and not

interfering with everyday activities. 2: Moderate: An adverse event which is sufficiently discomforting to interfere with normal everyday

activities. 3: Severe: An adverse event which prevents normal, everyday activities

(In a young child, such an adverse event would, for example, prevent attendance at school/kindergarten/a day-care center and would cause the parents/guardians to seek medical advice).

CAUSALITY / RELATIONSHIP TO INVESTIGATIONAL PRODUCTS Is there a reasonable possibility that the AE may have been caused by the investigational product? NO: The adverse event is not causally related to administration of the study vaccine(s) / placebo. There are other, more likely causes and administration of the study vaccine(s) / placebo is not suspected to have contributed to the adverse event. YES: There is a reasonable possibility that the vaccine / placebo contributed to the adverse event.

OUTCOME 1: Recovered / Resolved 2: Recovering / Resolving: Subject is recovering at the time she/he completes the study or at the time

she/he withdraws from study. 3: Not recovered / Not resolved: AE is ongoing at the time the subject completes the study or becomes lost

to follow-up; in case of death AEs that are not the cause of death. 4: Recovered with sequelae / Resolved with sequelae 5: Fatal: AE is the cause of death (only applicable for SAE reports)

SERIOUS ADVERSE EVENT A serious adverse event is any untoward medical occurrence that: • results in death • is life threatening • results in persistent or significant disability / incapacity • requires in-patient hospitalization • prolongation of existing hospitalization • is a congenital anomaly / birth defect in the offspring of a study subject • In addition, important medical events that may jeopardize the subject or may require intervention to

prevent one of the other outcomes listed above should be considered serious. (Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)

For each serious adverse event the investigator becomes aware of, please fill in a Serious Adverse Event (SAE) report and fax it to GSK Biologicals Study Contact for SAE reporting within 24 hours.

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107876 (Rota-061)

FLOW SHEET

Age 11-17 weeks 4 months 5 months 10 months Visit VISIT 1 VISIT 2 VISIT 3 CONTACT

Timing Day 0 Month 1 Month 2 Month 7 Sampling time point Pre Post-vacc 2

Informed consent • Check inclusion criteria • Check exclusion criteria • Check elimination criteria • • Check contraindications • • Medical history • Physical examination • •‡ •‡ Pre-vaccination body temperature • • Measure/record height and weight • Randomisation • Blood sampling: for antibody determination (2.0 ml) • • Study vaccination • • Routine vaccination (Infanrix hexa)† • • • Recording of oral vaccine intake characteristics (tick box*)

• •


• •


• • •

Recording of GE • • • Collection of stool samples if the child develops GE

• • •

Return of diary cards • • Diary card transcription • • Record any concomitant medication/vaccination§

• • • •

Reporting of Serious Adverse Events • • • • Study Conclusion • Contact for safety follow-up • Safety follow-up conclusion • Note: The triple-line border following Month 2 indicates the final analysis of immunogenicity, reactogenicity, unsolicited AEs and SAEs up to Visit 3 to be performed on all data up to Visit 3, as soon as all the data are available and cleaned. The safety results after Visit 3 up to the safety contact will be reported in an annex report. • is used to indicate a study procedure that requires documentation in the individual eCRF ‡ Physical examination at this visit can take place in case of request from the nurse or parents/guardians, and can be limited appropriate with local requirements for routine physical examination for a child at this age and appropriate for intervention that is to follow (blood draw etc.) †During the study, routine childhood vaccines (Infanrix hexa) will be administered at 3, 4, 5 months of age. The first two doses of Infanrix hexa will be coadministered with each dose of HRV vaccine. All routine vaccinations administered from birth up to Visit 3 should be recorded in the eCRF. Subjects will receive a booster dose of Infanrix hexa according to the approved prescribing information outside the scope of this study. *: See tick box in eCRF: smooth vaccine intake, vaccine intake interrupted due to coughing or choking, regurgitation after vaccine intake, vomiting after vaccine intake.

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§Recording of medications/vaccinations at each visit/contact will be according to the protocol.


107876 (Rota-061)

FLOW SHEET

It is the investigator’s responsibility to ensure that the intervals between visits/contacts are strictly followed. These intervals determine each subject’s evaluability in the according-to-protocol analyses.

Intervals between study visits

Interval Length of interval 1 (Visit 1→ Visit 2) 30 – 48 days 2 (Visit 2→ Visit 3) 30 - 48 days



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107876 (Rota-061) Protocol STUDY CONCLUSION Subject Number

107876 EXTENDED SAFETY FOLLOW-UP CONTACT

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DEMOGRAPHICS

Center number: |__|__|__|__|__|__| Date of Birth: |__|__| |__|__|__| |__|__|__|__| day month year Gender: [M] Male

[F] Female

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1.

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Final: 20 Mar 2008 5202748834c7630b371e350e538b41d145

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STUDY CONCLUSION

EXTENDED SAFETY FOLLOW-UP

CONTACT

168-202 days after the last dose of HRV vaccine

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107876 EXTENDED SAFETY FOLLOW-UP

CONTACT |__|__|__|__|__|__|

STUDY CONCLUSION EXTENDED SAFETY FOLLOW-UP CONTACT Could the subject's parents/guardians be contacted after the end of the active phase?

� Yes � Date of last contact: |__|__| |__|__|__| |__|__|__|__| day month year � Has the subject received any other investigational and/or non-registered vaccine and/or

drug after the end of the active phase? � No � Yes � GlaxoSmithKline might contact you for further investigation

� No � Give reason: [CWS] � Consent withdrawal

[LFU] � Lost to follow-up

Did the subject experience any serious adverse event(s) (SAE(s)) after the end of the active phase? � No

� Yes � please complete the complete Serious Adverse Event (SAE) report � Subject could not be contacted

2.

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107876 EXTENDED SAFETY FOLLOW-UP

CONTACT |__|__|__|__|__|__|

INVESTIGATOR'S SIGNATURE

I confirm that I have reviewed the Extended Safety Follow-Up data in this Case Report Form for this subject. All information entered by myself or my colleagues is, to the best of my knowledge, complete and accurate, as of the date below.

Investigator's signature: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: |__|__| |__|__|__| |__|__|__|__|

Printed Investigator's name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

day month year

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3.

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Final: 20 Mar 2008 5602748834c7630b371e350e538b41d145

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Protocol Subject number107876

(Rota-061)DIARY CARD DOSE 1

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SOLICITED SYMPTOMSPlease fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:Temperature:Please record the temperature every day. If temperature has been taken more than once a day, please report the highest value for the day.INTENSITY:Irritability / fussiness: Cough / runny nose Loss of appetite:0: Behavior as usual1: Crying more than usual / no effect on normal activity2: Crying more than usual / interferes with normal activity3: Crying that cannot be comforted / prevents normal activity

0: Normal1: Cough/ runny nose which is easily

tolerated2: Cough/ runny nose which interferes with

daily activity3 : Cough/ runny nose which prevents daily

activity

0: Appetite as usual1: Eating less than usual / no effect on normal activity2: Eating less than usual / interferes with normal activity3: Not eating at all

Vomiting : Diarrhea :One or more episodes of forceful emptying of partially digestedstomach contents ≥ 1 hour after feeding within a day

Diarrhea is defined as the passage of three or more looser than normal stools (loose or waterystools), within a day. A stool should be collected in case of diarrhea episode. Two episodes ofdiarrhea have to be considered as separated if there are five or more diarrhea- free days betweenthe episodes. A stool should be collected for each diarrhea episode

Day 0 = date of vaccination : |__|__||__|__|__||__|__|__|__|

GENERALSYMPTOMS Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Ongoing

after Day 7?Date of last Day of Symptoms

day month year Medical attention

Temperature! °C:! Axillary! Rectal! Oral

__ . _ __ . _ __ . _ __ . _ __ . _ __ . _ __ . _ __ . _! No! Yes !

|__|__| |__|__|__| |__|__|__|__| ! No! Yes !

HO/ER/MD/AD

|__|__|

Cough/runny nose! intensity: |___| |___| |___| |___| |___| |___| |___| |___|

! No! Yes !

|__|__| |__|__|__| |__|__|__|__| ! No! Yes !

HO/ER/MD/AD

|__|__|

Irritability/Fussiness! intensity: |___| |___| |___| |___| |___| |___| |___| |___| ! No

! Yes !|__|__| |__|__|__| |__|__|__|__| ! No

! Yes !

HO/ER/MD/AD

|__|__|

Loss of appetite! intensity: |___| |___| |___| |___| |___| |___| |___| |___|

! No! Yes !

|__|__| |__|__|__| |__|__|__|__| ! No! Yes !

HO/ER/MD/AD

|__|__|

Vomiting! number: |___| |___| |___| |___| |___| |___| |___| |___|

! No! Yes !

|__|__| |__|__|__| |__|__|__|__| ! No! Yes !

HO/ER/MD/AD

|__|__|

Diarrhea (*)! number of looserthan normal stool

|___| |___| |___| |___| |___| |___| |___| |___|! No! Yes �

|__|__| |__|__|__| |__|__|__|__| ! No! Yes �

HO/ER/MD/AD

|__|__|

(*) Please collect a stool sample in case of diarrhea

Stool collection : Please fill in the date: Day Month Year Day Month Year

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

MEDICATION Please fill in below if any medication has been taken between Visit 1 � Visit 2 (including medication taken in case ofdiarrhea)

Start date End date or check box if continuingTrade/Generic name Reason Route Total DailyDose day month year day month year

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

PLEASE DO NOT FORGET TO BRING BACK THE DIARY CARD ON |__|__| |__|__|__| |__|__|__|__|

IN CASE OF HOSPITALISATION, PLEASE INFORM �..�....�� ": �..�....��.

Medical attention :HO : HospitalizationER : Emergency RoomMD: Medical Personnel (Visit)AD: Medical contact without visit

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Day 8 – Visit 2 |__|__|__|__|__|__|

GASTROENTERITIS EPISODESPlease fill in below and assess the occurrence of any gastroenteritis according to the criteria listed hereafter.GASTROENTERITIS is defined by any episode of diarrhea.

DIARRHEA is defined a passage of three or more looser than normal stools within a day.INTENSITY:

0: Normal1: Gastroenteritis episode which is easily tolerated by the subject, causing minimal discomfort and not interfering

with everyday activities.2: Gastroenteritis episode which is sufficiently discomforting to interfere with normal everyday activities.3: Gastroenteritis episode which prevents normal, everyday activities. (In a young child, such an adverse event

would, for example, prevent attendance at school/ kindergarten / a day-care center and would cause the parents/ guardians to seek medical advice).

DIARRHEA EPISODESYMPTOMS

Start date End date or check box if continuing Medical AttentionIntensity

day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| ! ! No HO/ER/MD/AD

! Yes !|__|__|

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| ! ! No HO/ER/MD/AD

! Yes !|__|__|

! No ! Yes -> Please givedetails

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| ! ! No HO/ER/MD/AD

! Yes !|__|__|

STOOL COLLECTIONPlease fill in below the date of any stool collection

day month year day month year day month year day month year

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

OTHER GENERAL SYMPTOMSPlease fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:Other general symptoms:1:Mild: An adverse event which is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.2:Moderate: An adverse event which is sufficiently discomforting to interfere with normal everyday activities.3:Severe: An adverse event which prevents normal, everyday activities. (In a young child, such an adverse event would, for example, prevent

attendance at school/kindergarten/a day-care center and would cause the parents/guardians to seek medical advice).

OTHER GENERAL SYMPTOMS Please give details belowStart date End date or check box if continuing Medical attentionDescription - please give details below Intensity day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

! No! Yes !

HO/ER/MD/AD

|__|__|

|___| |__|__| |__|__|__|

|__|__|__|__| |__|__|

|__|__|__|

|__|__|__|__| !

! No! Yes !

HO/ER/MD/AD

|__|__|

|___| |__|__| |__|__|__|

|__|__|__|__| |__|__|

|__|__|__|

|__|__|__|__| !

! No! Yes !

HO/ER/MD/AD

|__|__|

|___| |__|__| |__|__|__|

|__|__|__|__| |__|__|

|__|__|__|

|__|__|__|__| !

! No! Yes !

HO/ER/MD/AD

|__|__|

PLEASE DO NOT FORGET TO BRING BACK THE DIARY CARD ON |__|__| |__|__|__| |__|__|__|__|IN CASE OF HOSPITALISATION, PLEASE INFORM �..�....�� ": �..�....��

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|__|__|__|__|__|__|

SOLICITED SYMPTOMSPlease fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:Temperature:Please record the temperature every day. If temperature has been taken more than once a day, please report the highest value for the day.INTENSITY:Irritability / fussiness: Cough / runny nose Loss of appetite:0: Behavior as usual1: Crying more than usual / no effect on normal activity2: Crying more than usual / interferes with normal activity3: Crying that cannot be comforted / prevents normal activity

0: Normal1: Cough/ runny nose which is easily

tolerated2: Cough/ runny nose which interferes with

daily activity3 : Cough/ runny nose which prevents daily

activity

0: Appetite as usual1: Eating less than usual / no effect on normal activity2: Eating less than usual / interferes with normal activity3: Not eating at all

Vomiting : Diarrhea :One or more episodes of forceful emptying of partially digestedstomach contents ≥ 1 hour after feeding within a day

Diarrhea is defined as the passage of three or more looser than normal stools (loose or waterystools), within a day. A stool should be collected in case of diarrhea episode. Two episodes ofdiarrhea have to be considered as separated if there are five or more diarrhea- free days betweenthe episodes. A stool should be collected for each diarrhea episode

Day 0 = date of vaccination : |__|__||__|__|__||__|__|__|__|

GENERALSYMPTOMS Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Ongoing

after Day 7?Date of last Day of Symptoms

day month year Medical attention

Temperature! °C:! Axillary! Rectal! Oral

__ . _ __ . _ __ . _ __ . _ __ . _ __ . _ __ . _ __ . _! No! Yes !

|__|__| |__|__|__| |__|__|__|__| ! No! Yes !

HO/ER/MD/AD

|__|__|

Cough/runny nose! intensity: |___| |___| |___| |___| |___| |___| |___| |___| ! No

! Yes !|__|__| |__|__|__| |__|__|__|__| ! No

! Yes !

HO/ER/MD/AD

|__|__|

Irritability/Fussiness! intensity: |___| |___| |___| |___| |___| |___| |___| |___|

! No! Yes !

|__|__| |__|__|__| |__|__|__|__| ! No! Yes !

HO/ER/MD/AD

|__|__|

Loss of appetite! intensity: |___| |___| |___| |___| |___| |___| |___| |___|

! No! Yes !

|__|__| |__|__|__| |__|__|__|__| ! No! Yes !

HO/ER/MD/AD

|__|__|

Vomiting! number: |___| |___| |___| |___| |___| |___| |___| |___| ! No

! Yes !|__|__| |__|__|__| |__|__|__|__| ! No

! Yes !

HO/ER/MD/AD

|__|__|

Diarrhea (*)! number of looserthan normal stool

|___| |___| |___| |___| |___| |___| |___| |___|! No! Yes �

|__|__| |__|__|__| |__|__|__|__| ! No! Yes �

HO/ER/MD/AD

|__|__|

(*) Please collect a stool sample in case of diarrhea

Stool collection : Please fill in the date: Day Month Year Day Month Year

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

MEDICATION Please fill in below if any medication has been taken between Visit 2 � Visit 3 (including medication taken in case ofdiarrhea)

Start date End date or check box if continuingTrade/Generic name Reason Route Total DailyDose day month year day month year

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

PLEASE DO NOT FORGET TO BRING BACK THE DIARY CARD ON |__|__| |__|__|__| |__|__|__|__|

IN CASE OF HOSPITALISATION, PLEASE INFORM �..�....�� ": �..�....��.

Medical attention :HO : HospitalizationER : Emergency RoomMD: Medical Personnel (Visit)AD: Medical contact without visit

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(Rota-061)DIARY CARD DOSE 2 |__|__|__|__|__|__|

GASTROENTERITIS EPISODESPlease fill in below and assess the occurrence of any gastroenteritis according to the criteria listed hereafter.GASTROENTERITIS is defined by any episode of diarrhea.

DIARRHEA is defined a passage of three or more looser than normal stools within a day.INTENSITY:

0: Normal1: Gastroenteritis episode which is easily tolerated by the subject, causing minimal discomfort and not interfering

with everyday activities.2: Gastroenteritis episode which is sufficiently discomforting to interfere with normal everyday activities.3: Gastroenteritis episode which prevents normal, everyday activities. (In a young child, such an adverse event

would, for example, prevent attendance at school/ kindergarten / a day-care center and would cause the parents/ guardians to seek medical advice).

DIARRHEA EPISODESYMPTOMS

Start date End date or check box if continuing Medical AttentionIntensity

day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| ! ! No HO/ER/MD/AD

! Yes !|__|__|

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| ! ! No HO/ER/MD/AD

! Yes !|__|__|

! No ! Yes -> Please givedetails

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| ! ! No HO/ER/MD/AD

! Yes !|__|__|

STOOL COLLECTIONPlease fill in below the date of any stool collection

day month year day month year day month year day month year

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

OTHER GENERAL SYMPTOMSPlease fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:Other general symptoms:1:Mild: An adverse event which is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.2:Moderate: An adverse event which is sufficiently discomforting to interfere with normal everyday activities.3:Severe: An adverse event which prevents normal, everyday activities. (In a young child, such an adverse event would, for example, prevent

attendance at school/kindergarten/a day-care center and would cause the parents/guardians to seek medical advice).

OTHER GENERAL SYMPTOMS Please give details belowStart date End date or check box if continuing Medical attentionDescription - please give details below Intensity day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

! No! Yes !

HO/ER/MD/AD

|__|__|

|___| |__|__| |__|__|__|

|__|__|__|__| |__|__|

|__|__|__|

|__|__|__|__| !

! No! Yes !

HO/ER/MD/AD

|__|__|

|___| |__|__| |__|__|__|

|__|__|__|__| |__|__|

|__|__|__|

|__|__|__|__| !

! No! Yes !

HO/ER/MD/AD

|__|__|

|___| |__|__| |__|__|__|

|__|__|__|__| |__|__|

|__|__|__|

|__|__|__|__| !

! No! Yes !

HO/ER/MD/AD

|__|__|

PLEASE DO NOT FORGET TO BRING BACK THE DIARY CARD ON |__|__| |__|__|__| |__|__|__|__|IN CASE OF HOSPITALISATION, PLEASE INFORM �..�....�� ": �..�....��

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1

List of Independent Ethics Committees /Institutional ReviewBoards

Independent Ethics Committees /Institutional Review Boards

Centre Number(s) * Ethics Review Body Location

Finland

phone: fax:

Finland

* GSK Biologicals assigned centre number

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Representative written information for patient and sampleconsent forms

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Informed Consent Form CONFIDENTIAL107876 (rota-061)

Version Number: 1 1/11Date: 05/07/2006

INFORMED CONSENT FORM

Study Identification: 107876 (rota-061)

EUDRACT NUMBER: 2006-003239-61

Study Title: A phase III, randomised study to evaluate the clinicalconsistency in terms of immunogenicity and reactogenicity of threeproduction lots of the liquid formulation of GlaxoSmithKline (GSK)Biologicals� oral live attenuated human rotavirus (HRV) vaccine and toevaluate the liquid formulation as compared to the lyophilised formulationof the HRV vaccine in terms of immunogenicity, reactogenicity and safetywhen administered as a two-dose primary vaccination in healthy infantspreviously uninfected with HRV.

Simplified Study Title: A study in infants to test two preparations (freeze-dried or liquid) of the rotavirus vaccine (HRV vaccine).

Version Number: 1 Date: 05/07/2006

Company Name: GlaxoSmithKline (GSK) Biologicals

Subject Identification: _____________

This document should be presented to the subject/ Legally Acceptable Representative infull; no page(s) or section(s) should be omitted. The document contents should beexplained verbally to the subject/Legally Acceptable Representative.

What does giving consent for this study mean?

Consent means agreeing to take part in this clinical research study. You have the right todecide if you want your child/ward to take part in the study or not. Please take time toread the following information carefully and discuss it if you wish with friends, relativesand your personal doctor. Ask us if there is anything that is not clear or if you would likemore information.

Why is this study being carried out?

The most common cause of diarrhoeal illness in infants and young children is a viruscalled �rotavirus�. Virtually all children suffer from rotavirus diarrhoea, and most oftenchildren between 6 and 24 months of age are affected.

Symptoms of rotavirus disease (or gastroenteritis) mainly include diarrhoea andvomiting. Other symptoms such as fever and abdominal pain may also occur. The

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diarrhoeal stools are loose and watery with up to ten stools per day. The symptoms lastfrom 3 to 9 days. Diarrhoea can cause loss of water and important nutrients resulting indehydration (excessive loss of water from the body) that may require hospital treatment.Indeed, gastroenteritis due to rotavirus is a common cause of hospitalisation of youngchildren in developed countries and is a leading cause of death in poorer countries.

Since there is no specific treatment available for rotavirus, vaccination is the best way toprevent rotavirus gastroenteritis. GSK Biologicals, a pharmaceutical company that testsnew vaccines has developed a new rotavirus vaccine, the human rotavirus vaccine(referred to as HRV vaccine). The human rotavirus in the new vaccine has beenweakened so that when a child swallows the vaccine, it is expected to cause only a mildinfection with few or no symptoms. The child is expected to develop antibodies(substance in the blood that fights infection) and thus be protected against rotavirusgastroenteritis.

In clinical trials with GSK Biologicals� freeze-dried HRV vaccine, the vaccine wasshown to be effective in developing specific antibodies in infants. Administration ofHRV vaccine also decreased the occurrence of rotavirus gastroenteritis during one yearafter vaccination in Finland, Latin America and Europe. The HRV vaccine also decreasesoccurrence of severe rotavirus diarrhoea in infants and reduces hospitalisation due torotavirus disease.

The freeze-dried HRV vaccine was shown to be safe and well tolerated with only mildside effects in adults, children (1 to 3 years old) and infants (approximately 2 monthsold). The reactions observed in infants vaccinated with the HRV vaccine were similar tothose observed in infants who were given a placebo (a product that looks like the vaccinebut does not contain any active ingredient).

To date, the freeze-dried HRV vaccine has been approved for use in infants in severalcountries in Latin America, Asia, Middle-East and Africa and recently in Europe.

This study involves medical research and is being carried out to test a vaccine (humanrotavirus [HRV] vaccine) in infants.

GSK Biologicals� freeze-dried HRV vaccine (Rotarix�) has to be mixed with a liquidbefore it is administered. A liquid preparation of the HRV vaccine is also available now.The liquid formulation might have some advantages compared to the freeze-driedproduct, e.g. easier to prepare for administration.

We are conducting this research study to test the liquid preparation of GSK Biologicals'HRV vaccine.

We will evaluate the liquid preparation of GSK Biologicals' HRV vaccine compared tothe freeze-dried preparation of GSK Biologicals� HRV vaccine by testingimmunogenicity (ability of the vaccine to develop antibodies that fight infection),reactogenicity (any side effects) and safety (in terms of occurrence of any serious adverseevents) of the two preparations.

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We will also evaluate the reliability of the production method of the liquid preparation ofGSK Biologicals' HRV vaccine by testing immunogenicity (ability of the vaccine todevelop antibodies that fight infection) and reactogenicity (any side effects) of threebatches of the liquid preparation.

During the study, all participating infants will receive the combined Infanrix hexa�vaccine 3, 4, 5 months of age (for protection from diphtheria, tetanus, pertussis(whooping cough), hepatitis B virus, poliomyelitis caused by poliovirus types 1, 2, and 3and H. influenzae type b bacteria). In addition to the nationally recommended routineimmunizations, the Infanrix hexa vaccine will provide immunization against hepatitis Bvirus. This vaccine is not routinely used for infant immunization in Finland. The first twodoses of Infanrix hexa will be coadministered with each dose of HRV vaccine.Participating infants will receive a booster dose of Infanrix hexa according to theapproved prescribing information outside the scope of this study.

We wish to invite your child/ward to take part in this research study.

Are there alternative products or treatment?

Disease caused by rotavirus is treated with oral rehydration solutions (special fluids givenby mouth to prevent or treat excessive fluid loss) or if necessary, intravenous (IV) fluidreplacement. This is to prevent dehydration (excessive loss of water from the body).There is no treatment to shorten the illness or to reduce vomiting or diarrhoea.

Rotarix (GSK Biologicals� the freeze-dried HRV vaccine) has been licensed in Finland,hence an alternative would be to buy the Rotarix� vaccine outside the study and not be apart of this study.

Joining this study is voluntary. If you decide against joining, there will be no penalty.You and your child/ward will lose no benefits.

What does this study involve?

If you are interested in having your child/ward participate in this research study, the studystaff will ask you questions about your child�s/ward�s medical history and any medicinesthat he/she may be taking. The doctor will perform a physical examination of yourchild/ward at Visit 1. Your child/ward will not be able to participate in the study if he/sheis taking certain kinds of medicines or has certain illnesses.

During the study, you will need to visit the clinic three times with your child/ward. Thedoctor may perform a physical examination of your child/ward at Visit 2 and Visit 3. Thestudy visits will be scheduled approximately one month apart, with the first visit takingplace when your child/ward is approximately 3 months of age. You will be contacted (bytelephone call or any other convenient method) by the study staff when your child/ward isapproximately 10 months old to ask about your child�s/ward�s health since his/her lastvisit. The expected duration of your child�s/ward�s participation in this study isapproximately 7 months including the extended safety follow-up contact.

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A blood sample will be collected from your child/ward at Visit 1 and Visit 3. The amountof the blood sample taken will be approximately 2 ml (which is slightly less than halfteaspoon). Tests performed on these blood samples will show how your child�s/ward�simmune system (body system that fights infection) reacts to the vaccines.

Randomisation will be used to assign eligible infants to one of the four treatment groups(one group will receive the freeze-dried preparation of the HRV vaccine and three groupswill each receive a different batch of the liquid preparation of the HRV vaccine).Randomisation means that the participants are put into a group by chance. It is likeflipping a coin. Your child/ward will have 1 out of 4 chances to receive the freeze-driedpreparation of the HRV vaccine and 3 out of 4 chances to receive one of three batches ofthe liquid preparation of the HRV vaccine.

Each child will receive two doses of HRV vaccine by mouth given approximately onemonth apart (at Visit 1 and Visit 2). All study subjects will be observed closely for atleast 30 minutes following the administration of vaccines.

During the study, your child/ward will receive the combined Infanrix hexa vaccine at 3,4, 5 months of age with the first two doses of Infanrix hexa given at the same time aseach dose of HRV vaccine. Your child/ward will receive a booster dose of Infanrix hexaaccording to the approved prescribing information outside the scope of this study.

You will receive diary cards to daily record information on specific symptoms (any lossof appetite, fussiness/irritability, fever, diarrhoea, vomiting or cough/runny nose) you�reyour child/ward experiences between the day of each HRV vaccine dose and thefollowing 7 days. You will also record on the diary card any medications and any othersymptoms that your child/ward experiences between the day of each HRV vaccine doseand the following 30 days.

If your child/ward experiences any gastroenteritis [gastroenteritis is any episode ofdiarrhoea. Diarrhoea is 3 or looser than normal stools in a 24 hour period] at any timefrom Dose 1 of HRV vaccine up to Visit 3, the information on the gastroenteritis episodeshould be recorded on the provided diary card. You should collect a stool sample fromyour child/ward during each gastroenteritis episode. If gastroenteritis recurs after 5 dayswithout symptoms, it should be considered as a separate episode and a stool sampleshould be taken again. Stool samples should be collected as soon as possible after illnessbegins and preferably not later than 7 days after the occurrence of GE.

During the study, you should contact the doctor or study staff immediately should yourchild/ward show any signs or symptoms that you think are serious.

The study staff will review study visits and procedures planned for your child/ward.

How many other subjects are there in the study?

A total of 1200 eligible infants are planned to participate in this study. All participantswill be enrolled in Finland.

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Do you have to stay in the study?

Your child�s/ward�s participation in this study is voluntary. If you do decide for yourchild/ward to take part, you will be given this information to keep and be asked to signthis consent form.

You may choose that your child/ward will not participate in the study or stop taking partin the study at any time without giving a reason. You must inform the study doctor if youdecide to do this. Your decision to not allow your child/ward to take part in this study orto stop participating in the study will not affect your child�s/ward�s current or futuremedical care, or any benefits to which he/she may otherwise be entitled.

Any new information that becomes available which might affect your willingness toallow your child/ward to continue in the study will be made available to you in a timelymanner.

The investigator or GSK may stop the study at any time. The reason for that decision willbe given to you.

Any information and results collected before your child�s/ward�s withdrawal from thestudy will be used by GSK.

What are the foreseeable risks for taking part in the study?

There may be momentary, mild discomfort and bruising of the skin where the needle isinserted to draw blood. The amount of blood to be taken is so small that it will not causeany general symptoms or anaemia (a condition with insufficient red blood cells).

As with any experimental vaccine, unexpected serious adverse experiences, includingallergic reactions to the vaccine, may occur. All the medical equipment necessary to treatany serious reactions to the study vaccine will be available at the investigation site.

You will be informed of any new findings during the course of this research study.

The lyophilized HRV vaccine (Rotarix) has been studied in research studies in whichapproximately 40,200 infants who received the HRV vaccine. The HRV vaccine wasshown to be similar to the placebo (product that looks like the real vaccine, but does notcontain any active ingredient i.e. virus) in terms of any side-effects during studies ininfants.

Only mild side effects occurred in some infants receiving the HRV vaccine or theplacebo.

The occurrence of irritability (fussiness) and loss of appetite were reported in more than 1in 10 subjects. The following reactions were commonly (less than 1 in 10 subjects)reported: fever, fatigue, diarrhoea, vomiting, flatulence (excessive gas), abdominal painand regurgitation of food (bring back already swallowed food). The following wereuncommonly (less than 1 in 100 subjects) or some even rarely reported (less than 1 in1000): crying, sleep disorder, somnolence (sleepiness) and constipation, upper respiratory

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tract infection, hoarseness, rhinorrhoea (runny nose), dermatitis (inflammation of theskin), rash and muscle cramp.

In the past, a different rotavirus vaccine called RotaShield� may have caused a very rarecondition called intussusception. Intussusception is a blockage of the small intestinewhereby a part of the intestine slips inside another part (�like an antenna folding up�),which requires immediate attention by a doctor. Results of a large safety trial in over63,000 infants showed that Rotarix vaccine does not increase the risk of intussusceptionas compared to placebo.

In the previous study of the liquid preparation of HRV vaccine conducted in Finland, thereactogenicity profile of the liquid preparation was similar to the freeze-dried preparation.

Your child/ward should not receive the HRV vaccine if he/she has uncorrectedmalformation of the gastrointestinal tract since birth (such as Meckel�s diverticulum) thatwould predispose for intussusception nor if he/she has developed an allergic reaction to aprevious dose or to an ingredient of the vaccine

If your child/ward experiences fever, diarrhoea or vomiting at the planned time forvaccination, he/she may be vaccinated at a later date or withdrawn at the discretion of theinvestigator.

Infanrix� Hexa vaccine

Your child/ward will receive Infanrix� Hexa vaccine in place of the routine infantvaccinations during the study. This vaccine may cause some side effects. Mild andtemporary side effects such as pain, redness and swelling at the injection site arecommon. Extensive swelling of the entire limb where the vaccine was injected andallergic reactions have been very rarely observed. Short-lived general reactions such asfever, loss of appetite, vomiting, diarrhoea and drowsiness may sometimes occur. Yourchild/ward may also cry continuously after vaccination and you may find it difficult tocomfort him/her. In extremely rare cases convulsions within 2 to 3 days after vaccinationand cases of collapse have been observed.

Are there any benefits for taking part in the study?

Infants who receive the HRV vaccine may have the benefit of being protected againstrotavirus disease.

There will be no charge for study-related doctor visits, examinations and laboratory tests.

In addition to the nationally recommended routine immunizations, your child/ward willalso receive immunization against the Hepatitis B virus which is a benefit because it isnot part of the national vaccination programme.

What payments will be made for the study?

You will not receive any payments for your child�s/ward�s participation in this study.

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Will you have to meet any cost/expenses for taking part in the study?

You will not have to bear any cost/expenses for your child�s/ward�s participation in thisstudy.

Who should you contact to answer any questions on the study?

If you have any questions about this trial, require any additional information, if you thinkyour child/ward has experienced a research-related illness or injury or if you want anyinformation regarding your child�s/ward�s rights as a research participant, please contactthe principal investigator:

Name: Prof. Address:

Finland.

Phone: Fax: email:

In the event if your child/ward is injured in the study, whatcompensation will be available?

If you are injured by a medicine or a clinical procedure that you would not have beengiven outside this study, you will be compensated. Your study doctor can give you a copyof the compensation guidelines for this kind of injury.

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Who will have access to medical and personal information about yourchild/ward that is collected in this study?

If you decide that your child/ward can participate in the study, the study doctor and staffwill collect medical and personal information about you as part of doing the study.People who work for or with GSK, and others like the independent ethics committee orthe institutional review board (IEC/IRB) for the study or regulatory authoritiesresponsible for approving medicines, will have access to this information at the site inorder to check that the study is done properly. GSK staff who sees this information at thesite will keep it confidential.

The study site will also transfer to GSK some of the information it collects, in a codedform. The information transferred will not include your name, initials, address, or otherdirect identifiers. It will be assigned a code number that only the site can connect back toyour name.

Your permission to the study doctor and staff to use this information or share it with GSKand others as described below for the study does not automatically end at a particulartime.

Medical information about your child/ward may be produced as part of the research orstudy procedures. If at the time of the study, this information is known to be relevant toyour child�s/ward�s medical care it will be given to the study doctor who will beencouraged to share it with you or your doctor. While your child/ward are in the study,however, the study site will not share certain new medical information about yourchild/ward that is created as part of the study (such as whether or not your child/ward aregetting study drug, or the results of certain tests) unless the study doctor decides it ismedically important to do so. This is done to stop the study results from being distorted.Once the study is over, you will be given access to medical information about yourchild/ward that you are entitled to see. You will be told if any of this medical informationrequires confirmation using a clinical test. This is important because some researchresults are for research purposes and may have only limited relevance for clinicaldiagnosis or treatment. At any time, you may ask your child�s/ward�s study doctor to letyou see your personal information, e.g. name and address and to correct it if necessary.

What will GlaxoSmithKline do with the information it gets?

GSK may use the information that the study doctor gives it (i.e. the coded information):

• By storing and analyzing it electronically to find out what this study is telling us.

• By sharing it with regulatory authorities that approve new medicines, or with groupsthat check that research is done properly

• By publishing the results of the study (this will not include any information thatdirectly identifies you)

• By sharing it as part of research with other companies or universities for the purposeof further understanding or developing this vaccine and with other GlaxoSmithKlineoffices in this country and in other countries. If the information is sent to another

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country, GSK will apply the same level of protection to your information, to theextent permitted by local law

• By using it to plan new studies or other types of research or other medical purposesrelated to the development of the vaccine.

What will happen to samples from this study?

Collected samples may be stored for up to 15 years and used for purposes related to thequality assurance of laboratory tests. This may include the set up of new test methods aswell as making sure that new tests are comparable to previous methods and work reliably.Samples will not be labelled with information that directly identifies your child/ward butwill be coded with your child�s/ward�s study subject number.

For the collected samples to be used for other research purposes, the link between yourchild/ward and the sample may be destroyed.

How is GlaxoSmithKline involved?

The study doctors (and the institution, if applicable) are paid to conduct this researchstudy by GSK.

The information and the materials that are given to you in relation to the study areconfidential information belonging to GSK and should be kept private. You can discussthis information in confidence with your doctor or friends and family to decide abouttaking part in this study and talking about your child�s/ward�s healthcare.

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Consent statement

I, (Printed name of Subject�s parents/guardian)

• confirm that I have read the written information (or have had the information read tome) for study 107876 (rota-061), ICF Version Number: 1 , dated 05/07/2006, 11pages, and the study procedures have been explained to me by study staff during theconsent process for this study.

• confirm that I have had the opportunity to ask questions about this study and I amsatisfied with the answers and explanations that have been provided.

• understand that I grant access to data to authorized persons described in theinformation sheet.

• have been given time and opportunity to consider allowing my child/ward to take partin this study.

Tick as appropriate (this decision will not affect your ability to enter the study):I agree that my child�s/ward�s primary health care physician will be notified of mychild�s/ward�s participation in this study. Yes No

I agree that my child/ward may take part in this study.

*Signature of LegalRepresentative

_____________________________ Date: _________

*Printed name ofLegalRepresentative

_____________________________

*Signature ofWitness

_____________________________ Date: _________

*Printed name ofWitness

_____________________________

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Signature of Personconducting Consent

_____________________________ Date:

Printed Name ofPerson conductingConsent

_____________________________

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1

List of investigators and other important participants in the study, contact information and numberand distribution of subjects

List of investigators and other important participants in the study, contact information and number and distribution of subjects

Investigator�s name Centernumber*

Number of subjects enrolled percenter

(% of enrollment)Investigational site Location Phone number

Fax numberProf. -

Finland

Finland

5

FINLAND

11.8

FINLAND

Dr. (prev. Dr.

9.8

FINLAND 6.5

FINLAND 7.5

FINLAND

9.0

FINLAND

6.7 FINLAND

12.6 FINLAND

7.4

FINLAND 7.5

FINLAND


Annex

Final: 20 Mar 2008 127d76f497c3b9eab4c0661fc6ad345dc


Annex

Final: 20 Mar 2008 297e819ebc1d89b1fa0c2d778801d1a0f9a

2

9.3

FINLAND

6.8

FINLAND

* GSK Biologicals� assigned center number


Annex

Final: 20 Mar 2008 227d76f497c3b9eab4c0661fc6ad345dc


Annex

Final: 20 Mar 2008 298e819ebc1d89b1fa0c2d778801d1a0f9a

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.


Annex

1

Signature of principal or coordinating investigator

GlaxoSmithKline BiologicalsGlobal Clinical Research and Development

Investigator Approval PageSTUDY TITLE: A phase III, randomised study to evaluate the clinical consistency interms of immunogenicity and reactogenicity of three production lots of the liquidformulation of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus(HRV) vaccine and to evaluate the liquid formulation as compared to the lyophilisedformulation of the HRV vaccine in terms of immunogenicity, reactogenicity and safetywhen administered as a two-dose primary vaccination in healthy infants previouslyuninfected with HRV.

Study: 107876 (Rota-061) Development Phase: III

I have read this report and confirm that to the best of my knowledge it accuratelydescribes the conduct and results of the study.

Name of Investigator:

Affiliation /investigationalcentre:

Signature of Investigator:

Date:

For internal use only

------------Checksum------------!Ver.!Created On193a906871c468a320786f7060461731 1.3 21/03/2008 3bee1a2bfe1832ffb8945ccc366a6054 1.0 20/03/2008 3a74ab8635581fb5b0976a7a9be48cb6 1.0 20/03/2008 12e06b40f131097366335aff30da9f77 1.1 20/03/2008 9127de990b1cdd6bd1dbd6115e679e0c 1.0 20/03/2008 cc464eb1cfa6485fa3f314221cd3304b 1.1 21/03/2008 1bb476cd975045b78ff3e932e384ca83 1.0 20/03/2008 ff263e3b0ca05cec4214e927919d3444 1.0 20/03/2008 d3be71157955c3ad7685a3c9237b8538 1.0 20/03/2008 e819ebc1d89b1fa0c2d778801d1a0f9a 1.0 20/03/2008 4511bef1ba41b6b977f1a40c22bf41d4 1.1 21/03/2008 257b26ec35f289d9845d56963db75a20 1.0 20/03/2008 b609fa1cb2cb87b1c49aa2e084789031 1.0 21/03/2008 c0ed224f5de3bfdc779834d633ee5e30 1.0 21/03/2008 72a8064e87f3d44273f14791cb7c4f79 1.0 21/03/2008 28baf3ca914c749fdd89ac92a15561d2 1.0 20/03/2008 ecd2d30ffccfee7d4111de23026b9b07 1.0 21/03/2008 27ab9b8f84475e8803337532f40eebf5 1.0 21/03/2008 32748cc668646e8d67d6982f9b9e9975 1.0 21/03/2008 22f4f769ef742e20bb8d4d122ace5ca4 1.0 21/03/2008 3270d687e06eb99c7dc34b87341553e0 1.1 21/03/2008 ------------------------------------------------

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Final: 20 Mar 2008 318257b26ec35f289d9845d56963db75a20


Annex

2

GlaxoSmithKline BiologicalsGlobal Clinical Research and Development

Sponsor Signatory Approval Page

STUDY TITLE: A phase III, randomised study to evaluate the clinical consistency interms of immunogenicity and reactogenicity of three production lots of the liquidformulation of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus(HRV) vaccine and to evaluate the liquid formulation as compared to the lyophilisedformulation of the HRV vaccine in terms of immunogenicity, reactogenicity and safetywhen administered as a two-dose primary vaccination in healthy infants previouslyuninfected with HRV.

Study: 107876 (Rota-061) Development Phase: III

I have read this report and confirm that to the best of my knowledge it accuratelydescribes the conduct and results of the study.

Name of Sponsor Signatory:

Title of Sponsor Signatory:

Signature:

Date:

For internal use only

------------Checksum------------!Ver.!Created On193a906871c468a320786f7060461731 1.3 21/03/2008 3bee1a2bfe1832ffb8945ccc366a6054 1.0 20/03/2008 3a74ab8635581fb5b0976a7a9be48cb6 1.0 20/03/2008 12e06b40f131097366335aff30da9f77 1.1 20/03/2008 9127de990b1cdd6bd1dbd6115e679e0c 1.0 20/03/2008 cc464eb1cfa6485fa3f314221cd3304b 1.1 21/03/2008 1bb476cd975045b78ff3e932e384ca83 1.0 20/03/2008 ff263e3b0ca05cec4214e927919d3444 1.0 20/03/2008 d3be71157955c3ad7685a3c9237b8538 1.0 20/03/2008 e819ebc1d89b1fa0c2d778801d1a0f9a 1.0 20/03/2008 4511bef1ba41b6b977f1a40c22bf41d4 1.1 21/03/2008 257b26ec35f289d9845d56963db75a20 1.0 20/03/2008 b609fa1cb2cb87b1c49aa2e084789031 1.0 21/03/2008 c0ed224f5de3bfdc779834d633ee5e30 1.0 21/03/2008 72a8064e87f3d44273f14791cb7c4f79 1.0 21/03/2008 28baf3ca914c749fdd89ac92a15561d2 1.0 20/03/2008 ecd2d30ffccfee7d4111de23026b9b07 1.0 21/03/2008 27ab9b8f84475e8803337532f40eebf5 1.0 21/03/2008 32748cc668646e8d67d6982f9b9e9975 1.0 21/03/2008 22f4f769ef742e20bb8d4d122ace5ca4 1.0 21/03/2008 3270d687e06eb99c7dc34b87341553e0 1.1 21/03/2008 ------------------------------------------------

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Final: 20 Mar 2008 319257b26ec35f289d9845d56963db75a20


Annex

1

Listings of patients receiving test drug(s) /investigationalproduct(s) from specific batches, where more than one batchwas used

Not applicable.

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Final: 20 Mar 2008 320b609fa1cb2cb87b1c49aa2e084789031

Randomisation list

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Final: 20 Mar 2008 1c05dac5219adeb5a516f8345122552e2

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Final: 20 Mar 2008 321c0ed224f5de3bfdc779834d633ee5e30

CDMCI\ RDE\ ENABLE Randomisation list

ROTA-061 (A.04DEC2007)

Subjects from Group : LIQ_A - HRV Liquid lot A -------------------------------------------------------------------

Trt. Bl. Repl. Trt. Bl. Repl. Trt. Bl. Repl. Trt. Bl. Repl. Trt. Bl. Repl. Trt. Bl. Repl. Trt. Bl. Repl. No nb flag No nb flag No nb flag No nb flag No nb flag No nb flag No nb flag --------------- --------------- --------------- --------------- --------------- --------------- ---------------


Annex



Annex



ROTA-061 (A.04DEC2007)

Subjects from Group : LIQ_A - HRV Liquid lot A -------------------------------------------------------------------

Trt. Bl. Repl. Trt. Bl. Repl. Trt. Bl. Repl. No nb flag No nb flag No nb flag --------------- --------------- ---------------

Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y


Annex



Annex



ROTA-061 (A.04DEC2007)

Subjects from Group : LIQ_B - HRV Liquid lot B -------------------------------------------------------------------



Annex



Annex



ROTA-061 (A.04DEC2007)

Subjects from Group : LIQ_B - HRV Liquid lot B -------------------------------------------------------------------




Annex



Annex



ROTA-061 (A.04DEC2007)

Subjects from Group : LIQ_C - HRV Liquid lot C -------------------------------------------------------------------



Annex



Annex



ROTA-061 (A.04DEC2007)

Subjects from Group : LIQ_C - HRV Liquid lot C -------------------------------------------------------------------




Annex



Annex



ROTA-061 (A.04DEC2007)

Subjects from Group : LYO - HRV Lyo -------------------------------------------------------------------



Annex



Annex



ROTA-061 (A.04DEC2007)

Subjects from Group : LYO - HRV Lyo -------------------------------------------------------------------




Annex



Annex



1

Audit certificates

Not applicable.

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Final: 20 Mar 2008 193293c7e85076596f58d6e106bd8e628

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Final: 20 Mar 2008 33072a8064e87f3d44273f14791cb7c4f79


1

Documentation of statistical methods

Refer to Section 5.9 of the report.

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Final: 20 Mar 2008 1249f7a8fdc278bea120b373ea4f3cce6

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Final: 20 Mar 2008 33128baf3ca914c749fdd89ac92a15561d2


1

Documentation of inter-laboratory standardization methods andquality assurance procedures

Not applicable.

CONFIDENTIAL


Final: 20 Mar 2008 121c87a4dc9767241722fc38685ba92e4

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Final: 20 Mar 2008 332ecd2d30ffccfee7d4111de23026b9b07


1

Publications based on the study

Not applicable.

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Final: 20 Mar 2008 1584ecef9e3d866c4953477b16ca2e8d3

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Final: 20 Mar 2008 33327ab9b8f84475e8803337532f40eebf5

Important publications referenced in the report

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Final: 20 Mar 2008 1b9df427f14837f4178453ed76943dc0f

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Final: 20 Mar 2008 33432748cc668646e8d67d6982f9b9e9975

This section contained journal publication(s), which are protected by copyright laws and therefore have been excluded.

Individual Listings

CONFIDENTIAL


Final: 20 Mar 2008 154cb2aa7f731165f0087d88fa48d70ab

CONFIDENTIAL


Final: 20 Mar 2008 40222f4f769ef742e20bb8d4d122ace5ca4

This section contained data from each individual patient, rather than in aggregate. They have

been excluded to protect patient privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clinical Study Register.

CRF /eCRFs for deaths, other SAEs and withdrawals due toadverse events

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Final: 20 Mar 2008 15c158766997aa6e9aa312c1481a79131

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Final: 20 Mar 2008 16723270d687e06eb99c7dc34b87341553e0

This section contained patient narratives which are textual descriptions of medical history,

treatment and outcome for individual patients who experienced a clinically important adverse

event including serious adverse events during the trial. They have been excluded to protect

patient privacy. This data may be made available subject to an approved research proposal and

a determination of the ability to provide information from the specific narratives whilst protecting

the patient’s privacy. For further information please see the Patient Level Data section of

the GSK Clinical Study Register.

June 8, 2007 GlaxoSmithKline Biologicals Study Reporting and Analysis Plan Rota-061 (107876)

Confidential and Proprietary Information

1


Clinical Research & Development

Study Reporting and Analysis Plan Approval

Title: A phase III, randomised study to evaluate the clinical consistency in terms of immunogenicity and reactogenicity of three production lots of the liquid formulation of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus (HRV) vaccine and to evaluate the liquid formulation as compared to the lyophilised formulation of the HRV vaccine in terms of immunogenicity, reactogenicity and safety when administered as a two-dose primary vaccination in healthy infants previously uninfected with HRV.

CPMS (e-Track) number – (alias):

107876(Rota-061)

Date: June 8, 2007

Co-ordinating authors:

Others author(s):

Approved by:

Director, Worldwide Clinical Development, Rotavirus Vaccines

Signature

dd-mmm-yyyy

Senior Manager, Clinical Management

Signature

dd-mmm-yyyy

Project Statistician Signature dd-mmm-yyyy Associate Director, Biostatistics

Signature

dd-mmm-yyyy



2

TABLE OF CONTENTS

PAGE

1. LIST OF AMENDMENTS TO THE RAP ................................................................... 5

2. INTRODUCTION ...................................................................................................... 5

3. OBJECTIVES ........................................................................................................... 5 3.1. Primary Objectives ........................................................................................ 5 3.2. Secondary objectives .................................................................................... 5

4. STUDY DESIGN OVERVIEW .................................................................................. 6

5. CONDUCT OF STUDY ............................................................................................ 8 5.1. Outline of study procedures .......................................................................... 8

5.1.1. Laboratory assays ......................................................................... 9 5.1.1.1. Serum analysis ............................................................. 9 5.1.1.2. GE Stool analysis ....................................................... 10 5.1.1.3. Serology/Stool analysis plan ....................................... 10

5.1.2. Solicited adverse events .............................................................. 10 5.1.3. Unsolicited adverse events ` ........................................................ 11 5.1.4. Assessment of intensity ............................................................... 11 5.1.5. Assessment of causality .............................................................. 12 5.1.6. Medically attended visits .............................................................. 13

6. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES ............... 13 6.1. Endpoints .................................................................................................... 13

6.1.1. Co-primary endpoints ................................................................... 13 6.1.2. Secondary endpoints ................................................................... 13

6.2. Study cohorts .............................................................................................. 14 6.2.1. Total vaccinated cohort ................................................................ 14 6.2.2. ATP cohort for safety ................................................................... 14 6.2.3. ATP cohort for immunogenicity .................................................... 14

6.3. Derived and transformed data ..................................................................... 15 6.4. Group description ....................................................................................... 16 6.5. Interim analysis ........................................................................................... 17 6.6. Demography/baseline characteristics ......................................................... 17 6.7. Safety ......................................................................................................... 18

6.7.1. Between groups assessment ....................................................... 22 6.8. Immunogenicity ........................................................................................... 23

6.8.1. Within groups assessment ........................................................... 23 6.8.2. Between groups assessment ....................................................... 24

6.9. Methodology for computing CI .................................................................... 24

7. CHANGE FROM PROTOCOL ................................................................................ 25



3

8. INDIVIDUAL LISTINGS .......................................................................................... 26

9. ANNEX 1: TEMPLATE OF TABLES ....................................................................... 27

10. ANNEX 2: ELIMINATION CODE CRITERION TO USE ......................................... 62

11. ANNEX 3: STATISTICAL METHODS ..................................................................... 72 11.1. Confidence interval for a proportion within a group ..................................... 72 11.2. Confidence interval for a geometric mean within a group ............................ 72



4

LIST OF ABBREVIATIONS

AE Adverse event Anti- Antibody ATP According-To-Protocol BMI Body Mass Index CI Confidence Interval CRF Case Report Form ELISA Enzyme-linked immunosorbent assay GE Gastroenteritis GMC Geometric mean antibody concentration GSK GlaxoSmithKline HRV Human Rotavirus IgA Immunoglobulin A LL Lower limit MedDRA Medical Dictionary for Regulatory Activities ml Milliliter PCR Polymerase Chain reaction RAP Report Analysis Plan RDE Remote Data Entry RV Rotavirus SAE Serious adverse event SBIR GSK Biological’s Internet Randomization System U/ml Units per milliliter UL Upper limit



5

1. LIST OF AMENDMENTS TO THE RAP

No amendment was done.

2. INTRODUCTION

This document summaries the study features as per protocol amendment 1 dated 06-Oct-2006 (sections 3-5) and the planned statistical analyses (section 6). The changes in the analyses as compared to the protocol amendment 1 are provided in section 7. A lay-out of the tables as they will be produced in the statistical report is available in annex 1.

3. OBJECTIVES

3.1. Primary Objectives

• To demonstrate the lot-to-lot consistency of the liquid formulation of GSK Biologicals’ HRV vaccine in terms of immunogenicity as measured by serum anti-rotavirus IgA antibody levels one month after Dose 2.

Consistency will be reached if, for all pairs of lots, the two-sided 95% CIs for the ratio of anti-rotavirus IgA antibody GMCs one month after Dose 2 are within the [0.5; 2] clinical limit interval.

• To demonstrate non-inferiority of the liquid formulation of GSK Biologicals' HRV vaccine to that of lyophilised formulation of GSK Biologicals’ HRV vaccine in terms of seroconversion rates one month after Dose 2.

Non-inferiority will be reached if the upper limit of the two-sided asymptotic standardised 95% CI for the difference in seroconversion rate between the lyophilised formulation of HRV vaccine and (minus) the liquid formulation of HRV vaccine is less than or equal to 10%.

3.2. Secondary objectives

• To demonstrate non-inferiority of the liquid formulation of GSK Biologicals' HRV vaccine to that of lyophilised formulation of GSK Biologicals’ HRV vaccine in terms of serum anti-rotavirus IgA antibody levels one month after Dose 2.

Non-inferiority will be reached if the upper limit of the two-sided 95% CI for the ratio of anti-rotavirus IgA antibody GMCs one month after Dose 2 between the lyophilised formulation of HRV vaccine and (over) the liquid formulation of HRV vaccine is less than or equal to 2.



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• To assess the lot-to-lot consistency of the liquid formulation of GSK Biologicals’ HRV vaccine in terms of reactogenicity.

• To assess the safety of the study vaccines.

4. STUDY DESIGN OVERVIEW Ra ndo mizat io n

(1 :1 :1 :1)

V isit 1 A ge: 1 0 -17 weeks (70 -1 25 da ys) D ay 0 D ose 1 B lood samp ling

V acc ina tion v is its

V isit 3 M onth 2 B lood samp ling Study conc lus ion

H R V v acc ine l iq u id fo rmu la t io n (Lo t A ), N = 300

H R V v acc in e ly op h il ized fo rm u lat ion , N = 3 00

V isit 2 M onth 1 D ose 2

Fo llow -up v is it

Extended sa fety contac t† Sa fe ty follow -up conc lus io n

H R V v acc ine l iq u id fo rmu la t io n (Lo t B), N = 3 00

H R V v acc ine l iq u id fo rmu la t io n (Lo t C), N = 3 00

†Contact (by telephone call or any other convenient procedure) for safety follow-up will take place 6 months after the last dose of HRV vaccine N = number of subjects planned to be enrolled

• Experimental design: Phase III, randomised study with four parallel groups. Double blind for three lots of the liquid formulation of GSK Biologicals’ HRV vaccine, and open label for liquid formulation versus the lyophilised formulation.


• Vaccination schedule: Two-dose immunisation at 3 and 4 months of age in healthy infants aged between 10 and 17 weeks (70 - 125 days) at the time of the first dose and previously uninfected with HRV.

• During the study, routine childhood vaccines (Infanrix hexa™) will be administered at 3, 4, 5 months of age. The first two doses of Infanrix hexa will be coadministered with each dose of HRV vaccine. All routine vaccinations administered from birth up to Visit 3 should be recorded in the eCRF. Subjects will receive a booster dose of Infanrix hexa according to the approved prescribing information outside the scope of this study.




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• Blood samples will be collected from all subjects at Visits 1 and 3 to measure serum anti-rotavirus IgA antibody concentrations using ELISA.

• Solicited symptoms occurring between the day of each HRV vaccine dose and the following 7 days (Day 0 to Day 7) will be recorded daily using diary cards for all subjects.

• Unsolicited symptoms occurring within 31 days (Day 0 to Day 30) after each HRV vaccine dose will be recorded for all subjects.

• SAEs will be recorded from Dose 1 of HRV vaccine up to 6 months after the last dose of HRV vaccine.

• Any GE episodes occurring from Dose 1 of HRV vaccine up to Visit 3 should be recorded in the diary card. Parents/guardians should be instructed to collect stool sample(s) if the subject develops GE during the period from Dose 1 of HRV vaccine up to Visit 3. A stool sample should be collected as soon as possible after illness begins and preferably not later than 7 days after the start of diarrhoea. A stool sample should be collected for each separate diarrhoea episode. A second stool sample should be collected if the first sample was insufficient. Two occurrences of diarrhoea should be classified as separate episodes if there are 5 or more diarrhoea-free days between the episodes.


• Data collection: By Remote Data Entry (RDE) using individual electronic Case Report Forms (eCRF).

• Duration of the study: The intended duration of the study, per subject will be approximately 7 months including the 6-month safety follow-up period after Dose 2 of HRV vaccine.



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5. CONDUCT OF STUDY

5.1. Outline of study procedures

An outline of study procedures is provided in Table 1


Age 10 - 17 weeks (70 - 125 days)


Visit VISIT 1 VISIT 2 VISIT 3 CONTACT Timing Day 0 Month 1 Month 2 Month 7

Sampling time point Pre Post-vacc 2

Informed consent •

Check inclusion criteria •

Check exclusion criteria •

Check elimination criteria • •

Check contraindications • •

Medical history •

Physical examination • •‡ •‡

Pre-vaccination body temperature • •

Measure/record height and weight •

Randomisation •

Blood sampling: for antibody determination (2.0 ml) • •

Study vaccination • •

Routine vaccination (Infanrix hexa)† • • •

Recording of oral vaccine intake characteristics (tick box*)

• •


• •


• • •

Recording of GE • • •

Collection of stool samples if the child develops GE

• • •

Return of diary cards • •

Diary card transcription • •

Record any concomitant

medication/vaccination§

• • • •

Reporting of Serious Adverse Events • • • • Study Conclusion •

Contact for safety follow-up • Safety follow-up conclusion •



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Note: The triple-line border following Month 2 indicates the final analysis of immunogenicity, reactogenicity, unsolicited AEs and SAEs up to Visit 3 to be performed on all data up to Visit 3, as soon as all the data are available and cleaned. The safety results after Visit 3 up to the safety contact will be reported in an annex report. • is used to indicate a study procedure that requires documentation in the individual eCRF ‡ Physical examination at this visit can take place in case of request from the nurse or parents/guardians, and can be limited appropriate with local requirements for routine physical examination for a child at this age and appropriate for intervention that is to follow (blood draw etc.) †During the study, routine childhood vaccines (Infanrix hexa) will be administered at 3, 4, 5 months of age. The first two doses of Infanrix hexa will be coadministered with each dose of HRV vaccine. All routine vaccinations administered from birth up to Visit 3 should be recorded in the eCRF. Subjects will receive a booster dose of Infanrix hexa according to the approved prescribing information outside the scope of this study. *: See tick box in eCRF: smooth vaccine intake, vaccine intake interrupted due to coughing or choking, regurgitation after vaccine intake, vomiting after vaccine intake. §Recording of medications/vaccinations at each visit/contact will be according to the guidelines

Age at first visit :

Interval Length of interval

(DOB→Visit 1) 10 and 17 weeks (70 - 125 days)

DOB : Date Of Birth

It is the investigator’s responsibility to ensure that the intervals between visits/contacts are strictly followed. The adapted intervals determine each subject’s evaluability in the according to protocol analyses of immunogenicity.


Interval Length of interval as per Protocol

Length of adapted interval

1 (Visit 1→ Visit 2) 30 – 48 days 21 – 48 days

2 (Visit 2→ Visit 3) 30 - 48 days 21 - 48 days


No subject will be eliminated for not respecting this time interval


5.1.1. Laboratory assays

5.1.1.1. Serum analysis

Serum obtained from whole blood samples collected from subjects at Visit 1 and Visit 3 will be tested by ELISA at GSK Biologicals laboratory to measure serum anti-rotavirus IgA antibody concentrations. The assay cut-off is 20 U/ml.

A seronegative subject for anti-rotavirus IgA antibodies is defined as a subject who has antibody concentration below the assay cut-off value. A seropositive subject for anti-rotavirus IgA antibodies is defined as a subject who has antibody concentration greater than or equal to the assay cut-off value.



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Table 3 Laboratory Assays

Antibody Assay method

Test Kit/ Manufacturer

Assay unit

Assay cut-off

Core Laboratory

Rotavirus IgA ELISA In-house U/ml 20 GSK

5.1.1.2. GE Stool analysis

Stool samples collected during each GE episode from Visit 1 until Visit 3 will be tested at GSK Biologicals using ELISA to detect RV. If positive, the sample will be tested by PCR at DDL laboratory to determine the G and the P genotypes. If any G1 RV is detected, vaccine virus will be differentiated from the wild type serotype by RT-PCR followed by reverse hybridization assay or an equivalent approach

5.1.1.3. Serology/Stool analysis plan

The laboratory analysis plan for serology and stool analysis is described in Table 4.

Table 4 Laboratory Analysis Plan

Timing Month Visit no. Antigen Antigen priority rank No. subjects

Blood sampling time point

Pre Day 0 1 HRV None All Post-vacc 2 Month 2 3 HRV None All

Stool sampling time point

GE stools from Visit 1 to Visit 3 HRV None All

5.1.2. Solicited adverse events

Solicited adverse events will be evaluated during the 8-day follow-up period (Day 0 to Day 7) after each HRV vaccine dose. Diary cards will be provided to the parents/ guardian’s of the subject to daily record the specific solicited symptoms observed between the day of each HRV vaccine dose and the following 7 days (Day 0 to Day 7).

The following adverse events will be solicited:

Table 5 Solicited general adverse events

Fever Irritability/ Fussiness Diarrhoea Vomiting Loss of appetite Cough/ runny nose

N.B. Temperature will be recorded in the evening. Should additional temperature measurements be performed at other times of day, the highest temperature will be recorded.



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5.1.3. Unsolicited adverse events`

All AEs occurring within 31 days following administration of each dose of HRV vaccine as well as all diarrhoea occurring from Visit 1 to Visit 3 must be recorded on the Adverse Event form in the subject's CRF, irrespective of intensity or whether or not they are considered vaccination-related.

The standard time period for collecting and recording SAEs will begin at randomisation or the first receipt of HRV vaccine and will end at the last contact foreseen for the subject (from Dose 1 of HRV vaccine up to 6 months after the last dose of HRV vaccine).

5.1.4. Assessment of intensity

Intensity of the following AEs will be assessed as described in Table 6. Table 6 Intensity scales for solicited symptoms

Adverse Event Intensity grade Parameter

Fever* Record temperature in °C

Irritability/Fussiness 0 Behaviour as usual 1 Crying more than usual/ no effect on normal activity 2 Crying more than usual/ interferes with normal activity 3 Crying that cannot be comforted/ prevents normal activity Diarrhoea¶ Record the number of looser than normal stools /day Vomiting§ Record the number of vomiting episodes/day Cough/runny nose 0 Normal 1 Cough/runny nose which is easily tolerated 2 Cough/runny nose which interferes with daily activity 3 Cough/runny nose which prevents daily activity Loss of appetite 0 Appetite as usual 1 Eating less than usual/ no effect on normal activity 2 Eating less than usual/ interferes with normal activity 3 Not eating at all

*Fever is defined as: rectal temperature ≥ 38 °C (/ axillary temperature ≥ 37.5 °C). ¶Diarrhoea is defined as passage of three or more looser than normal stools within a day. §Vomiting is defined as one or more episodes of forceful emptying of partially digested stomach contents ≥ 1 hour after feeding within a day.

The maximum intensity of diarrhea, fever and vomiting occurring during the solicited follow-up period will be scored at GSK Biologicals as described in Table 7:



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Table 7 Intensity scales for diarrhoea, vomiting an d fever reported during the solicited follow-up period

Adverse Experience

Intensity grade Parameter

Diarrhoea 0 Normal (0 – 2 looser than normal stools/day) 1 3 looser than normal stools/day 2 4 – 5 looser than normal stools/day 3 ≥ 6 looser than normal stools/day

Vomiting 0 Normal (no emesis) 1 1 episode of vomiting/day 2 2 episodes of vomiting/day 3 ≥ 3 episodes of vomiting/day

Fever 0 Rectal temperature < 38.0°C or axillary temperature < 37.5°C 1 Rectal temperature ≥ 38.0 – < 38.5°C or axillary temperature ≥ 37.5 – ≤ 38.0°C 2 Rectal temperature > 38.5 – < 39.5°C or axillary temperature > 38.0 – ≤ 39.0°C

3 Rectal temperature > 39.5°C or axillary temperature > 39.0°C

The investigator will make an assessment of intensity for all other AEs, i.e. unsolicited adverse events, including SAEs reported during the study. The assessment will be based on the investigator’s clinical judgement. The intensity of each AE and SAE recorded in the CRF or SAE Report Form, as applicable, should be assigned to one of the following categories:

1 (mild) = An AE which is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.

2 (moderate) = An AE which is sufficiently discomforting to interfere with normal everyday activities.

3 (severe) = An AE which prevents normal, everyday activities. (In a young child, such an AE would, for example, prevent attendance at school/ kindergarten/ a day-care centre and would cause the parents/ guardians to seek medical advice).

An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 3 is a category utilised for rating the intensity of an event; and both AEs and SAEs can be assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 8.2 of the protocol.

5.1.5. Assessment of causality

Causality of all AEs should be assessed by the investigator using the following question:



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Is there a reasonable possibility that the AE may have been caused by the investigational product?

NO : The AE is not causally related to administration of the study vaccine(s). There are other, more likely causes and administration of the study vaccine(s) is not suspected to have contributed to the AE.

YES : There is a reasonable possibility that the vaccine(s) contributed to the AE.

5.1.6. Medically attended visits

For each solicited and unsolicited symptom the subject experiences, the subject’s parents/guardians will be asked if they received medical attention defined as hospitalisation, an emergency room visit or a visit to or from medical personnel (medical doctor) for any reason and this information will be recorded in the CRF.

6. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES

6.1. Endpoints

6.1.1. Co-primary endpoints

• Serum anti-rotavirus IgA antibody concentration at Visit 3 in each HRV vaccine liquid formulation group.


Seroconversion is defined as appearance of anti-rotavirus IgA antibody concentration ≥ 20 units (U)/millilitre (ml) in subjects initially (i.e. prior to the first dose of HRV vaccine) seronegative (i.e. with anti-rotavirus IgA antibody concentration< 20 U/ml)

6.1.2. Secondary endpoints

• Serum anti-rotavirus IgA antibody concentration at Visit 3 in the HRV vaccine lyophilised formulation group.

• Occurrence of each type of solicited symptom within the 8-day solicited follow-up period (Day 0 to Day 7) after each dose of HRV vaccine.



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• Occurrence of unsolicited AEs within 31 days (Day 0 – Day 30) after any dose of HRV vaccine, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification.

• Occurrence of SAEs from Dose 1 of HRV vaccine up to 6 months after the last dose of HRV vaccine.

• Presence of RV in GE stools collected from Dose 1 of HRV vaccine up to Visit 3.

6.2. Study cohorts

Three cohorts will be evaluated, as described below.

6.2.1. Total vaccinated cohort

The total vaccinated cohort will include all subjects with at least one study vaccine administration documented:

• a safety analysis based on the total vaccinated cohort will include all vaccinated subjects,

• an immunogenicity analysis based on the total vaccinated cohort will include all vaccinated subjects for whom immunogenicity data are available.

6.2.2. ATP cohort for safety

The ATP cohort for safety will include all subjects from the Total Vaccinated cohort

• who have received at least one dose of study vaccine,

• for whom the HRV vaccine liquid or lyophilised formulation was administered according to protocol

• who have not received a vaccine forbidden by or not specified in the protocol.

• who were seronegative for serum anti-rotavirus IgA antibodies on the day of Dose 1.

6.2.3. ATP cohort for immunogenicity

The ATP immunogenicity cohort will include all subjects from the ATP safety cohort:

• who have not received medication forbidden by the protocol,

• whose underlying medical condition was not forbidden by the protocol,

• with no protocol violation of demographics (unknown age at study entry or outside protocol defined age-interval),



15

• who comply with vaccination schedule for HRV vaccine liquid or lyophilised formulation,

• who comply with blood sampling schedule,

• for whom immunogenicity data are available at post-sampling time point.

• who have no RV other than vaccine strain in GE stool samples collected up to Visit 3.

• who have no concomitant infection unrelated to the vaccine which may influence the immune response.

The total vaccinated cohort will be used for the primary analysis of safety. The analysis on the ATP cohort for safety will only be performed if more than 5% of the vaccinated subjects are excluded from the ATP safety cohort.

The ATP immunogenicity cohort will be used for the primary analysis of immunogenicity. An analysis of immunogenicity based on the total vaccinated cohort will only be performed if more than 5% of the vaccinated subjects with immunological results available are excluded from the ATP immunogenicity cohort. In such a case, the total vaccinated cohort analyses will evaluate whether exclusion from the ATP cohort have biased the results.

The list of applicable elimination codes for each cohort can be found in Annex 2.

Cohort Elimination codes

Total vaccinated cohort 1010-1030

ATP cohort for safety 1010-1500

ATP cohort for immunogenicity 1010-2500

6.3. Derived and transformed data

Demography

• For a given subject and a given demographic variable, missing measurement will not be replaced.

Immunogenicity

• The cut-off value of anti-rotavirus IgA antibody is defined by the laboratory before the analysis and is described in Section 5.1.1.1.



16

• A seronegative subject is a subject whose antibody concentration is below the cut-off value.

• A seropositive subject is a subject whose antibody concentration is greater than or equal to the cut-off value.

• Seroconversion is defined as the appearance of anti-rotavirus IgA antibody concentration ≥ 20 U/ml in subjects initially (i.e. prior to the first dose of HRV vaccine) seronegative (i.e. with anti-rotavirus IgA antibody concentration< 20 U/ml).

• The GMC calculations are performed by taking the anti-log of the mean of the log concentration transformations. Antibody concentrations below the cut-off of the assay will be given an arbitrary value of half the cut-off for the purpose of GMC calculation.

• For a given subject and a given immunogenicity measurement, missing or non-evaluable measurements will not be replaced.

Reactogenicity and safety

• Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) will be treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).

• Additional analysis based on the total vaccinated cohort including only subjects/doses with documented safety data (i.e. symptom screen completed) will also be performed.

6.4. Group description

The following group description will be used for the safety, immunogenicity, demography and compliance analyses.

Study Group order in tables Group label in tables (8 characters only) 107876 1

LIQ_LotA

2

LIQ LotB

3 LIQ_LotC

4 LIQ_POOL

5 LYO



17

6.5. Interim analysis

No interim analysis is planned.

6.6. Demography/baseline characteristics

The following tables will be generated:

TABLE # in reference of annex 1

Abbreviated Title (see annex 1 for the proposed wording in the statistical report)

Final Analysis

Annex Report

Table 8 Number of subjects enrolled into the study as well as the number of subjects excluded from ATP analyses with reasons for exclusion.

CR

Table 9 Number of subjects at each visit and list of withdrawn subjects from visit 1 to visit 3 (Total Vaccinated Cohort)

WT

Table 10 Number of subjects vaccinated, completed and withdrawn with reason for withdraw at visit 3 (Total Vaccinated Cohort)

CR

Table 10 Number of subjects vaccinated, completed and withdrawn with reason for withdrawal at last contact

CR

Table 11 Deviations from specifications for age and intervals between study visits (Total Vaccinated Cohort)

ST

Table 11 Deviations from specifications for age and intervals between study visits (ATP cohort for Immunogenicity)

WT

Table 12 Minimum and maximum visit dates from visit 1 to the last contact (Total Vaccinated Cohort)

WT WT

Table 13 Number of subjects by center (Total Vaccinated Cohort)

CR

Table 14 Summary of demographic characteristics (ATP cohort for Immunogenicity)

CR

Table 14 Summary of demographic characteristics (Total Vaccinated Cohort)

ST

Table 15 Summary of vaccine intake characteristics (Total vaccinated cohort)

ST

Table 16 Summary of co-administered vaccination by dose (Total vaccinated cohort)

ST

Table 17 Summary of vaccinations other than HRV administered from birth until Visit 3, excluding vaccination given on the day of HRV doses (Total vaccinated cohort)

ST

Table 18 Compliance in returning symptom sheets (Total Vaccinated Cohort)

ST*

Table 19 Demography of CTRS CTRS CR = Within the clinical report ST = As a supplementary table or figure WT = As a working table or figure



18

CTRS = table for use in the clinical trial registry summary *: a complementary analysis based on the ATP cohort for safety will be provided if more than 5% of the vaccinated subjects are excluded from that cohort. The resulting tables will appear as supplemental tables

6.7. Safety

The safety results after visit 3 up to the safety contact, and the CTR table for SAEs will be reported in an annex report




Final Analysis

Table 20 Number and percentage of subjects who received Study vaccine dose(s) (Total vaccinated cohort)

CR*

Table 21 Percentage of doses and of subjects reporting symptoms (solicited or unsolicited) reported during the 8-day (Days 0-7) follow-up period (Total vaccinated cohort)

CR*

Table 21 Percentage of doses and of subjects reporting grade 3 symptoms (solicited or unsolicited) reported during the 8-day (Days 0-7) follow up period (Total vaccinated cohort)

ST*

Table 21 Percentage of doses and of subjects reporting symptoms (solicited or unsolicited) assessed as related and reported during the 8-day (Days 0-7) follow up period (Total vaccinated cohort)

ST*

Table 22$ Percentage of subjects reporting each solicited general symptom included those graded 3 in intensity and those assessed as related to vaccination during the 8-day (Days 0-7) follow-up period, for each dose (Total Vaccinated Cohort)

CR*/CTRS

Table 23$ Percentage of doses and subjects reporting each solicited general symptom included those graded 3 in intensity and those assessed as related to vaccination during the 8-day (Days 0-7) follow-up period, for all doses (Total Vaccinated Cohort)

ST*/CTRS (for % of subjects only)

Table 26 Percentage of doses and of subjects reporting each solicited general included those symptoms graded 3 in intensity and those considered to be related to vaccination, during the first 3-day (Days 0-2) after vaccination (Total vaccinated cohort)

WT

Table 27 Percentage of subjects with missing values for diarrhea, by day, during the solicited 8 days follow-up period (Total vaccinated cohort)

WT

Table 27 Percentage of subjects with missing values for vomiting, by day, during the solicited 8 days follow-up period (Total vaccinated cohort)

WT

Table 27 Percentage of subjects with missing values for fever, by day, during the solicited 8 days follow-up period (Total vaccinated cohort)

WT

Table 28 Duration (in days) of diarrhea, vomiting and fever during the solicited 8 days follow-up period (Total vaccinated cohort)

WT

Table 29

Percentage of subjects with unsolicited symptoms classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination in each HRV vaccine liquid formulation group (Total vaccinated cohort)

ST*



19



Final Analysis

Table 30 Percentage of subjects with unsolicited symptoms classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination in the pooled HRV vaccine liquid formulation group and in the HRV vaccine lyophilised formulation group (Total vaccinated cohort)

ST*

Table 31 Percentage of doses with unsolicited symptoms classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination (Total vaccinated cohort)

ST*

Table 29

Percentage of subjects with grade 3 unsolicited symptoms classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination in each HRV vaccine liquid formulation group (Total vaccinated cohort)

CR*

Table 30 Percentage of subjects with grade 3 unsolicited symptoms classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination in the pooled HRV vaccine liquid formulation group and in the HRV vaccine lyophilised formulation group (Total vaccinated cohort)

CR*

Table 31 Percentage of doses with grade 3 unsolicited symptoms classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination (Total vaccinated cohort)

ST*

Table 29

Percentage of subjects with unsolicited symptoms assessed as related to vaccination classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination in each HRV vaccine liquid formulation group (Total vaccinated cohort)

CR*

Table 30 Percentage of subjects with unsolicited symptoms assessed as related to vaccination classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination in the pooled HRV vaccine liquid formulation group and in the HRV vaccine lyophilised formulation group (Total vaccinated cohort)

CR*

Table 31 Percentage of doses with unsolicited symptoms assessed as related to vaccination classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination (Total vaccinated cohort)

ST*

Table 29

Percentage of subjects with unsolicited symptoms leading to medical attention (hospitalisation, emergency room visit or a visit to or from medical personnel) classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination in each HRV vaccine liquid formulation group (Total vaccinated cohort)

ST*

Table 30 Percentage of subjects with unsolicited symptoms leading to medical attention (hospitalisation, emergency room visit or a visit to or from medical personnel) classified by MedDRA system organ class and preferred term from Day 0 to Day 30 after any vaccination in the pooled HRV vaccine liquid formulation group and in the HRV vaccine lyophilised formulation group (Total vaccinated cohort)

ST*

Table 32 Number of GE episode(s) reported from Dose 1 of HRV vaccine up to Visit 3, (Total vaccinated cohort)

ST

Table 33 Percentage of GE episodes with no available stools results from dose 1 up to visit 3 (Total vaccinated cohort)

ST

Table 34 Percentage of subjects reporting GE episode(s) from Dose 1 up to visit 3 (Total vaccinated cohort)

CR

Table 35 Percentage of subjects reporting RV (vaccine strain or wild-type rotavirus) GE episode(s) from Dose 1 up to Visit 3 (Total vaccinated cohort)

CR/CTRS

Table 36 Number of RV GE episode(s) reported from Dose 1 of HRV vaccine up to Visit 3, by G and P type (Total vaccinated cohort)

ST



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Final Analysis

Table 37 Summary of RV GE episodes reported from Dose 1 of HRV vaccine up to VISIT3 (Total vaccinated cohort)

CR

Table 38 Subjects with serious adverse events reported up to the data lock point for the final analysis up to Visit 3 (Total Vaccinated Cohort)

ST

Table 38 Subjects with serious adverse events reported up to the safety contact (Total vaccinated cohort)

ST (annex report)

Table 39 Number and percentage of doses and of subjects who took at least one concomitant medication from Day 0 to Day 7 after vaccination by type (Total vaccinated cohort)

ST

Table 39 Number and percentage of doses and of subjects who took at least one concomitant medication after vaccination up to Visit 3 by type (Total vaccinated cohort)

ST

Table 40 Number and percentage of subjects with adverse events (Total Vaccinated Cohort) CTRS

Table 41 Number and percentage of subjects with serious adverse events up to the safety contact (Total Vaccinated Cohort)

CTRS (annex report)

CR = Within the clinical report ST = As a supplementary table or figure WT = As a working table or figure CTRS = table for use in the clinical trial registry summary *: a complementary analysis based on the ATP cohort for safety will be provided if more than 5% of the vaccinated subjects are excluded from that cohort. The resulting tables will appear as supplemental tables. $will also be generated for documented doses (refer to RAP from study ROTA-041 for the footnote)

The following figures will be generated.

Figure # in reference of annex 1

Abbreviated Title (See annex 1 for the proposed wording in the statistical report)

Final Analysis

Figure 1 Prevalence of diarrhea by day after Dose 1, during the 8-day (Day 0 to Day 7) solicited follow-up period (Total vaccinated cohort)

ST

Figure 1 Prevalence of diarrhea by day after Dose 2, during the 8-day (Day 0 to Day 7) solicited follow-up period (Total vaccinated cohort)

ST

Figure 1 Prevalence of vomiting by day after Dose 1, during the 8-day (Day 0 to Day 7) solicited follow-up period (Total vaccinated cohort)

ST

Figure 1 Prevalence of vomiting by day after Dose 2, during the 8-day (Day 0 to Day 7) solicited follow-up period (Total vaccinated cohort)

ST

Figure 1 Prevalence of fever by day after Dose 1, during the 8-day (Day 0 to Day 7) solicited follow-up period (Total vaccinated cohort)

ST



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Figure 1 Prevalence of fever by day after Dose 2, during the 8-day (Day 0 to Day 7) solicited follow-up period (Total vaccinated cohort)

ST

Figure 2 Percentage of subjects who took antipyretics after Dose 1, by day from Day 0 to Day 30 (Total vaccinated cohort)

ST

Figure 2 Percentage of subjects who took antipyretics after Dose 2, by day from Day 0 to Day 30 (Total vaccinated cohort)

ST

ST = As a supplementary table or figure



22

6.7.1. Between groups assessment

All group comparisons with respect to reactogenicity will be exploratory.

The two-sided asymptotic standardized 95% CIs for group difference (Risk Difference) and the two-sided asymptotic score test for the null hypothesis of identical incidence in both groups (significance level of alpha = 0.05) will be computed between each pair of the HRV vaccine liquid formulation group and between the pooled HRV vaccine liquid formulation group and the HRV vaccine lyophilised formulation group for the following endpoints:

• For a given symptom, the percentage of subjects with solicited symptom of any intensity within 8-day after any dose

• For a given symptom, the percentage of subjects with a grade “3” solicited symptom within 8-day after any dose

• For a given symptom, the percentage of subjects with a solicited symptom assessed as related to vaccination within 8-day after any dose

The two-sided asymptotic standardized 95% CIs for group difference (Risk Difference) and the two-sided asymptotic score test for the null hypothesis of identical incidence in both groups (significance level of alpha = 0.05) will be computed between the pooled HRV vaccine liquid formulation group and the HRV vaccine lyophilised formulation group for the following endpoints:

• For unsolicited symptoms , unsolicited symptoms grade “3” in intensity and unsolicited symptoms assessed as related to the vaccination, the percentage of subjects with a symptom within 31 days after any vaccination

P-values less than 0.05 are used as an indicator of a possible difference between groups. However, since p-values are not adjusted for multiplicity of comparisons and did not account for clinical relevant differences, statistically significant findings should be interpreted with caution.

The following tables will be generated.



Final Analysis

Table 24 Statistical comparisons between each HRV vaccine liquid formulation group for the percentage of subjects reporting each solicited symptom during the 8-day (Day 0 to Day 7) follow-up period, after any dose (Total vaccinated Cohort)

ST

Table 25 Statistical comparisons between the pooled HRV vaccine liquid formulation group and the HRV vaccine lyophilised formulation group for the percentage of subjects

ST



23



Final Analysis

reporting each solicited symptom during the 8-day (Day 0 to Day 7) follow-up period, after any dose (Total vaccinated Cohort)

Table 30 For comparison on unsolicited symptoms CR

6.8. Immunogenicity

Anti-Rota IgA will be the single antigen which will be investigated

Antibody type GM C or T?

Assay Cut-off Number of decimal digits

Method Unit GMC GMC ratio Difference

anti-ROTA IgA C ELISA U/ml 20 1 2 2

6.8.1. Within groups assessment



Abbreviated Title (see annex 1 for the proposed wording in the statistical

report)

FINAL ANALYSI

S Table 42 Anti-rotavirus IgA antibody GMC and seroconversion rates - ATP cohort for

immunogenicity CR*/CTRS

Table 43 Anti-rotavirus IgA antibody GMC calculated on subjects seropositive for anti-rotavirus IgA antibodies - ATP cohort for immunogenicity

CR*

CR = Within the clinical report ST = As a supplementary table or figure WT = As a working table or figure CTRS = table for use in the clinical trial registry summary *: a complementary analysis based on the Total Vaccinated cohort will be provided if more than 5% of the vaccinated subjects with immunogenicity results available are excluded from that cohort. The resulting tables will appear as supplemental tables.

The following figures will be generated:

Figure # in reference of annex 1

Abbreviated Title (See annex 1 for the proposed wording in the statistical report)

Final Analysis

Figure 3 Reverse cumulative distribution curves for anti-rotavirus IgA antibody concentrations at Visit 3- ATP cohort for immunogenicity

ST



24

ST = As a supplementary table or figure

6.8.2. Between groups assessment



Abbreviated Title (see annex 1 for the proposed wording in the stat report)

Final Analysis

Table 44 Ratio of anti-rotavirus IgA antibody GMCs at Visit 3 between any pair of the three lots of the liquid formulation of HRV vaccine - ATP cohort for immunogenicity

CR/CTRS

Table 45 Ratio of anti-rotavirus IgA antibody GMCs at visit 3 between the HRV lyophilised formulation group and the HRV liquid formulation groups - ATP cohort for immunogenicity

CR/CTRS

Table 46 Difference between groups in percentage of subjects who seroconverted at visit 3 for serum anti-rotavirus IgA antibody - ATP cohort for immunogenicity

CR/CTRS (for primary endpoints)

CR = Within the clinical report ST = As a supplementary table or figure WT = As a working table or figure CTRS = table for use in the clinical trial registry summary

6.9. Methodology for computing CI

All CI will be 95% CI.

− The exact 95% CIs for proportion within a group will be calculated from Proc StatXact 5.0 assuming independence between doses. Proc StatXact 5.0 was also used to derive the standardized asymptotic 95% CI for the group difference in proportion.

− The 95% CI for GM will be obtained within each group separately. The 95% CI for the mean of log-transformed titre/concentration will be first obtained assuming that log-transformed titres were normally distributed with unknown variance. The 95% CI for the GM will be then obtained by exponential-transformation of the 95% CI for the mean of log-transformed titre/concentration.

− The 95% CI for the ratio of anti-rotavirus IgA antibody GMCs at Visit 3 between the HRV vaccine liquid formulation group will be obtained using an ANOVA model on the logarithm- transformed concentrations. The ANOVA model will include the vaccine group as fixed effect. The GMC ratio and their 95% CI will be derived as exponential-transformation of the corresponding group contrast in the model.

− The 95% CI for the ratio of anti-rotavirus IgA antibody GMCs at Visit 3 between the HRV lyophilised formulation group and (over) the HRV liquid formulation group will be computed. This will be done using the group contrast between the HRV lyophilised



25

formulation group and the average of the HRV liquid formulation groups: (1, -1/3, -1/3, -1/3), in a one-way ANOVA model on the logarithm10 transformation of the titres

7. CHANGE FROM PROTOCOL

Incidence of solicited and unsolicited adverse events will be compared between the HRV groups using

• two-sided asymptotic standardized 95% CIs for group difference (Risk Difference)

• and two-sided asymptotic score test for the null hypothesis of identical incidence in both groups

instead of two-sided Fisher Exact test.



26

8. INDIVIDUAL LISTINGS

Appendix Table I.A - Elimination codes

Appendix Table I.B - Demography

Appendix Table I.Ci - Dates of birth, Informed consent, Vaccination and blood sampling, Visit

Appendix Table I.Cii - Reason for visit not done

Appendix Table I.D - General medical history - Physical examination

Appendix Table I.Ei – Study conclusion

Appendix Table IGi – Vaccination procedure for each subject: list of the administered vaccines and all related information

Appendix Table IGii – Routine vaccine administration

Appendix Table I.H – Vaccine intake characteristics

Appendix Table I.I - Reason for not administration of vaccine

Appendix Table I.I - Reason for non-Eligibility

Appendix Table II.B - Solicited general symptoms

Appendix Table II.Ci - Unsolicited adverse events within 31 days post-vaccination

Appendix Table II.Cii - Unsolicited adverse events started more than 31 days post-vaccination

Appendix Table II.Ciii – Serious adverse events during the study period

Appendix Table II.Di - Concomitant medications

Appendix Table II.Dii - Concomitant vaccinations

Appendix Table III.A – Immunogenicity

Appendix Table IV.B - Gastroenteritis stool collection results



27

9. ANNEX 1: TEMPLATE OF TABLES

The values in the tables and graphs below have just been taken as an example.

Table 8 Number of subjects enrolled into the study as well as the number of subjects excluded from ATP analyses with reasons fo r exclusion.

Total LIQ_LOTA LIQ_LOTB LIQ_LOTC LYO

Title n s % n S n S n S n S Total enrolled cohort 1200

Total vaccinated cohort 1200 100 300 300 300 300 Administration of vaccine(s) forbidden in the protocol ( code 1040 )

26 26 2 2 11 11 2 2 11 11

Study vaccine dose not administered according to protocol ( code 1070 )

11 11 2 2 1 1 2 2 1 1

ATP safety cohort 1200 100 400 400 300 400

Protocol violation (inclusion/exclusion criteria) ( code 2010 )

3 3 0 0 1 1 0 0 1 1

Initially seropositive or initially unknown antibody status ( code 2020 )

3 3 0 0 1 1 0 0 1 1

Underlying medical condition forbidden by the protocol ( code 2050 )

1 1 0 0 0 0 0 0 0 0

Non compliance with vaccination schedule ( including wrong and unknown dates ) ( code 2080 )

3 4 1 1 2 3 1 1 2 3

Non compliance with blood sampling schedule ( including wrong and unknown dates ( code 2090 )

4 8 1 2 1 3 1 2 1 3

Essential serological data missing ( code 2100 )

30 33 9 9 9 10 9 9 9 10

Obvious incoherence or abnormality or error in data ( code 2120 )

2 4 0 0 1 1 0 0 1 1

ATP immunogenicity cohort 1195 98 298 299 299 299 Note: Subjects may have more than one elimination code assigned n = number of subjects with the elimination code assigned excluding subjects who have been assigned a lower elimination code number s = number of subjects with the elimination code assigned % = percentage of subjects in the considered ATP cohort relative to the Total vaccinated cohort Data source = Appendix table IA The ATP cohort for safety includes all vaccinated subjects with no elimination codes beginning with one thousand. The ATP cohort for immunogenicity includes all vaccinated subjects with no elimination codes beginning with one or two thousand.



28

Table 9 Number of subjects at each visit and list of withdrawn subjects from visit 1 to visit 3 (Total Vaccinated Cohort)

Group VISIT N Withdrawn Subject numbers

Reason for withdrawal

Data source = Appendix table IC, Appendix table IEi

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the

Patient Level Data section of the Sponsor Clinical Study Register.



29

Table 10 Number of subjects vaccinated, completed a nd withdrawn with reason for withdraw at visit 3 (Total Vaccinated Co hort)

Group LIQ_LOTA LIQ_LOTB LIQ_LOTC LYO Total

Number of subjects vaccinated 300 300 300 300 1200 Number of subjects completed 245 248 252 245 990 Number of subjects withdrawn 3 1 4 1 4 Reasons for withdrawal : Serious Adverse Event 0 0 0 0 0 Non-serious adverse event 0 0 0 0 0 Protocol violation 0 0 0 0 0 Consent withdrawal (not due to an adverse event) 1 0 1 0 1 Migrated/moved from study area 0 0 0 0 0 Lost to follow-up (subjects with incomplete vaccination course)

2 1 3 1 3

Lost to follow-up (subjects with complete vaccination course) 0 0 0 0 0 Others 0 0 0 0 0 Vaccinated = number of subjects who were vaccinated in the study Completed = number of subjects who completed study visit 3 Withdrawn = number of subjects who did not come for study visit 3 Data source = Appendix table IEi

Table 11 Deviations from specifications for age and intervals between study visits (Total Vaccinated Cohort)

AGE Dose 1 – Dose 2 Dose 2 – PII(M3)

GROUP Protocol Protocol Adapted Protocol Adapted

from 10 to 17 weeks from 30 to 48 days

from 21 to 48 days from 30 to 48 days from 21 to 48 days

LIQ_LOTA N 635 Xxx Xxx Xxx Xxx n Xxx Xxx Xxx Xxx Xxx % Xxx Xxx Xxx Xxx Xxx range Xxx Xxx Xxx Xxx Xxx LIQ_LOTB N 635 Xxx Xxx Xxx Xxx n Xxx Xxx Xxx Xxx Xxx % Xxx Xxx Xxx Xxx Xxx range Xxx Xxx Xxx Xxx Xxx LIQ_LOTC N 635 Xxx Xxx Xxx Xxx n Xxx Xxx Xxx Xxx Xxx % Xxx Xxx Xxx Xxx Xxx range Xxx Xxx Xxx Xxx Xxx LYO N 635 Xxx Xxx Xxx Xxx n Xxx Xxx Xxx Xxx Xxx % Xxx Xxx Xxx Xxx Xxx range Xxx Xxx Xxx Xxx Xxx Adapted = interval used for defining the ATP cohorts for immunogenicity N = total number of subjects with available results



30

n/% = number / percentage of subjects with results outside of the interval range = minimum-maximum for age and intervals Data source = Appendix table IB, Appendix table ICi

Table 12 Minimum and maximum visit dates from visit 1 to the last contact

(Total Vaccinated Cohort)

Visit number Activity number Minimum date Maximum date Visit 1 10 12MAY2005 29JUL2005 Visit 2 20 27JUN2005 05OCT2005 Visit 3 30 08AUG2005 21NOV2005 Contact 08DEC2005 21MAR2007

Table 13 Number of subjects by center (Total Vaccinated Cohort)

LIQ_LOTA LIQ_LOTB LIQ_LOTC LYO Total Center n n n n n %

4 4 4 4 14 1.0 4 4 4 4 14 1.0 … … … … … … 28 28 28 28 98 6.8 11 11 11 11 37 2.6 3 3 3 3 11 0.8

All 300 300 300 300 1200 100 n = number of subjects included in each group or in total for a given center or for all centers All = sum of all subjects in each group or in total (sum of all groups) % = n/All x 100 Center = GSK Biologicals assigned center number Data source = Appendix table IB



31

Table 14 Summary of demographic characteristics (AT P cohort for Immunogenicity)

LIQ_LOTA N = 103

LIQ_LOTB N = 52

LIQ_LOTC N = 155

LYOl N = 155

Total N = 1200

Characteristics

Parameters or Categories

Value or n % Value or n % Value or n % Value or n % Value or n %

Age at Dose 1 of HRV Mean 8.7 - 8.8 - 8.8 - 8.8 - 8.8 - vaccine (weeks) SD 1.75 - 1.66 - 1.66 - 1.49 - 1.66 - Median 8.0 - 8.0 - 8.0 - 8.0 - 8.0 - Minimum 1 - 1 - 1 - 5 - 1 - Maximum 13 - 13 - 13 - 13 - 13 - Age at Dose 2 of HRV Mean Xx - Xx - Xx - xx - Xx - vaccine (weeks) SD Xx - Xx - Xx - Xx - Xx - Median Xx - Xx - Xx - Xx - Xx - Minimum x - Xx - Xx - Xx - Xx - Maximum xx - Xx - Xx - Xx - Xx - Gender Female 51 49.5 74 47.

7 74 47.

7 23 44.

2 74 47.

7 Male 52 50.5 81 52.

3 81 52.

3 29 55.

8 81 52.

3 Ethnicity

American Hispanic or Latino

Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

Not American Hispanic or Latino

Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

Race Black 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 White/caucasian 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Arabic/north african 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 East/south east

asian 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0

South asian 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 American hispanic 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Japanese 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Other 0 0.0 1 0.6 1 0.6 1 1.9 1 0.6 Korean 103 100.0 154 99.

4 154 99.

4 51 98.

1 154 99.

4 Height at Visit 1 (cm) Mean 70.9 - 67.2 - 67.2 - 59.9 - 67.2 - SD 92.43 - 75.42 - 75.42 - 2.59 - 75.42 - Median 61.0 - 61.0 - 61.0 - 60.0 - 61.0 - Weight at Visit 1 (kg) Mean 6.2 - 6.2 - 6.2 - 6.1 - 6.2 - SD 0.82 - 0.83 - 0.83 - 0.84 - 0.83 - Median 6.2 - 6.2 - 6.2 - 6.3 - 6.2 - BMI at Visit 1 (kg/m²) Mean 6.2 - 6.2 - 6.2 - 6.1 - 6.2 - SD 0.82 - 0.83 - 0.83 - 0.84 - 0.83 - Median 6.2 - 6.2 - 6.2 - 6.3 - 6.2 - N = total number of subjects n/% = number / percentage of subjects in a given category Value = value of the considered parameter SD = standard deviation Data source = Appendix table IB



32

Table 15 Summary of vaccine intake characteristics (Total vaccinated cohort)

Each LIQ group LYO

Dose Characteristics N n % N n %

Dose 1 Smooth vaccine intake 635 Xxx Xxx 635 Xxx Xxx

Vaccine intake interrupted due to coughing or choking

635 Xxx Xxx 635 Xxx Xxx

Regurgitation after vaccine intake 635 Xxx Xxx 635 Xxx Xxx

Vomiting after vaccine intake 635 Xxx Xxx 635 Xxx Xxx

Dose 2 Smooth vaccine intake Xxx Xxx Xxx Xxx Xxx Xxx

Vaccine intake interrupted due to coughing or choking

Xxx Xxx Xxx Xxx Xxx Xxx

Regurgitation after vaccine intake Xxx Xxx Xxx Xxx Xxx Xxx

Vomiting after vaccine intake Xxx Xxx Xxx Xxx Xxx Xxx

N = number of subjects having received the considered dose n/%= number/percentage of subjects with the specified characteristics Data source = Appendix table ICi and IH



33

Table 16 Summary of co-administered vaccination by dose (Total vaccinated cohort)

Dose 1 LIQ_LOTA

(N = 300) LIQ_LOTB (N = 300)

LIQ_LOTC (N = 300)

LYO (N = 300)

Total (N = 1200)

Categories Value or n

% Value or n

% Value or n

% Value or n

% Value or n

%

Any Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx BCG Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Dose 2

LIQ_LOTA (N = 300)

LIQ_LOTB (N = 300)

LIQ_LOTC (N = 300)

LYO (N = 300)

Total (N = 1200)

Categories Value or n

% Value or n

% Value or n

% Value or n

% Value or n

%

Any Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx BCG Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx N = total number of subjects having received the considered dose of HRV n/% = number/percentage of subjects who received the specified vaccination on the same day as the considered dose of HRV vaccine Data source = Appendix table I.Ci and II.Dii

Table 17 Summary of vaccinations other than HRV adm inistered from birth until Visit 3, excluding vaccination given on the d ay of HRV doses (Total vaccinated cohort)

Before Dose 1

LIQ_LOTA (N=xxx)

LIQ_LOTB (N=xxx)

LIQ_LOTC (N=xxx)

LYO (N=xxx)

Total N=xxx

Characteristics # n % # n % # N % # N % # N %

Any Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx BCG Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Between Dose 1 and Dose 2§

LIQ_LOTA (N=xxx)

LIQ_LOTB (N=xxx)

LIQ_LOTC (N=xxx)

LYO (N=xxx)

Total N=xxx

Characteristics # N % # N % # N % # N % # N %

Any Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx BCG Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Between Dose 2 and Visit 3*

LIQ_LOTA (N=xxx)

LIQ_LOTB (N=xxx)

LIQ_LOTC (N=xxx)

LYO (N=xxx)

Total N=xxx

Characteristics # n % # n % # N % # N % # N % Any xxx xxx xxx xxx xxx xxx xxx xxx xxx Xxx Xxx Xxx Xxx Xxx Xxx BCG xxx xxx xxx xxx xxx xxx xxx xxx xxx Xxx Xxx Xxx Xxx Xxx Xxx N = Before Dose 1 and between Dose 1 and Dose 2 : total number of subjects having received dose 1 of HRV Between Dose 2 and visit 3: total number of subjects having received dose 2 of HRV #= number of doses administered of the specified vaccination excluding vaccination given on the day of HRV doses n/% = number/percentage of subjects who received at least one specified vaccination between the considered visits excluding vaccination given on the day of HRV doses §= up to last contact of conclusion at Visit 3 if dose 2 of HRV was not administered *= up to last contact of conclusion at Visit 3 if visit 3 was not done Data source: Appendix table I.Ci and II.Dii



34

Table 18 Compliance in returning symptom sheets (To tal Vaccinated Cohort)

Doses Number NOT Number Compliance of according of % Dose Group Doses to protocol general SS general

1 LIQ_LOTA Xxx Xxx Xxx Xxx LIQ_LOTB Xxx Xxx Xxx Xxx LIQ_LOTC Xxx Xxx Xxx Xxx LIQ_POOL Xxx Xxx Xxx Xxx LYO Xxx Xxx Xxx Xxx 2 LIQ_LOTA Xxx Xxx Xxx Xxx LIQ_LOTB Xxx Xxx Xxx Xxx LIQ_LOTC Xxx Xxx Xxx Xxx LIQ_POOL Xxx Xxx Xxx Xxx LYO Xxx Xxx Xxx Xxx Total LIQ_LOTA Xxx Xxx Xxx Xxx LIQ_LOTB Xxx Xxx Xxx Xxx LIQ_LOTC Xxx Xxx Xxx Xxx LIQ_POOL Xxx Xxx Xxx Xxx LYO Xxx Xxx Xxx Xxx SS = Symptom sheets used for the collection of solicited AEs Compliance % = (number of doses with symptom sheet return / number of administered doses) X 100 Doses not according to protocol = number of doses with regurgitation or vomiting Data source = Appendix table IG, Appendix table IIA, Appendix table IIB



35

Table 19 Demography of CTRS

Number of subjects LIQ_LOTA LIQ_LOTB LIQ_LOTC LYO

Planned, N Randomised, N (Total Vaccinated Cohort) Completed, n (%) Total Number Subjects Withdrawn, n (%) Withdrawn due to Adverse Events, n (%) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Not applicable Not applicable Withdrawn for other reasons, n (%) Demographics LIQ_LOTA LIQ_LOTB LIQ_LOTC LYO

N (Total Vaccinated Cohort) Females:Males Mean Age, months (SD) White/caucasian, n (%)



36

Table 20 Number and percentage of subjects who rece ived Study vaccine dose(s) (Total vaccinated cohort)

Total number of doses received

LIQ_LOTA (N = XXX)

LIQ_LOTB (N = XXX)

LIQ_LOTC (N = XXX)

LYO (N = XXX)

Total (N = XXX)

N % N N N % % % N %

1 XXX XX.X XXX XXX XXX XX.X XX.X XX.X XXX XX.X

2 XXX XX.X XXX XXX XXX XX.X XX.X XX.X XXX XX.X

Any XXX XX.X XXX XXX XXX XX.X XX.X XX.X XXX XX.X

N = number of subjects in each group or in total included in the considered cohort n/% = number/percentage of subjects receiving the specified total number of doses Any = number and percentage of subjects receiving at least one dose Data source = Appendix table IG

Table 21 Percentage of doses and of subjects report ing symptoms (solicited or unsolicited) reported during the 8-day (Days 0-7 ) follow-up period (Total vaccinated cohort)

Any symptom 95% CI

Group N n % LL UL Dose 1 LIQ_LOTA XXX XX XX.X XX.X XX.X LIQ_LOTB XXX XX XX.X XX.X XX.X LIQ_LOTC XXX XX XX.X XX.X XX.X Liq_Pool XXX XX XX.X XX.X XX.X LYO XXX XX XX.X XX.X XX.X Dose 2 LIQ_LOTA XXX XX XX.X XX.X XX.X LIQ_LOTB XXX XX XX.X XX.X XX.X LIQ_LOTC XXX XX XX.X XX.X XX.X Liq_Pool XXX XX XX.X XX.X XX.X LYO XXX XX XX.X XX.X XX.X Overall/dose LIQ_LOTA XXX XX XX.X XX.X XX.X LIQ_LOTB XXX XX XX.X XX.X XX.X LIQ_LOTC XXX XX XX.X XX.X XX.X Liq_Pool XXX XX XX.X XX.X XX.X LYO XXX XX XX.X XX.X XX.X Overall/subject LIQ_LOTA XXX XX XX.X XX.X XX.X LIQ_LOTB XXX XX XX.X XX.X XX.X LIQ_LOTC XXX XX XX.X XX.X XX.X Liq_Pool XXX XX XX.X XX.X XX.X LYO XXX XX XX.X XX.X XX.X For each dose:

N = number of subjects having received the considered dose n/% = number/percentage of subjects reporting at least one symptom for the considered dose For overall/dose:

N = number of administered doses n/% = number/percentage of doses followed by at least one symptom For overall/subject:

N= number of subjects with at least one administered dose n/%= number/percentage of subjects reporting at least one symptom



37

95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit Data source = Appendix table IIA, Appendix table IIB, Appendix table IICi

Table 22 Percentage of subjects reporting each soli cited general symptom

included those graded 3 in intensity and those asse ssed as related to vaccination during the 8-day (Days 0-7) follow-u p period, for each dose (Total Vaccinated Cohort)

LIQ_LOTA LIQ_LOTB LIQ_LOTC

95% CI 95% CI 95% CI

Symptom Type N n % LL UL N n % LL UL N n % LL UL Dose 1

Cough / runny nose Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Diarrhea Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Fever Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Irritability / Fussiness Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Loss of appetite Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Vomiting Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Liq_Pool LYO

95% CI 95% CI

Symptom Type N n % LL UL N n % LL UL Cough / runny nose Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Diarrhea Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Fever Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Irritability / Fussiness Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Loss of appetite Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Vomiting Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX



38


95% CI 95% CI 95% CI

Symptom Type N n % LL UL N n % LL UL N n % LL UL Dose 2


95% CI 95% CI

Symptom Type N n % LL UL N n % LL UL Cough / runny nose Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Diarrhea Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Fever Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Irritability / Fussiness Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Loss of appetite Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Vomiting Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX N = number of subjects having received the considered dose n/% = number/percentage of subjects reporting the specified symptom for the considered dose All = any occurrence of the specified symptom, irrespective of intensity grade and relationship to vaccination Grade 3 = any occurrence of the specified symptom rated as grade 3 Related = any occurrence of the specified symptom assessed as causally related to the vaccination 95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Data source = Appendix table IIB



39

Table 23 Percentage of doses and subjects reporting each solicited general symptom included those graded 3 in intensity and th ose assessed as related to vaccination during the 8-day (Days 0- 7) follow-up period, for all doses (Total Vaccinated Cohort)


95% CI 95% CI 95% CI

Symptom Type N n % LL UL N n % LL UL N n % LL UL Overall/dose


95% CI 95% CI

Symptom Type N n % LL UL N n % LL UL Cough / runny nose Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Diarrhea Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Fever Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Irritability / Fussiness Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Loss of appetite Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Vomiting Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX LIQ_LOTA LIQ_LOTB LIQ_LOTC

95% CI 95% CI 95% CI

Symptom Type N n % LL UL N n % LL UL N n % LL UL Overall/subject

Cough / runny nose Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX



40


95% CI 95% CI 95% CI

Symptom Type N n % LL UL N n % LL UL N n % LL UL Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Diarrhea Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Fever Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Irritability / Fussiness Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Loss of appetite Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Vomiting Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Liq_Pool LYO

95% CI 95% CI

Symptom Type N n % LL UL N n % LL UL Cough / runny nose Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Diarrhea Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Fever Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Irritability / Fussiness Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Loss of appetite Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Vomiting Total XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Grade 3 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX Related XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX For overall/dose: N= number of administered doses n/%= number/percentage of doses followed by the specified symptom For overall/subject: N= number of subjects with at least one administered dose n/%= number/percentage of subjects reporting at least once the specified symptom All = any occurrence of the specified symptom, irrespective of intensity grade and relationship to vaccination Grade 3 = any occurrence of the specified symptom rated as grade 3 Related = any occurrence of the specified symptom assessed as causally related to the vaccination 95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Data source = Appendix table IIB



41

Table 24 Statistical comparisons between each HRV v accine liquid formulation group for the percentage of subjects reporting each solicited symptom during the 8-day ( Day 0 to Day 7) follow-up period, after any dose (T otal vaccinated Cohort)

Risk Difference (LIQ_LOTA minus LIQ_LOTB)

Risk Difference (LIQ_LOTA minus LIQ_LOTC)

Risk Difference (LIQ_LOTB minus LIQ_LOTC)

Symptoms Type Value 95 % CI P-Value

Value 95 % CI P-Value

Value 95 % CI P-Value

Overall/subject L.L U.L L.L U.L L.L U.L

COUGH/runny nose All Grade3 Related

DIARRHEA All Grade3 Related

FEVER All Grade3 Related

IRRITABILITY All / FUSSINESS Grade3 Related

LOSS OF APPETITE All Grade3 Related

VOMITING All Grade3 Related

All = any occurrence of the specified symptom, irrespective of intensity grade and relationship to vaccination Grade 3 = any occurrence of the specified symptom rated as grade 3 Related = any occurrence of the specified symptom assessed as causally related to the vaccination 95% CI = asymptotic standardised 95% confidence interval; L.L. = lower limit, U.L. = upper limit



42

P-value = results of comparison of percentage of subjects reporting the specified solicited symptom after any doses between groups by two-sided asymptotic score test for the null hypothesis of identical incidence in both groups (P-value less than 0.05 will be used as an aid to highlight potential difference worth further attention. However care must be taken when interpreting putative statistically significant findings since there is no multiplicity adjustment and clinical significance must be taken into account). Data source = Appendix table IIB



43

Table 25 Statistical comparisons between the pooled HRV vaccine liquid formulation group and the HRV vaccine lyophilised f ormulation group for the percentage of subjects reporting each solicited symptom during the 8-day (Day 0 to Day 7) follow-up period, after any dose (Total vaccinated Cohort)

Risk Difference (LIQ_POOL minus LYO)

Symptoms Type Value 95 % CI P-Value

Overall/subject L.L U.L

COUGH/runny nose All Grade3 Related

DIARRHEA All Grade3 Related

FEVER All Grade3 Related

IRRITABILITY All / FUSSINESS Grade3 Related

LOSS OF APPETITE All Grade3 Related

VOMITING All Grade3 Related

All = any occurrence of the specified symptom, irrespective of intensity grade and relationship to vaccination Grade 3 = any occurrence of the specified symptom rated as grade 3 Related = any occurrence of the specified symptom assessed as causally related to the vaccination 95% CI = asymptotic standardised 95% confidence interval; L.L. = lower limit, U.L. = upper limit P-value = results of comparison of percentage of subjects reporting the specified solicited symptom after any doses between groups by two-sided asymptotic score test for the null hypothesis of identical incidence in both groups (P-value less than 0.05 will be used as an aid to highlight potential difference worth further attention. However care must be taken when interpreting putative statistically significant findings since there is no multiplicity adjustment and clinical significance must be taken into account). Data source = Appendix table IIB



44

Table 26 Percentage of doses and of subjects report ing each solicited general included those symptoms graded 3 in intensity and those considered to be related to vac cination, during the first 3-day (Days 0-2) after v accination (Total vaccinated cohort)

LIQ_LOTA LIQ_LOTB LIQ_LOTC Liq_Pool LYO 95 % CI 95 % CI 95 % CI 95 % CI 95%CI

Symptom Follow-up Type N n % LL UL N n % LL UL N n % LL UL N n % LL UL N n % LL UL Dose 1

Cough 3 days All Grade 3 Rel Diarrhoea 3 days All [6 - ... Rel Fever/(Rectally) (°C)

3 days All

[39.6 - ... Rel Irritability 3 days All Grade 3 Rel Loss of appetite 3 days All Grade 3 Rel Vomiting 3 days All [3 - ... Rel

Dose 2 Cough 3 days All Grade 3 Rel Diarrhoea 3 days All [6 - ... Rel Fever/(Rectally) (°C)

3 days All

[39.6 - ...



45


Symptom Follow-up Type N n % LL UL N n % LL UL N n % LL UL N n % LL UL N n % LL UL

Rel Irritability 3 days All Grade 3 Rel Loss of appetite 3 days All Grade 3 Rel Vomiting 3 days All [3 - ... Rel

Overall/dose Cough 3 days All Grade 3 Rel Diarrhoea 3 days All [6 - ... Rel Fever/(Rectally) (°C)

3 days All

[39.6 - ... Rel Irritability 3 days All Grade 3 Rel Loss of appetite 3 days All Grade 3 Rel Vomiting 3 days All [3 - ... Rel

Overall/subject Cough 3 days All Grade 3 Rel



46


Symptom Follow-up Type N n % LL UL N n % LL UL N n % LL UL N n % LL UL N n % LL UL

Diarrhoea 3 days All [6 - ... Rel Fever/(Rectally) (°C)

3 days All

[39.6 - ... Rel Irritability 3 days All Grade 3 Rel Loss of appetite 3 days All Grade 3 Rel Vomiting 3 days All [3 - ... Rel For each dose and overall/subject: N = number of subjects having received the considered dose n/% = number/percentage of subjects reporting the specified symptom for the considered dose For overall/dose: N= number of administered doses n/%= number/percentage of doses followed by the specified symptom For overall/subject: N= number of subjects with at least one administered dose n/%= number/percentage of subjects reporting at least once the specified symptom Onset 3 days = onset on day 0, 1 or 2 All = any occurrence of the specified symptom, irrespective of intensity grade and relationship to vaccination Grade 3 = any occurrence of the specified symptom rated as grade 3 Related = any occurrence of the specified symptom assessed as causally related to the vaccination 95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Data source = Appendix table IIB



47

Table 27 Percentage of subjects with missing values for diarrhea, by day, during the solicited 8 days follow-up period (Total vaccinated cohort)

LIQ_LOTA N=xxxx

LIQ_LOTB N=xxxx

LIQ_LOTC N=xxxx

Liq_Pool N=XXX

LYO N=xxxx

n % n % n % n % n % Dose 1 Day 0 … … … … … … … … Day 1 … … … … … … … … Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Dose 2 Day 0 … … … … … … … … Day 1 … … … … … … … … Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 N= number of subjects reporting diarrhea (vomiting, fever) n/%= number/percentage of subjects with missing values by day and by group



48

Table 28 Duration (in days) of diarrhea, vomiting a nd fever during the solicited 8 days follow-up period (Total vaccinated cohort)

Solicited symptom Dose Group n Mean Min Q1 Median Q3 Max

Diarrhea Dose 1 LIQ_LOTA XX X.x X.x X.x X.x X.x X.x LIQ_LOTB LIQ_LOTC

Liq_Pool

LYO Dose 2 LIQ_LOTA LIQ_LOTB LIQ_LOTC

Liq_Pool

LYO Overall/Dose LIQ_LOTA LIQ_LOTB LIQ_LOTC

Liq_Pool

LYO Vomiting Dose 1 LIQ_LOTA LIQ_LOTB LIQ_LOTC

Liq_Pool


Liq_Pool


Liq_Pool

LYO Fever Dose 1 LIQ_LOTA LIQ_LOTB LIQ_LOTC

Liq_Pool


Liq_Pool


Liq_Pool

LYO n = number of doses reporting the specified solicited symptom with value for at least one day of follow-up Q1 = 25th percentile, Q3 = 75th percentile Duration* = number of days, not necessarily consecutive days, with presence of the symptoms. Missing value at a specific day is considered as absence of the symptom on that day Data source: Appendix II.B



49

Table 29 Percentage of subjects with unsolicited sy mptoms classified by MedDRA system organ class and preferred term from D ay 0 to Day 30 after any vaccination in each HRV vaccine liquid formulation group (Total vaccinated cohort)

Primary System Organ Preferred Term LIQ_LOTA LIQ_LOTB LIQ_LOTC

PL Class (CODE) (CODE) n % 95% CI n % 95% CI n % 95% CI LL UL LL UL LL UL At least one symptom Gastrointestinal disorders (10017947)

Inguinal hernia (10022016)

General disorders and administration site conditions

Pain (10033371)

(10018065) Pyrexia (10037660) Source: Appendix Table IICi Notes: N = number of subjects having received at least one dose s/% = number/percentage of subjects reporting at least once a specified unsolicited symptom At least one symptom = number of subjects reporting at least one unsolicited symptom, whatever the MedDRA Preferred Term 95% CI = exact 95% confidence interval, LL = lower limit, UL = upper limit Source: Appendix Table IICi

Table 30 Percentage of subjects with unsolicited sy mptoms classified by MedDRA system organ class and preferred term from D ay 0 to Day 30 after any vaccination in the pooled HRV vaccine liquid formulation group and in the HRV vaccine lyophilise d formulation group (Total vaccinated cohort)

Liq_Pool LYO Risk Difference (Liq_Pool minus LYO)

P-Value

Primary System Organ Class (CODE)

N n % 95% CI* N n % 95% CI* Value 95 % CI**

LL UL LL UL L.L U.L

At least one symptom (each SOC)

At least one symptom = At east one symptom experienced regardless of the System Organ Class N = number of subjects having received at least one dose n/% = number/percentage of subjects reporting at least once a specified unsolicited symptom 95% CI* = exact 95% confidence interval, LL = lower limit, UL = upper limit 95% CI** = asymptotic standardised 95% confidence interval; L.L. = lower limit, U.L. = upper limit P-value = results of comparison of percentage of subjects reporting the specified symptom within 31 days after any doses between groups by two-sided asymptotic score test for the null hypothesis of identical incidence in both groups (P-value less than 0.05 will be used as an aid to highlight potential difference worth further attention. However care must be taken when interpreting putative statistically significant findings since there is no multiplicity adjustment and clinical significance must be taken into account). Individual subjects data can be found in Appendix Table IICi



50

Table 31 Percentage of doses with unsolicited sympt oms classified by MedDRA system organ class and pre ferred term from Day 0 to Day 30 after any vaccination (Total v accinated cohort)

Primary System Organ Preferred Term LIQ_LOTA LIQ_LOTB LIQ_LOTC Liq_Pool LYO

Class (CODE) (CODE) n % 95% CI n % 95% CI n % 95% CI n % 95% CI n % 95% CI LL UL LL UL LL UL LL UL LL UL At least one symptom Gastrointestinal disorders (10017947)

Inguinal hernia (10022016)

General disorders and administration site conditions

Pain (10033371)

(10018065) Pyrexia (10037660) Infections and infestations Abscess (10000269) (10021881) Bronchitis acute (10006452) Cellulitis (10007882) Furuncle (10017553) Gastroenteritis (10017888) Human herpesvirus 6 infection

(10020431)

Impetigo (10021531) Meningitis bacterial (10027202) Nasopharyngitis (10028810) Oral candidiasis (10030963) Pneumonia (10035664) Rhinitis (10039083) Skin infection (10040872) Upper respiratory tract infection

(10046306)

Viral infection (10047461) Notes: D = Total number of doses administered d/% = number/percentage of doses followed by at least one report of the specified unsolicited symptom At least one symptom = number of doses followed by at least one report of an unsolicited symptom whatever the MedDRA Preferred Term 95% CI = exact 95% confidence interval, LL = lower limit, UL = upper limit



51

Table 32 Number of GE episode(s) reported from Dose 1 of HRV vaccine up to Visit 3, (Total vaccinated cohort)

Group Between Dose 1 Between Dose 2 On combined and before Dose 2 and Visit 3 Doses n n n

LIQ_LOTA (N=xxx) Xxx Xxx Xxx LIQ_LOTB (N=xxx) Xxx Xxx Xxx LIQ_LOTC (N=xxx) Xxx Xxx Xxx LYO (N=xxx) Xxx Xxx Xxx

N = number of subjects having received at least one dose n= number of gastroenteritis episodes reported during the specified period Data source: Appendix IIB and IIC

Table 33 Percentage of GE episodes with no availabl e stools results from dose 1 up to visit 3 (Total vaccinated cohort)

LIQ_LOTA LIQ_LOTB LIQ_LOTC Liq_Pool LYO

(N’=xxx) (N’=xxx) (N’=xxx) (N’=xxx) (N’=xxx)

Category n % n % n % n % n %

No stools collected x xx.x x xx.x x xx.x x xx. x xx.x Stools collected but no results available No stool results available N’= number of gastroenteritis episodes reported n/%= number/percentage of gastroenteritis episodes reported with the specified category Data Source: Appendix table IIB, IIC, IVA and IVB

Table 34 Percentage of subjects reporting GE episod e(s) from Dose 1 up to visit 3 (Total vaccinated cohort)

Group Between Dose 1 and before Dose 2 Between Dose 2 and Visit 3 Between Dose 1 and Visit 3 N n % 95%CI N n % 95%CI N n % 95%CI L.L. U.L. L.L. U.L. L.L. U.L.

LIQ_LOTA Xx Xx Xx.x Xx.x Xx.x Xx Xx Xx.x Xx.x Xx.x Xx Xx Xx.x Xx.x Xx.x LIQ_LOTB Xx Xx Xx.x Xx.x Xx.x Xx Xx Xx.x Xx.x Xx.x Xx Xx Xx.x Xx.x Xx.x LIQ_LOTC Xx Xx Xx.x Xx.x Xx.x Xx Xx Xx.x Xx.x Xx.x Xx Xx Xx.x Xx.x Xx.x LYO Xx Xx Xx.x Xx.x Xx.x Xx Xx Xx.x Xx.x Xx.x Xx Xx Xx.x Xx.x Xx.x

Between Dose 1 and before Dose 2: N = number of subjects having received the first dose Between Dose 2 and Visit 3: N = number of subjects having received the second dose Between Dose 1 and Visit 3: N = number of subjects having received at least one dose n/% = number/percentage of subjects reporting at least one gastroenteritis episode during the specified period 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit Data source: Appendix table IIB, IIC, IVA and IVB



52

Table 35 Percentage of subjects reporting RV (vaccine strain or wild-type rotavirus) GE episode(s) from Dose 1 up to Visit 3 (Total vaccinated cohort)

Group Between Dose 1 and before Dose 2 Between Dose 2 and Visit 3 Between Dose 1 and Visit 3

N n % 95%CI N n % 95%CI N N % 95%CI

L.L. U.L. L.L. U.L. L.L. U.L.

LIQ_LOTA 100 Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

LIQ_LOTB 100 Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

LIQ_LOTC 100 Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

LYO 100 Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

Between Dose 1 and before Dose 2: N = number of subjects having received the first dose Between Dose 2 and Visit 3: N = number of subjects having received the second dose Between Dose 1 and Visit 3: N = number of subjects having received at least one dose n/% = number/percentage of subjects reporting at least one rotavirus gastroenteritis episode during the specified period 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit Individual subjects data can be found in Appendix table IIB, IIC, IVA and IVB

Table 36 Number of RV GE episode(s) reported from Dose 1 of HRV vaccine up to Visit 3, by G and P type (Total vaccinated cohort)

Serotype LIQ_LOTA LIQ_LOTB LIQ_LOTC Liq_Pool LYO

n’ % n’ % n’

% n’ % n’ %

Any x xx.x x xx.x x xx.x x xx x xx.x G1/P8 vaccine strain unknown

n’/% = number/percentage of the specified serotype rotavirus positive stool sample among all rotavirus positive stool samples collected in case of gastroenteritis episodes from Dose 1 to Visit 3 Any = any specified symptom reported, regardless of the serotype

Table 37 Summary of RV GE episodes reported from Dose 1 of HRV vaccine up to VISIT3 (Total vaccinated cohort)

Group Subject number Previous dose onset RV TYPE

Previous dose = Dose given prior to the start of the GE episode onset = Number of days since last vaccine dose WT=wild type Data source = Appendix table IIB, IIC and IVB



53

Table 38 Subjects with serious adverse events reported up to the data lock point for the final analysis up to Visit 3 (Total Vaccinated Cohort)

Group Pid Case Id Age (Week)

Sex Verbatim Preferred term System Organ Class MA type Dose Day of onset Duration Causality Outcome

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the

Patient Level Data section of the Sponsor Clinical Study Register.



54

Table 39 Number and percentage of doses and of subj ects who took at least one concomitant medication from Day 0 to Day 7 afte r vaccination by type (Total vaccinated cohort)

LIQ_LOTA LIQ_LOTB LIQ_LOTC LYO 95% CI 95% CI 95% CI 95% CI

N n % LL UL N n % LL UL N n % LL UL N n % LL UL Dose 1

Any Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Any antipyretic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Prophylactic antipyretic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Any antibiotic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

Dose 2 Any Xxx Xxx Xxx xxx xxx Xxx Xxx Xxx xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Any antipyretic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Prophylactic antipyretic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Any antibiotic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

Overall/dose Any Xxx Xxx Xxx xxx xxx Xxx Xxx Xxx xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Any antipyretic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Prophylactic antipyretic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Any antibiotic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx

Overall/subject Any Xxx Xxx Xxx xxx xxx Xxx Xxx Xxx xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Any antipyretic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Prophylactic antipyretic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Any antibiotic Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx Xxx For each dose and overall/subject: N= number of subjects with at least one administered dose n/%= number/percentage of subjects who started to take the specified concomitant medication at least once

during the mentioned period For overall/dose: N= number of administered doses n/%= number/percentage of doses after which the specified concomitant medication was started at least once

during the mentioned period 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit Source: Appendix Table II.D.1



55

Figure 1 Prevalence of diarrhea by day after Dose 1 , during the 8-day (Day 0 to Day 7) solicited follow-up period (Total vaccina ted cohort)

1.

Data source = Appendix table II.B



56

Figure 2 Percentage of subjects who took antipyreti cs after Dose 1, by day from Day 0 to Day 30 (Total vaccinated cohort)

Individual subjects data can be found in Appendix Table IIDi



57

Table 40 Number and percentage of subjects with ad verse events (Total Vaccinated Cohort)

Most frequent adverse events - On-Therapy (occuring within day 0-30 following vaccination)

LIQ_LOTA N = 300

LIQ_LOTB N = 300

LIQ_LOTC N = 300

LYO N = 300

Subjects with any AE(s), n(%) 172 (100.0) 86 (100.0) 172 (100.0) 86 (100.0) Rhinitis 59 (34.3) 26 (30.2) 59 (34.3) 26 (30.2) Nervousness 48 (27.9) 22 (25.6) 48 (27.9) 22 (25.6) Fever 30 (17.4) 8 (9.3) 30 (17.4) 8 (9.3) upper resp tract infection 22 (12.8) 11 (12.8) 22 (12.8) 11 (12.8) Conjunctivitis 17 (9.9) 15 (17.4) 17 (9.9) 15 (17.4) Coughing 20 (11.6) 8 (9.3) 20 (11.6) 8 (9.3) otitis media 18 (10.5) 6 (7.0) 18 (10.5) 6 (7.0) Gastroesophageal reflux 18 (10.5) 4 (4.7) 18 (10.5) 4 (4.7) Flatulence 16 (9.3) 4 (4.7) 16 (9.3) 4 (4.7) Fatigue 11 (6.4) 5 (5.8) 11 (6.4) 5 (5.8) abdominal pain 11 (6.4) 3 (3.5) 11 (6.4) 3 (3.5) crying abnormal 6 (3.5) 5 (5.8) 6 (3.5) 5 (5.8) tooth ache 4 (2.3) 5 (5.8) 4 (2.3) 5 (5.8)

Table 41 Number and percentage of subjects with ser ious adverse events up to the safety contact (Total Vaccinated Cohort)

All SAEs LIQ_LOTA N = 300

LIQ_LOTB N = 300

LIQ_LOTC N = 300

LYO N = 300

Subjects with any SAE(s), n(%) [n related] 15 (7.3) [0] 4 (4.0) [0] 15 (7.3) [0] 4 (4.0) [0] Appetite increased 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] Asthma 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] Bronchitis 3 (1.5) [0] 1 (1.0) [0] 3 (1.5) [0] 1 (1.0) [0] Crying abnormal 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] Eczema 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] Fever 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] Gastroenteritis 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] infection bacterial 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] infection viral 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] Injury 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] Laryngitis 0 (0.0) [0] 1 (1.0) [0] 0 (0.0) [0] 1 (1.0) [0] Meningitis 0 (0.0) [0] 1 (1.0) [0] 0 (0.0) [0] 1 (1.0) [0] otitis media 2 (1.0) [0] 0 (0.0) [0] 2 (1.0) [0] 0 (0.0) [0] Pneumonia 4 (2.0) [0] 0 (0.0) [0] 4 (2.0) [0] 0 (0.0) [0] Seborrhea 0 (0.0) [0] 1 (1.0) [0] 0 (0.0) [0] 1 (1.0) [0] Somnolence 1 (0.5) [0] 0 (0.0) [0] 1 (0.5) [0] 0 (0.0) [0] upper resp tract infection 1 (0.5) [0] 1 (1.0) [0] 1 (0.5) [0] 1 (1.0) [0] All fatal SAEs LIQ_LOTA

N = 300 LIQ_LOTB N = 300

LIQ_LOTC N = 300

LYO N = 300

Subjects with any SAE(s), n(%) [n related] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0]



58

Table 42 Anti-rotavirus IgA antibody GMC and seroc onversion rates - ATP cohort for immunogenicity

≥≥≥≥ 20 U/ml GMC 95% CI 95% CI Group Timing N n % LL UL value LL UL LIQ_LOTA PRE PII(M2) LIQ_LOTB PRE PII(M2) LIQ_LOTC PRE PII(M2) LIQ_POOL PRE PII(M2) LYO PRE PII(M2) Notes: N = number of subjects with available results n/% = number/percentage of subjects with concentration above the cut-off 95% CI=95% Confidence interval; L.L =Lower limit; U.L = upper limit Pre = pre-vaccination PII(M2) = blood sample taken one month after the second dose (Visit 3) Individual subjects data can be found in Appendix IIIA



59

Table 43 Anti-rotavirus IgA antibody GMC calculated on subjects seropositive for anti-rotavirus IgA antibodies - AT P cohort for immunogenicity

GMC 95% CI Group Timing N value LL UL LIQ_LOTA Pre

PII(M2) LIQ_LOTB Pre PII(M2) LIQ_LOTC Pre PII(M2) LIQ_POOL Pre PII(M2) LYO Pre PII(M2) Notes: N = number of subjects who were seropositive for anti-rotavirus IgA antibodies 95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper Limit PRE = pre-vaccination PII(M2) = blood sample taken one month after the second dose (Visit 3) Individual subjects data can be found in Appendix IIIA



60

Figure 3 Reverse cumulative distribution curves for anti-rotavirus IgA antibody concentrations at Visit 3- ATP cohort for immunogenicity

Individual subjects data can be found in Appendix IIIA



61

Table 44 Ratio of anti-rotavirus IgA antibody GMCs at Visit 3 between any pair of the three lots of the liquid formulation of HRV vaccine - ATP cohort for immunogenicity

Ratio of GMCs

Group ratio 95 % CI Group N GMT/C Group N GMT/C Value L.L U.L

LIQ_LOTA LIQ_LOTB LIQ_LOTA over LIQ_LOTB

LIQ_LOTA LIQ_LOTC LIQ_LOTA over LIQ_LOTC

LIQ_LOTB LIQ_LOTC LIQ_LOTB over LIQ_LOTC

Notes: N = number of subjects with available results 95% CI LL, UL: 95% lower and upper confidence interval limits (one-way ANOVA model) L.L. = lower limit, U.L. = upper limit Individual subjects data can be found in Appendix IIIA

Table 45 Ratio of anti-rotavirus IgA antibody GMCs at visit 3 between the HRV lyophilised formulation group and the HRV liqui d formulation groups - ATP cohort for immunogenicity

Ratio of GMCs

Group ratio 95 % CI Group N GMT/C Group N GMT/C Value L.L U.L

LIQ_POOL LYO LYO over LIQ_POOL

Notes: N = number of subjects with available results 95% CI LL, UL: 95% lower and upper confidence interval limits (one-way ANOVA model using the group contrast between the HRV lyophilised formulation group and average of the HRV liquid formulation groups) L.L. = lower limit, U.L. = upper limit Individual subjects data can be found in Appendix IIIA

Table 46 Difference between groups in percentage of subjects who seroconverted at visit 3 for serum anti-rotavirus I gA antibody - ATP cohort for immunogenicity

Difference in sero conversion rate

Value 95% CI Group N % Group N % Group Difference % LL UL LIQ_LOTA LIQ_LOTB LIQ_LOTA minusLIQ_LOTB

LIQ_LOTA LIQ_LOTC LIQ_LOTA minus LIQ_LOTC

LIQ_LOTB LIQ_LOTC LIQ_LOTB minus LIQ_LOTC

LIQ_POOL LYO LYO minus LIQ_ POOL

Individual subjects data can be found in Appendix IIIA N = number of subjects with available results, % = percentage of subjects who seroconverted at visit 3 95%CI = asymptotic standardised 95% confidence interval; LL = lower limit; UL = upper limit



62

10. ANNEX 2: ELIMINATION CODE CRITERION TO USE

CLEANING REPORT

Study Id: 107876 Abbreviated Title: Rota-061

Version: � RAP � Draft ver. …. � Final Date: 09 March 2007

Cleaning Scope: Cleaning Level: Interim analysis Full cleaning

Active phase (all subjects, all data) Abridged cleaning

Safety follow-up Automatic

Immunology Manual

Other, specify: Only SAE cleaned

Cleaning site: Rixensart CDMCI Other: __

CDR: __

CLC:

CDA:

CSC:

CDM:

STAT:

Safety:

1. SUMMARY

Nr of subjects enrolled: __

Nr of subjects completed: __

Nr of subjects drop-outs: __ ( attach study conclusion listing for reasons of drop out)



63

2. SERIOUS ADVERSE EVENTS: (Final version not available before analysis)

Total Nr of subjects with SAEs: __

Nr of SAEs related and possibly related to vaccination:

__

(subject number: ) __

Nr of SAEs leading to withdrawal from the study:

__

(subject number: ) __

Nr of SAEs still ongoing at the end of the study:

__

(subjets numbers: ) __

Comments: __

3. PREGNANCIES:

Nr of pregnancies: __

Comments, data not available in the unsolicited AE section:

4. INTERVALS CONSIDERED:

Schedule DM From DM To DM Adapted interval (days/weeks/months)

Age (days/weeks/months/years) – code 2010 1__ DOB VAC_1 10-17 weeks __ Time between vaccinations (days/weeks/months/years) – code 2080

VAC_1 VAC_2 21-48 days VAC_2 VIS_3 21-48 days Time between vaccination and blood sample (days/wee ks/months/years) – code 2090

1 VAC_2 BL_2 21-48 days

DOB=date of birth; VAC=vaccination; BL=Blood sample



64

5. ELIM CODES ALLOCATED AND POINTS TO BE DISCUSSED

(Please annex the Elimination Codes listing)

Elimination from safety and immunology analysis

Code Description

1010 Subject or vaccine number not allocated

Vaccine not administered at all

No subject allocated to the randomised number

Subject No.: __

Comments: __

1030 Study vaccine dose not administered AT ALL but subject number allocated

Subj. __

Comments: __

1040 Administration of concomitant vaccine(s) forbidden in the protocol (see also eligibility criteria)

Subject No.: __

Comments: __

1050 Randomisation failure (subject not randomized in the correct group)

TO BE ATTRIBUTED ONLY BY STAT :

(Check SBIR, replacement, vaccine administration)

Subject No.: __

Comments: __

1060 Randomisation code broken at the investigator site OR at GSK Safety department (ONLY for DOUBLE-BLIND or OBSERVER-BLIND studies)

Subject number Date of unblinding Reason for unblinding

Comments: __

1070 Study vaccine dose not administered according to protocol (attach CL_14):

- One of planned injections not administered and NOT due to drop out



65

Elimination from safety and immunology analysis

Code Description

- Side, site or route of study vaccine administration wrong or unknown

- Replacement vial used NOT corresponding to the correct randomization group

- Subject number not in the randomization list and not requested by the sponsor

- Extra PID

- Wrong vaccine vials given

Subject No.: __

Comments: __

1500 Other (specify): Initially seropositive or unknown ant-rotavirus IgA antibody

Subj. __

Comments: __



66

Elimination from immunology analysis

Code Description

2010 Protocol violation linked to the inclusion/exclusion criteria including age and excluding codes mentioned below.

Subject No.: __

Comments: __

2020 Initially seropositive OR initially unknown antibody status (pre BS missing or unable to test because of hemolysis, insufficient volume, AP ). Please specify the applicable rule:

elimination code if all values are positive or unknown

elimination code if at least one value is positive or unknown

Schedule DM Blood sample DM Antigen DM

__ __ __ __ __ __

Subject No.: __

Comments: __

2030 Biochemistry, haematology and other laboratory values outside range before any vaccination. Please specify the applicable rule:

elimination code if all values are out of range

elimination code if at least one value is out of range


__ __ __ __ __ __

Subject No.: __

Comments: __

2040 Administration of any medication forbidden by the protocol (responsibility of CDM following review of individual data listings)

Subj. __



67

Elimination from immunology analysis

Code Description

2050 Underlying medical condition forbidden by the protocol (responsibility of CDM following review of individual data listings)

Subject No.: __

Comments: __

2060 Concomitant infection related to the vaccine which may influence immune response (responsibility of CDM following review of individual data listings)

Infection related to any of the vaccine component(e.g. lyme infection in a lyme study) (responsibility of CDM following review of individual data listings)

Subject No.: __

Comments: __

2070 Concomitant infection not related to the vaccine which may influence immune response (e.g. Hepatitis infection in a lyme study) (responsibility of CDM following review of individual data listings)

Subject No.: __

Comments: __

2080 Non compliance with vaccination schedules (dates of vaccination not corresponding to adapted protocol intervals or unknown vaccination dates)

Subject No.: __

Comments: __

2090 Non compliance with blood sampling schedules (dates of BS not corresponding to adapted protocol intervals or unknown BS dates)

Subj. __

Comments: __



68

Important remark: if code 2100 is attributed to a subject, codes 2080 and/or 2090 should not be assigned to the same subject

2100 Serological results not available for antigens POST vaccination (including BS lost, Not Done, unable to test, absence of parallelism,). Please specify the applicable rule:

elimination code if all are missing

elimination code if at least one is missing


1__ __ PII(M2)__ __ __ __

Subject No.: __

Comments: __

2110 Essential serological temporarily missing because of not yet tested (interim analysis only)

Antig. __

Subject No.: __

Comments: __

2120 Obvious incoherence, abnormal serology evolution or error in data (incoherence between CRF and results, wrong labeling in BS)

Subject No.: __

Comments: __

2130 Subjects not planned in the protocol to be bled for their all blood sampling visits

Subject No.: __

Comments: __

2500 Other (specify): __

Subject No.: __

Comments: __



69

Extra Elimination from __ analysis

Code Description

Subject No.: __

Comments: __

OTHER POINTS TO CONSIDER

Inform Consent procedure not respected:

Subject Number

Problem Oral IC date if available

__ __ __

Comments: __

Subjects who did not perform their last visit at least 30 days after last vaccination, specify subject numbers: __

Subjects with numbered replacements or wrong vials (version < 12.1): __

Subject Number Replacement Treatment Number

__ __

Comments: __



70

Pending Queries not to be resolved:

Subject Number

Query Id Reason for not sending

__ __ __

Comments: __

Subjects unblinded during the study period

(ONLY for PARTIALLY-BLIND / SINGLE-BLIND / OPEN stu dies) Subject Number

Date of unblinding

Reason for unblinding

__ __ __

Comments: __

Others: __



71

DRAFT VERSION (When FINAL Post-cleaning meeting completed)

CDR signature: (mandatory)

CLC \ CSC signature: (mandatory)

Date of meeting:

FINAL VERSION (When FINAL Pre-analysis meeting completed)

CLC \ CSC signature: (mandatory) __

Date of meeting:



72

11. ANNEX 3: STATISTICAL METHODS

11.1. Confidence interval for a proportion within a group

Let θ, the parameter used for indicating the proportion of subjects in a (infinite) target population developing a specified characteristic within a specified follow-up period after an assumed vaccination. Let N, the size of a randomly selected sample from this population. If n is the number of subjects presenting a given characteristic among these N subjects, the true percentage of subjects with the characteristic (‘θ’) can be estimated by (n/N)*100. Its exact (1-α )% confidence interval is obtained from:

))1222/2

1*21

1

-n*(N+*n, ,*n*finv(

-n)(N+

α+

as the lower boundary

and

))222))2/(1()22(

*21

1

*(N-n, *n,*finv(*n

(N-n)

+−++

α

as the upper boundary.

where finv(probability, degrees of freedom 1, degrees of freedom 2) returns the inverse of the F probability distribution and α is the type I error rate.

11.2. Confidence interval for a geometric mean with in a group

Let m the parameter used for indicating the median of the titers obtained after an assumed vaccination in a (infinite) target population. Let N the size of a randomly selected sample from this population. If Ti is the antibody titer measured for a subject i (i=1,...., N), then, assuming a log normal distribution for Ti, the true median is derived from the geometric mean titer as

∑

= =

NTN

ii

GMT 110 )(log

10

and its (1-α )% confidence interval is obtained from ( )*

10 LLLL = with ( ) 2/1* ))1(*/(*)1),2/(1( −−−−= NNSSDNtinvGMTLL α

( )*

10ULUL = with ( ) 2/1* ))1(*/(*)1),2/(1( −−−+= NNSSDNtinvGMTUL α

as lower limit and upper boundary, respectively



73

where tinv(p, N-1) returns the pth percentile of the Student’s t distribution with (N-1) degrees of freedom, α is the type I error rate and SSD is the sum of the squared deviations on the log10 transformed antibody titers.

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.

in february 2013, glaxosmithkline (gsk) announced a ... · reported during the entire study period...

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