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2011N115015_01 CONFIDENTIAL The GlaxoSmithKline group of companies MEA115575

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Division: Worldwide Development Retention Category: GRS019 Information Type: Protocol Amendment

Title: MEA115575: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study of Mepolizumab Adjunctive Therapy to Reduce Steroid Use in Subjects with Severe Refractory Asthma

Compound Number: SB-240563

Effective Date: 16-AUG-2012

Protocol Amendment Number: 01

Subject: Severe Refractory Asthma, Mepolizumab, Eosinophils, SB-240563, Efficacy, Safety, Steroid Reduction, Quality of Life

Author:

Copyright 2012 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

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Revision Chronology:

2011N115015_00 2012-MAY-29 Original

2011N115015_01 2012-AUG-16 Amendment No.: 01: Modified wording of primary and select secondary efficacy endpoints for clarity and reduced the number of secondary efficacy endpoints.

Provided additional direction for the treatment of exacerbations during the various study phases

Clarified error in Inclusion criteria #6 and modified cardiovascular exclusion criteria and related assessment to provide additional direction on how to assess this criterion. Appendix 5 and Appendix 6 were added to support this modification.

The term biologic removed throughout and replaced with more specific term monoclonal antibody/ies

Randomisation criterion 4 modified to allow for airway hyper-responsiveness testing with mannitol.

Added normal saline as the placebo to the Investigational Product Section 5.1

Clarified Table 5 to indicate that all scheduled phone visits should be called into RAMOS

Clarified definition of clinically significant exacerbations to include worsening of asthma requiring hospitalization and/or Emergency Department visits

Added Section 6.3.5 and Section 6.3.6 to document the additional data to be collected and the timeframe of collection for cardiovascular AE/SAEs and for death, to be consistent with a new GSK wide initiative using standard protocol language

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Clarified that subjects to not have to be in the fasted state for an unscheduled Early Withdrawal Visit (Section 6.3.10.3)

Typographical errors corrected throughout

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2011N115015_01 CONFIDENTIAL MEA115575

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SPONSOR INFORMATION PAGE

Clinical Study Identifier: MEA115575

Sponsor Legal Registered Address:

GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK

Sponsor Contact Address:

GlaxoSmithKline Research & Development Limited Iron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK Telephone:

GlaxoSmithKline Research & Development Limited Five Moore Drive P.O. 13398 Research Triangle Park, NC 27709-3398, USA Telephone: 2100

In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission.

Sponsor Global Medical Monitor Contact Information:

MD (Director, Respiratory & Immuno-Inflammation Medicine Discovery and Development)

Tel:

Mobile:

Sponsor Back-up Global Medical Monitor Contact Information:

MD (Medical Director, Respiratory and Immuno-Inflammation Medicine Discovery and Development)

Tel:

Mobile:

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Sponsor Serious Adverse Events (SAE) Contact Information:

Case Management Group, Global Clinical Safety and Pharmacovigilance (GCSP)

Email:

Fax:

Regulatory Agency Identifying Number(s):

IND No: 006971

EudraCT: 2012-001497-29

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INVESTIGATOR AGREEMENT PAGE

For protocol number MEA115575

I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.

I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study.

I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.

Investigator Name: _____________________________

Investigator Signature Date

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TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS ............................................................................................. 11

PROTOCOL SUMMARY ................................................................................................. 13

1. INTRODUCTION ..................................................................................................... 15 1.1. Background .................................................................................................. 15 1.2. Rationale ...................................................................................................... 16

2. OBJECTIVE(S) ........................................................................................................ 16

3. INVESTIGATIONAL PLAN ...................................................................................... 17 3.1. Study Design ................................................................................................ 17 3.2. Discussion of Design .................................................................................... 18

3.2.1. Screening and OCS Optimisation Phase ...................................... 18 3.2.1.1. Exacerbation Management during Optimisation

Phase .......................................................................... 20 3.2.2. Induction Phase (Randomisation) ................................................. 21

3.2.2.1. Exacerbation Management during Induction Phase .......................................................................... 21

3.2.3. OCS Reduction Phase and Maintenance Phase .......................... 22 3.2.3.1. Exacerbation Management during Reduction

and Maintenance Phases ............................................ 23 3.2.4. Open-Label Extension and Study Completion .............................. 24

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA ....................................... 24 4.1. Number of Subjects ...................................................................................... 24 4.2. Inclusion Criteria .......................................................................................... 24 4.3. Exclusion Criteria ......................................................................................... 26 4.4. Randomisation Criteria ................................................................................. 27 4.5. Withdrawal Criteria ....................................................................................... 29 4.6. Screening/Run-in Failures ............................................................................ 30

5. STUDY TREATMENTS ........................................................................................... 30 5.1. Investigational Product and Other Study Treatment .................................... 30 5.2. Dosage and Administration .......................................................................... 31 5.3. Treatment Assignment ................................................................................. 32 5.4. Blinding ........................................................................................................ 32 5.5. Product Accountability .................................................................................. 33 5.6. Treatment Compliance ................................................................................. 33 5.7. Concomitant Medications and Non-Drug Therapies .................................... 33

5.7.1. Permitted Medications and Non-Drug Therapies .......................... 33 5.7.2. Prohibited Medications and Non-Drug Therapies ......................... 34

5.8. Treatment after the End of the Study ........................................................... 35 5.9. Treatment of Study Treatment Overdose ..................................................... 35

6. STUDY ASSESSMENTS AND PROCEDURES ...................................................... 36 6.1. Critical Baseline Assessments ..................................................................... 41

6.1.1. Critical Procedures Performed at Screening Visit 1 ...................... 41

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6.1.2. Critical Procedures Performed at Visit 2 ....................................... 42 6.1.3. Critical Procedures Performed at Visit 3 ....................................... 43 6.1.4. Pulmonary Function Testing including Reversibility using

the Maximum Post-Bronchodilator Method ................................... 43 6.1.5. Cardiovascular Assessment ......................................................... 44

6.2. Efficacy ......................................................................................................... 44 6.2.1. Efficacy Endpoints ........................................................................ 44 6.2.2. OCS Dose Adjustment and eDiary ............................................... 45 6.2.3. Exacerbation ................................................................................. 46 6.2.4. St. George’s Respiratory Questionnaire ....................................... 47 6.2.5. Beck Depression Inventory II (BDI II) ............................................ 48 6.2.6. Asthma Control Questionnaire -5 (ACQ-5) ................................... 48 6.2.7. Nasal Symptoms Individual Analogue Scale (VAS) ...................... 49

6.3. Safety ........................................................................................................... 49 6.3.1. Safety Endpoints ........................................................................... 49 6.3.2. Liver chemistry stopping and follow up criteria ............................. 50 6.3.3. Adverse Events ............................................................................. 53

6.3.3.1. Definition of an AE ....................................................... 53 6.3.3.2. Definition of a SAE ...................................................... 54

6.3.4. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs .......................................................... 55

6.3.5. Cardiovascular Events .................................................................. 55 6.3.6. Death Events ................................................................................ 55 6.3.7. Pregnancy ..................................................................................... 56 6.3.8. Medical Devices ............................................................................ 56 6.3.9. Time Period and Frequency of Detecting AEs and SAEs ............. 57 6.3.10. Prompt Reporting of Serious Adverse Events and Other

Events to GSK .............................................................................. 58 6.3.10.1. Regulatory reporting requirements for SAEs ............... 59

6.3.11. Vital Signs ..................................................................................... 59 6.3.12. Twelve-lead electrocardiogram (ECG) .......................................... 60 6.3.13. Clinical Laboratory Parameters ..................................................... 60

6.4. Health Outcomes.......................................................................................... 60 6.4.1. Health Outcome Endpoints ........................................................... 60 6.4.2. Clinician/Subject Rated Response to Therapy ............................. 61 6.4.3. Work Productivity and Activity Impairment Questionnaire:

General Health (WAPI-GH) ........................................................... 61 6.4.4. Steroid Perception Questionnaire ................................................. 62 6.4.5. Medical Outcomes Study (MOS) Sleep Scale .............................. 62 6.4.6. Missed Days of School/Work ........................................................ 62

6.5. Pharmacokinetics ......................................................................................... 62 6.6. Pharmacodynamics ...................................................................................... 62 6.7. Immunogenicity ............................................................................................ 63 6.8. Pharmacogenetic Research ......................................................................... 63 6.9. Exploratory Biomarkers ................................................................................ 63

7. DATA MANAGEMENT ............................................................................................. 63

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 64 8.1. Hypotheses .................................................................................................. 64 8.2. Study Design Considerations ....................................................................... 64

8.2.1. Sample Size Assumptions ............................................................ 64

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8.2.2. Sample Size Sensitivity ................................................................. 65 8.2.3. Sample Size Re-estimation ........................................................... 65

8.3. Data Analysis Considerations ...................................................................... 65 8.4. Analysis Populations .................................................................................... 65

8.4.1. Analysis Data Sets ........................................................................ 66 8.4.2. Treatment Comparisons ............................................................... 66

8.4.2.1. Primary Comparisons of Interest ................................. 66 8.4.3. Interim Analysis ............................................................................. 66 8.4.4. Key Elements of Analysis Plan ..................................................... 67

8.4.4.1. Efficacy Analyses ........................................................ 67 8.4.4.2. Safety Analyses ........................................................... 69 8.4.4.3. Health Outcomes Analyses ......................................... 70 8.4.4.4. Pharmacokinetic Analyses .......................................... 70 8.4.4.5. Pharmacodynamic Analyses ....................................... 70 8.4.4.6. Pharmacogenetic Analyses ......................................... 70 8.4.4.7. Exploratory Biomarker(s) Analyses ............................. 71

9. STUDY CONDUCT CONSIDERATIONS ................................................................. 71 9.1. Posting of Information on Publicly Available Clinical Trial Registers ............ 71 9.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process .......................................................................................... 71 9.3. Quality Control (Study Monitoring) ............................................................... 72 9.4. Quality Assurance ........................................................................................ 72 9.5. Study and Site Closure................................................................................. 72 9.6. Records Retention........................................................................................ 73 9.7. Provision of Study Results to Investigators, Posting of Information

on Publicly Available Clinical Trials Registers and Publication .................... 73 9.8. Independent Data Monitoring Committee (IDMC) ........................................ 74

10. REFERENCES ........................................................................................................ 75

11. APPENDICES .......................................................................................................... 78 11.1. Appendix 1: Acceptable Birth Control ........................................................... 78 11.2. Appendix 2: Genetics and Pharmacogenetic Research ............................... 80 11.3. Appendix 3: Country Specific Requirements ................................................ 86 11.4. Appendix 4: Liver Chemistry Stopping and Follow up Criteria ..................... 87 11.5. Appendix 5: Cardiovascular Screening Questions ....................................... 88 11.6. Appendix 6: New York Heart Association Functional Classification

of Congestive Heart Failure.......................................................................... 89 11.7. Appendix 7: Daily Asthma Symptom Score .................................................. 90 11.8. Appendix 8: Anaphylaxis Criteria ................................................................. 91 11.9. Appendix 9: Eosinophil Progenitor Sub-study .............................................. 92 11.10. Appendix 10: Protocol Changes ................................................................... 93

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LIST OF ABBREVIATIONS

ACQ Asthma Control Questionnaire AE Adverse Event ALT Alanine transaminase AST Aspartate transaminase ATS American Thoracic Society BDI II Beck Depression Inventory II CPAP Continuous Positive Airway Pressure CTAL Container Treatment Assignment List DNA Deoxyribonucleic acid ECG Electrocardiogram eCRF Electronic case report form ED Emergency Department eDiary Electronic Diary ERS European Respiratory Society FCBP Female of child bearing potential FEV1 Forced Expiratory Volume in one second FVC Forced Vital Capacity GCP Good Clinical Practice GCSP Global Clinical Safety and Pharmacovigilence GINA Global Initiative for Asthma GSK GlaxoSmithKline HBsAg Hepatitis B Surface Antigen HPA Hypothalamic-pituitary-adrenal axis HIV Human Immunodeficiency Virus IB Investigator’s Brochure ICS Inhaled Corticosteroid ICU Intensive care unit IDMC Independent data monitoring committee IEC Independent Ethics Committee Ig Immunoglobulin IL Interleukin IM intramuscular IP Investigational Product IRB Institutional review Board ITT Intent to Treat IUD Intrauterine device IV Intravenous IVRS Interactive Voice Response System LABA Long acting beta2 agonist LTRA Leukotriene receptor antagonist MedRA Medicinal Dictionary for Regulatory Activities MCG micrograms MDI Metered dose inhaler Mg milligrams MOS Medical Outcomes Study NA Not applicable

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NHANES National Health and Nutrition Examination Survey NHLBI National Human Lung Blood Institute OCS Oral Corticosteroid OLE Open Label Extension PEF Peak Expiratory Flow PEFR Peak Expiratory Flow Rate PK pharmacokinetics PGx Pharmacogenetics RAP Reporting and Analysis Plan SABA Short acting beta-agonist SAE Serious Adverse Evebt SC subcutaneous SGRQ St.George’s Respiratory Questionnaire SPM Study procedures manual ULN Upper limit of normal WPAI Work Productivity Activity Index VAS Visual Analog Scale

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

NONE Xolair

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PROTOCOL SUMMARY

Rationale

Asthma is a chronic heterogeneous lung disease characterized by inflammation, narrowing of the airways, and reversible airway obstruction. Severe difficult to control asthma is differentiated by a greater frequency and severity of high-risk outcomes, such as emergency department visits and hospitalizations [Jarjour 2012]. Clinicians now recognize that severe asthma is a heterogeneous syndrome with multiple distinct phenotypes based on several clinical, functional and inflammatory parameters [Clienti 2011; Hashimoto 2012; McDonald 2012]. From the clinical point of view, severe asthma has been divided into 3 categories 1) frequent exacerbations with relatively stable periods in between; 2) asthma with fixed airway obstruction and; 3) corticosteroid-dependent asthma [Bel 2011; Marjoria 2010].

Patients with severe asthma have a greater need for more medication, have more persistent symptoms, lower lung function, and suffer serious outcomes despite optimized treatments and often require treatment with large doses of corticosteroids in attempts to maintain disease control. Corticosteroids are highly effective in patients with severe asthma, however the regular use of systemic steroids can result in serious deleterious side effects affecting numerous body systems (i.e., HPA axis, eye, liver, heart, bone, skin, adipose tissue, muscle weakening, central nervous system) [Walsh 2001; Huscher 2009, Ververeli 2004].

The purpose of this study is to investigate the efficacy of adjunctive mepolizumab therapy, in comparison to standard of care, to reduce the use of OCS while maintaining asthma control in subjects with severe refractory asthma. This study will also investigate the effects of mepolizumab on clinical markers of asthma control, including asthma exacerbation rate, quality of life, and lung function (FEV1).

Objective(s)

To compare the effects of mepolizumab adjunctive therapy with placebo on reducing the use of maintenance oral corticosteroids (OCS) in systemic corticosteroid dependent subjects with severe refractory asthma with elevated eosinophils.

To compare the efficacy, safety, and tolerability of mepolizumab compared with placebo, in subjects with severe refractory asthma with elevated eosinophils including an evaluation of the effects of mepolizumab on markers of asthma impairment and risk including, asthma symptoms, pulmonary function, exacerbation rate and quality of life as assessed by the St. George’s Respiratory Questionnaire.

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Study Design

This is a multi-centre, randomised, placebo-controlled, double-blind, parallel group study (Figure 1). The study consists of four phases: 1) Oral Corticosteroid (OCS) Optimisation; 2) Treatment Induction Phase; 3) OCS Reduction Phase and 4) Maintenance Phase followed by a follow-up period for those subjects who do not continue into an open-label extension study (see Section 3.2.4).

It is estimated that approximately 200 subjects will be screened to randomise approximately 120 subjects (60 subjects per arm).

During this study, all subjects will remain on their existing maintenance asthma therapy throughout this study, in addition to the study treatment (mepolizumab or placebo), while reducing oral corticosteroids. The active treatment arm in this study will be standard of care plus mepolizumab while the comparator arm will be standard of care plus placebo. Subjects will be randomized 1:1 to study treatment and it will be administered. In this study mepolizumab (100 mg) will be administered through subcutaneous (SC) injection.

The OCS dose titration will occur throughout the Optimisation Phase and Reduction Phase of the study and may not necessarily coincide with the Visits scheduled for study treatment administration.

Study Endpoints/Assessments

Primary Efficacy Endpoint

The primary efficacy endpoint is the percent reduction of OCS dose during weeks 20 - 24 compared to the baseline dose, while maintaining asthma control.

Secondary Efficacy Endpoints

• The proportion of subjects who achieve a reduction of 50% or greater in their daily OCS dose, compared to baseline dose, during weeks 20-24 while maintaining asthma control.

• The proportion of subjects who achieve a reduction of OCS dose to less than or equal to 5.0mg, while maintaining asthma control during weeks 20 – 24

• The proportion of subjects who achieve a total reduction of OCS dose while maintaining asthma control during weeks 20 - 24

• Median percentage reduction from baseline in daily OCS dose during weeks 20 – 24, while maintaining asthma control

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1. INTRODUCTION

1.1. Background Asthma is a chronic heterogeneous lung disease characterized by inflammation, narrowing of the airways, and reversible airway obstruction. Severe difficult to control asthma is differentiated by a greater frequency and severity of high-risk outcomes, such as emergency department visits and hospitalizations [Jarjour 2012]. Clinicians now recognize that severe asthma is a heterogeneous syndrome with multiple distinct phenotypes based on several clinical, functional and inflammatory parameters [Clienti 2011; Hashimoto 2012; McDonald 2012]. From the clinical point of view, severe asthma has been divided into 3 categories 1) frequent exacerbations with relatively stable periods in between; 2) asthma with fixed airway obstruction and; 3) corticosteroid-dependent asthma [Bel 2011; Marjoria 2010].

Patients with severe asthma have a greater need for more medication, have more persistent symptoms, lower lung function, and suffer serious outcomes despite optimized treatments and often require treatment with large doses of corticosteroids in attempts to maintain disease control. Corticosteroids are highly effective in patients with severe asthma, however the regular use of systemic steroids can result in serious deleterious side effects affecting numerous body systems (i.e., HPA axis, eye, liver, heart, bone, skin, adipose tissue, muscle weakening, central nervous system) [Walsh 2001, Huscher 2009, Ververeli 2004]. The 2007 Expert Panel Report (EPR) recommends that for the treatment of asthma every consideration should be given to minimize systemic corticosteroids doses and maximize other modes of therapy [National Institutes of Health 2007] because of the magnitude of adverse effects related to the dose, frequency of administration, and the duration of corticosteroid use. For patients with severe refractory asthma with elevated blood eosinophils, especially those treated with maintenance oral corticosteroids, there is a need to minimize both frequency of high risk outcomes associated with severe asthma and the risks associated with the adverse events associated with corticosteroid use.

Mepolizumab is currently under clinical development for severe asthma, and details of the pharmacology, efficacy and safety can be found in the Investigator Brochure [GlaxoSmithKline Document CM2003/00010/07]. Mepolizumab is a humanized anti-interleukin 5 (anti-IL5) antibody (IgG Kappa) that binds to and inactivates IL-5. IL-5 is the principle eosinophilic regulatory cytokine [Sumitas 2011]. It is critical for the development and release of eosinophils from the bone marrow, enhances adhesion to endothelial cells, and promotes the persistence and activation of eosinophils [Walsh 2012; Polosa, 2012]. Eosinophils are not normally present in healthy lungs, and are thought to play a major role in maintaining airway inflammation [Walsh 2012; Wadsworth 2011]. Mepolizumab binds with high affinity to human interleukin-5 and blocks its binding to and the activation of the IL-5 receptor (CD125). It is hypothesized that blocking IL-5 with mepolizumab will have a positive effect in reducing eosinophilic inflammation in patients with severe refractory asthma who are dependent on maintenance steroid to treat their asthma. This concept has been previously investigated in a small study (N= 20) of asthmatics with persistent sputum eosinophils. The results of this study demonstrated that mepolizumab was well tolerated and effective in reducing

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the dose of prednisone while preventing exacerbations, decreasing blood and sputum eosinophil numbers, and improving lung function and quality of life [Nair 2009].

GSK recently completed a randomized controlled study of mepolizumab (MEA112997) of over 600 subjects with severe refractory uncontrolled asthma. The dose selected for the current study is based on the results of the MEA112997 study, which investigated a 10-fold dose range from 75mg to 750mg administered IV every 4 weeks. All 3 doses investigated (75mg, 250 mg and 750mg) resulted in a clinically significant reduction in the frequency of severe exacerbations when compared to placebo. All 3 doses produced a marked and sustained suppression of blood eosinophils throughout the dose interval. The safety profile was similar across all treatment arms and was similar to placebo. Further details are available in the Clinical Investigator’s Brochure (CIB) [GlaxoSmithKline Document Number CM2003/00010/07]. The safety and efficacy profile demonstrated in MEA112997 supports further progression to Phase 3.

A PK/PD model has been developed for mepolizumab with data obtained from 5 prior asthma studies and 1 healthy volunteer study. Two of these 5 studies administered mepolizumab via the subcutaneous (SC) route. The model well describes the relationship between plasma mepolizumab concentration and eosinophil counts (irrespective of the route of administration), with an IC50 (the concentration at which 50% of the maximum reduction of eosinophils) of 226ng/ml [GlaxoSmithKline Document Number CM2003/00010/07]. Based on prior PK studies, the bioavailability of mepolizumab administered SC into the upper arm is approximately 75% [GlaxoSmithKline Document Number CM2003/00010/07], and therefore a dose of 100mg SC is anticipated to provide similar exposure to the 75mg IV effective dose from 112997.

In summary, the 100 mg dose via the SC route has been selected for this study based primarily on the efficacy and safety profile observed in the MEA 112997 study, and is additionally supported by the previously developed PK/PD model. A SC route of administration has been chosen for this study as it is generally preferred by patients and is easy to administer.

1.2. Rationale

The purpose of this study is to investigate the efficacy of adjunctive mepolizumab therapy, in comparison to standard of care, to reduce the use of OCS while maintaining asthma control in subjects with severe refractory asthma. This study will also investigate the effects of mepolizumab on clinical markers of asthma control, including asthma exacerbation rate, quality of life, and lung function (FEV1).

2. OBJECTIVE(S)

Primary:

To compare the effects of mepolizumab adjunctive therapy with placebo on reducing the use of maintenance oral corticosteroids (OCS) in systemic corticosteroid dependent subjects with severe refractory asthma with elevated eosinophils.

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Secondary:

To compare the efficacy, safety, and tolerability of mepolizumab compared with placebo, in subjects with severe refractory asthma with elevated eosinophils including an evaluation of the effects of mepolizumab on markers of asthma impairment and risk including, asthma symptoms, pulmonary function, exacerbation rate and quality of life as assessed by the St. George’s Respiratory Questionnaire.

3. INVESTIGATIONAL PLAN

3.1. Study Design

Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential and required for study conduct.

This is a multi-centre, randomised, placebo-controlled, double-blind, parallel group study (Figure 1). The study consists of four phases: 1) Oral Corticosteroid (OCS) Optimisation; 2) Treatment Induction Phase; 3) OCS Reduction Phase and 4) Maintenance Phase followed by a follow-up period for those subjects who do not continue into an open-label extension study (see Section 3.2.4).

During this study, all subjects will remain on their existing maintenance asthma therapy throughout this study, in addition to the study treatment (mepolizumab or placebo), while reducing oral corticosteroids. The active treatment arm in this study will be standard of care plus mepolizumab while the comparator arm will be standard of care plus placebo. Subjects will be randomized 1:1 to study treatment and it will be administered as outlined in Figure 1. In this study mepolizumab (100 mg) will be administered through subcutaneous (SC) injection. The bioavailability of mepolizumab administered as a SC injection into the upper arm is approximately 75% of that administered through intravenous (IV) injection [GlaxoSmithKline Document Number CM2003/00010/07]. Based on the bioavailability of SC mepolizumab combined with the pharmacodynamic modeling of blood eosinophil suppression, a 100mg SC regimen was selected for this study. As compared to an IV route of administration the SC route of administration provides an easy to administer and is generally preferred by patients.

The OCS dose titration will occur throughout the Optimisation Phase and Reduction Phase of the study and may not necessarily coincide with the Visits scheduled for study treatment administration. Subject reported data, collected through eDiary must be reviewed via study portal prior to any OCS dose titration as described in Section 3.2.1 and Section 3.2.3. It is expected that the OCS dose titration will be managed through scheduled Phone Visits but can occur at scheduled in-clinic visit if the schedules coincide OR at optional in-clinic Visits, per the Investigator’s discretion. Thus, Figure 1 below outlines the required scheduled for study treatment administration and not necessarily the OCS dose reduction schedule.


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Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.

Figure 1 Study Schematic

3.2. Discussion of Design

3.2.1. Screening and OCS Optimisation Phase

Subjects who meet all eligibility criteria at the Screening visit will enter the oral corticosteroid dose Optimisation Phase. The Optimisation Phase is intended to assure that subjects enter the double-blind treatment phase on the lowest dose of OCS that will manage their symptoms. By doing so, changes in OCS made during the OCS Reduction Phase of the study should more accurately reflect the effect of the subject’s assigned treatment.

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Prednisone or prednisolone will be used as the oral corticosteroid (see Section 5.1). At the screening visit subjects who are not currently using prednisone or prednisolone as their maintenance corticosteroid will be switched to the corresponding prednisone/prednisolone equivalent dose. Further information regarding determining dose equivalency can be found in the SPM. Subjects must understand and agree to use the study supplied prednisone/prednisolone for the treatment of asthma, or asthma exacerbation, for the duration of the study.

The OCS adjustments (increase or decrease) during the Optimisation Phase and the length of Optimisation Phase are deemed suitable because subjects, per the study inclusion criteria, have been managed on a stable dose of OCS for a significant period of time prior to study start (i.e. use in the 6 months prior to randomisation and at a stable dose for 4 weeks prior to randomisation). A similar optimisation approach was successfully employed in two recently published OCS reduction studies [Bateman 2006; Karpel 2007].

The lowest effective OCS dose will be defined during this phase by the emergence of asthma symptoms or the occurrence of an exacerbation. The emergence of asthma symptoms will be determined by an increase in ACQ-5 of at least +0.5 from the Visit 1 score. The lowest effective OCS dose will be identified as the OCS dose that the subject was taking just prior to the dose they were on when the symptoms emerged or the exacerbation occurred. Once the optimized dose is determined the subject must be able to remain on the optimized prednisone/prednisolone dose, for 2 consecutive weeks prior to randomisation.

Investigators will oversee the adjustment of the corticosteroid dose during the Optimisation Phase according to the titration schedule specified in Table 1 and further described below. The decision rule of the titration schedule will be based on changes in the subject’s asthma control, assessed by their ACQ-5 score as captured by electronic Diary (eDiary) or the occurrence of the exacerbation. A similar methodology was recently reported [Hashimoto 2011] and successfully allowed titration of OCS.

At Visit 1, the screening visit, subjects will enter the study on their screening dose of prednisone/prednisolone, if prior to Visit 1 the subject is not using prednisone or prednisolone as their maintenance oral corticosteroid then the prednisone/prednisolone dose equivalent must be determined. Dose equivalency tables are provided SPM. At Visit 1 the screening ACQ-5 score will be captured. Subjects’ who meet study eligibility criteria, including the use of OCS between 5.0 mg/day and 35 mg/day (or equivalent) at Visit 1, are eligible to enter the Optimisation Phase. One week after screening, subjects will return to the clinic for Visit 2. At Visit 2 and weekly throughout the Optimisation Phase, subject stability will be assessed by review of ACQ-5 score and exacerbation review. The prednisone/prednisolone adjustments during the Optimisation Phase will be made based on the titration schedule described in Table 1.

The ACQ has been validated in several separate studies and the minimal clinically important difference value of +0.5 has been established to demonstrate a significant clinical change in asthma status [Juniper 1999; Korn 2011].

The Optimisation Phase will last a minimum of three weeks and a maximum of 8 weeks, unless an exacerbation occurs (see Section 3.2.1.1).

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Table 1 Optimisation Titration Schedule

Sequential Time Course Prednisone/prednisolone Optimisation Phase Oral Corticosteroid Dose (mg/day)

Visit 2 starting dose 35 30 25 20 15 12.5 10.0 7.5 5.0 1st dose reduction (Visit 2) 30.0 25.0 20.0 15.0 12.5 10.0 7.5 5.0 5.0

+ 1 Week 25.0 20.0 15.0 12.5 10.0 7.5 5.0 + 1 Week 20.0 15.0 12.5 10.0 7.5 5.0 + 1 Week 15.0 12.5 10.0 7.5 5.0 + 1 Week 12.5 10.0 7.5 5.0 + 1 Week 10.0 7.5 5.0 + 1 Week 7.5 5.0 +1 Week 5.0

If at Visit 2 the subjects’ asthma status remains stably controlled or improves as measured by a change in the ACQ-5 score of less than +0.5 from the Visit 1 score, the subject will down titrate OCS by one step. The OCS down titration will continue until a point when deterioration is noted. Deterioration is defined as an increase in ACQ of +0.5 or more (≥+0.5) from the Visit 1 score or the occurrence of an exacerbation. Once deterioration is detected subjects will return to the prior OCS dose at which asthma status was last stable.

If at Visit 2 the subjects’ asthma status deteriorates as measured by an increase in ACQ-5 by +0.5 or more from the Visit 1 score, their OCS dose should be increased by one step. Subjects will continue to test their ACQ-5 score on a weekly basis and adjust OCS dose per the titration schedule if necessary. The optimal OCS dose is achieved when the ACQ-5 score value is less than +0.5 from Visit 1 score.

Following Visit 2 subjects will be contacted by a scheduled phone call on a weekly basis during the Optimisation Phase to adjust OCS dose as needed. The decision to adjust OCS dose will be made following the review of subject eDiary data (i.e. ACQ-5 score) and a review of the subject’s exacerbation history.

Once the optimized dose has been identified the subject will be maintained on their optimized prednisone/prednisolone dose for 2 weeks prior to randomisation along with their baseline asthma medications.

3.2.1.1. Exacerbation Management during Optimisation Phase

Anytime during the study when a subject experiences an exacerbation the exacerbation should be treated according to the protocol with the use of oral [or parenteral [IV or intramuscular (IM)] corticosteroids at a dose at least equivalent to double the dose of current maintenance dose of OCS for a minimum of 3 days and a maximum of 7 days, this is to ensure that exacerbations are managed in a timely manner and consistently, where possible, for all subjects participating in this study. If the exacerbation is not resolved after 7 days the treatment of the exacerbation may continue at the discretion of the Investigator.

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If a subject experiences an asthma exacerbation during the Optimisation Phase the exacerbation should be treated. Following exacerbation treatment the subject should be placed on the prednisone/prednisolone dose they were on prior to the exacerbation, according to Table 1. That is the subject should be placed on a dose of prednisone/prednisolone one step higher than the dose they were on when the exacerbation occurred. In the instance that a subject experiences an exacerbation during the Optimisation Phase the Optimisation Phase may be extended up to 10 weeks, if required. However the subject must maintain the optimal dose for the protocol required 2 weeks prior to randomisation (See Randomization criteria Section 4.4), if the subject is unable to do so they will be determined to be a run-in failure.

3.2.2. Induction Phase (Randomisation)

At Visit 3 (Week 0), subjects who meet the randomisation eligibility criteria will be randomised in a 1:1 ratio to receive one of the following treatments:

• Mepolizumab 100mg SC every 4 weeks

• Placebo (saline 0.9%) SC every 4 weeks

At the time of randomisation subjects will be stratified based on their prior duration of OCS use (≥5 years and <5 years) to ensure equal distribution of subjects across treatment groups.

The double-blind treatment period will be divided into an Induction Phase, and a Reduction Phase + Maintenance Phase. The duration of the double-blind treatment period will be 24 weeks (Induction Phase = 4 weeks; Reduction + Maintenance Phase = 20 weeks. During the Induction Phase, subjects will receive one SC dose of double-blind medication at Visit 3. Subjects will remain on their optimised dose of OCS during the Induction Phase, along with their baseline asthma medications.

The rationale for the Induction Phase is to allow sufficient time for those subjects randomised to the mepolizumab arm to achieve a decrease in the eosinophilic inflammation prior to the reduction in OCS.

3.2.2.1. Exacerbation Management during Induction Phase

Anytime during the study when a subject experiences an exacerbation the exacerbation should be treated according to the protocol with the use of oral or parenteral corticosteroids at least double the dose (or equivalent) of current maintenance dose of OCS for a minimum of 3 days and a maximum of 7 days, this is to ensure that exacerbations are managed in a timely manner and consistently, when possible, for all subjects participating in this study. If the exacerbation is not resolved after 7 days the treatment of the exacerbation may continue at the discretion of the Investigator.

Following treatment the subject should be placed on the dose of prednisone/prednisolone one step above the optimal dose, the subject should be assessed to determine eligibility for further OCS dose reduction when 4-weeks have subsequently passed, in accordance with Table 2, and continue to be assessed for OCS dose reduction at 4-week intervals throughout the study per Table 2.

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The subject will return for study Visit 4, to receive their 2nd dose of double blind study treatment, as scheduled.

3.2.3. OCS Reduction Phase and Maintenance Phase

Visit 4 will mark the beginning of the OCS Reduction Phase. During the Reduction Phase subjects will receive 5 additional doses of double blind study treatment, at Visits 4 – 8 (i.e., a dose every 4 weeks). The prednisone/prednisolone dose will be titrated during the Reduction Phase following the schedule described in Table 2. Subjects should be assessed for OCS dose reduction every 4-weeks. The assessment may or may not coincide with the scheduled in-clinic Visit as outlined in Figure 1. The OCS dose reduction assessment and subject instruction will be preferentially managed by scheduled phone visits but can be managed at in-clinic visits if the timing coincides or at the Investigator’s discretion.

The OCS titration schedule outlined for the Reduction Phase (Table 2) has larger dose steps and longer duration between steps (i.e. 4 weeks) as compared to the schedule outlined for the Optimisation Phase (Table 1). The longer duration between dose steps was implemented as it is anticipated that the magnitude of the decrease in the OCS dose during the Reduction Phase will be greater than that during the Optimisation Phase. A four week timeframe should allow for carryover effects from the prior dose to be minimised, and should also minimise the risk for adrenal insufficiency complications.

Table 2 Reduction Phase Titration Schedule

Sequential Time Course Prednisone/Prednisolone Reduction Phase Oral Corticosteroid Dose (mg/day)

Optimized OCS dose 35 30 25 20 15 12.5 10.0 7.5 5.0 1st dose reduction 25.0 20.0 15.0 10.0 10.0 10.0 5.0 5.0 2.5

+ 4 Weeks 15.0 10.0 10.0 5.0 5.0 5.0 2.5 2.5 1.25* + 4 Weeks 10.0 5.0 5.0 2.5 2.5 2.5 1.25* 1.25* 0 + 4 Weeks 5.0 2.5 2.5 1.25* 1.25* 1.25* 0 0 0 + 4 Weeks 2.5 2.5 2.5 0 0 0 0 0 0

1. *Subject taking 1.25mg/day should take this as 2.5mg administered every other day During the Reduction Phase the subjects’ prednisone/prednisolone dose will be reduced as scheduled per Table 2. The last possible dose reduction can occur at Week 20 and no further OCS dose adjustments can occur following Week 20. OCS dose reduction should occur per the schedule unless the subject meets protocol defined criteria indicating that it is not acceptable for the subject to reduce OCS. An assessment should be completed prior to each reduction. The assessment should include a review of eDiary parameters including a review the subjects’ prednisone/prednisolone dose record, the subjects’ exacerbation history, and a review of the signs and symptoms of adrenal insufficiency. The primary reasons for not following the scheduled reduction algorithm include: 1) the presence of an exacerbation, 2) loss in asthma control as assessed by prior week electronic diary (eDiary) measures, or 3) presence of symptoms associated with adrenal insufficiency (Table 3). If the eDiary record of the subjects’ daily prednisone/prednisolone dose is significantly divergent from the schedule the Investigator must determine appropriateness for dose reduction.

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Table 3 Criteria for Not Following OCS Dose Reduction Schedule

Criteria1 Definition 1 Mean AM PEF <80% of baseline stability limit 2 Mean asthma-related night time awakenings >50% increase over the baseline period (per night), >150% of

the baseline mean 3 Rescue medication use requiring 4 or more puffs/day above the mean baseline value for any 2 consecutive

days in the prior week, or 12 puffs or more on any one day in the prior week 4 Change in ACQ-5 ≥ +0.5 from the prior month OCS dose assessment 5 Symptoms of adrenal insufficiency 1. Baseline means for AM PEF, night time awakenings, and rescue medication use are calculated on a per night or

per day basis using subject diary information from the 7 completed eDiary records prior to Randomisation Visit (Visit 3)

When a decision is made to not reduce the OCS dose according to the reduction algorithm the primary reason for not reducing OCS must be documented in the source notes and captured in the electronic data capture tool. Depending on the rationale for not reducing per schedule the Investigator should decide whether to maintain the subject on their current dose of OCS or increase up one step. The decision should be captured in the electronic data capture tool.

During the OCS Reduction Phase subjects on lower doses of OCS at baseline may be completely weaned from OCS, while subjects on relativity higher doses of OCS at baseline (25mg/day and higher) will not be weaned completely. This is to protect the subject from potentially experiencing adrenal crisis. Throughout the Reduction Phase subjects should be monitored for the signs and symptoms of adrenal insufficiency.

A 20 week reduction timeframe, with 4-weeks between OCS dose titration, was chosen as this duration was found to be adequate in two recent trials [Bateman 2006, Karpel 2007], and will minimise temporal influences on asthma control.

Subjects will be maintained during the last 4-weeks of the study without any further OCS dose adjustment (i.e. Maintenance Phase).

3.2.3.1. Exacerbation Management during Reduction and Maintenance Phases

If an exacerbation occurs during the Reduction or Maintenance Phase the exacerbation should be treated with the use of oral or parenteral corticosteroids at a dose at least equivalent to double the dose of current maintenance dose of OCS for a minimum of 3 days to a maximum of 7 days, this is to ensure that exacerbations are managed in a timely manner and consistently, when possible, for all subjects participating in this study. If the exacerbation is not resolved after 7 days the treatment of the exacerbation may continue at the discretion of the Investigator.

Following resolution the subject should be placed on the OCS dose one step higher than that which they were on when the exacerbation occurred (according to Table 2) for 4-weeks and continue as scheduled with the Reduction Phase of the study. If a subject experience 2 exacerbations they should be maintained for the remaining duration of the treatment period at the OCS dose which asthma control was maintained.

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3.2.4. Open-Label Extension and Study Completion

Subjects who complete the 24 week double-blind period (Induction + Reduction + Maintenance Phases), and meet the eligibility criteria, will be offered the opportunity to participate in an open label extension (OLE) study.

Subjects who complete all phases of the study (Optimisation, Induction, Reduction, and Maintenance Phases), and participate in the OLE study, will therefore participate in this study for a minimum of 27weeks.

Subjects who are not eligible for the OLE study, or who chose not enter the OLE study after the 24 week treatment period, will be requested to return for a follow-up Visit 12 weeks after their last dose of double blind study treatment and will therefore participate in this study for a minimum of 35 weeks. In this case the subject will be considered complete upon completion of the follow up Visit.

For subjects not entering the extension study and who have a positive neutralizing antibody response at the 12 week follow-up visit (or last study visit at which immunogenicity was assessed if 12 week follow-up visit immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-mepolizumab antibodies and a blood sample for eosinophils at least 4 months after the last dose of study agent or upon completion and/or un-blinding of the study, whichever is later.

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA

4.1. Number of Subjects


A review of each subject’s medical records must be performed prior to a subject entering the Optimisation Phase to confirm eligibility. To be randomised into the trial, subjects will also be required to meet the additional specific randomisation criteria specified separately below.

Patients eligible for enrolment and entry into the Optimisation Phase of the study must meet all of the following criteria:

4.2. Inclusion Criteria

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the Investigator’s Brochure [GlaxoSmithKline Document Number CM2003/00010/07]

Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

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Subjects eligible for enrolment in the study must meet all of the following criteria:

1. Informed Consent and Study Compliance: Subjects must be able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.

2. Age: At least 12 years of age at Visit 1 and a minimum weight of 45kg

[For those countries where local regulations permit enrolment of adults only, subject recruitment will be restricted to those who are >18 years of age]

3. Systemic Corticosteroids: Subjects with severe asthma and a well-documented requirement for regular treatment with maintenance systemic corticosteroids in the 6 months prior to Visit 1 and using a stable oral corticosteroid dose for 4 weeks prior to Visit 1. Subjects must be taking 5.0 – 35 mg/day of prednisone or equivalent at Visit 1 and must agree to switch to study required prednisone/prednisolone as their oral corticosteroid and use it per protocol for the duration of the study.

4. Inhaled Corticosteroids: A documented requirement for regular treatment with high dose inhaled corticosteroid in the 6 months prior to Visit 1.

• For 18 years of age and older:

• ICS dose must be ≥880 mcg/day fluticasone propionate (FP) (ex-actuator) or equivalent daily.

• For ICS/LABA combination preparations, the highest approved maintenance dose in the local country will meet this ICS criterion.

• For ages 12-17

• ICS dose must be ≥440 µg/day fluticasone propionate (FP) (ex-actuator) or equivalent daily.

• For ICS/LABA combination preparations, the mid-strength approved maintenance dose in the local country will meet this ICS criterion.

5. Controller Medication: Current treatment with an additional controller medication for at least 3 months OR documentation of having used and failed an additional controller medication for at least 3 successive months during the prior 12 months [e.g., long-acting beta2-agonist (LABA), leukotriene receptor antagonist (LTRA), or theophylline].

6. Eosinophilic asthma: Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma as per Randomisation Criteria 2 and 3.

7. Gender: Male or Eligible Female

To be eligible for entry into the study, females of childbearing potential (FCBP) must commit to consistent and correct use of an acceptable method of birth control Appendix 1) beginning with consent for the duration of the trial and for 4 months after the last study drug administration.

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Subjects in France: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

4.3. Exclusion Criteria

Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

Subjects meeting any of the following criteria must not be enrolled in the study:

1. Smoking history: Current smokers or former smokers with a smoking history of ≥10 pack years. A former smoker is defined as a subject who quit smoking at least 6 months prior to Visit 1.

2. Concurrent Respiratory Disease: Presence of a clinically important lung condition other than asthma. This includes but is not limited to current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer.

3. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior screening (Subjects that had localized carcinoma (ie, basal or squamous cell) of the skin which was resected for cure will not be excluded).

4. Liver Disease: Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).

5. Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment. Including but not limited to:

• known ejection fraction of <30% OR

• severe heart failure meeting New York Heart Association Class IV (see Appendix 6) OR

• hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III (see Appendix 6) OR

• angina diagnosed less than 3 months prior to Visit 1 or at Visit 1

6. Other Concurrent Medical Conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment.

7. Eosinophilic Diseases: Subjects with other conditions that could lead to elevated eosinophils such as Hypereosiniophilic Syndromes, including Churg-Strauss Syndrome, or Eosinophilic Esophaghitis. Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also to be excluded.

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8. ECG: ECG assessment QTcF ≥ 450msec or QTcF ≥ 480 msec for subjects with Bundle Branch Block.

9. Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus – HIV), other than that explained by the use of corticosteroids taken as therapy for asthma.

10. Omalizumab Use: Subjects who have received omalizumab [Xolair] within 130 days of Visit 1.

11. Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1

12. Investigational Medications: Subjects who have received treatment with an investigational drug within the past 30 days or five terminal phase half-lives of the drug whichever is longer, prior to Visit 1 (this also includes investigational formulations of marketed products).

13. Hypersensitivity: Subjects with a known allergy or intolerance to a monoclonal antibody or biologic.

14. Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation.

15. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.

16. Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.

17. Previous participation: Subjects who have previously participated in any study of mepolizumab and received Investigational Product (including placebo).

Re-screening of subjects will be allowed only upon approval by the medical monitor.

4.4. Randomisation Criteria

Those subjects who meet the randomisation criteria will be randomised into the study until the target of approximately 120 randomised subjects is reached.

At the end of the Optimisation Phase study subjects must fulfil the following additional criteria in order to be randomised to study treatment:

1. Optimized OCS dose: Achieved a stable dose of OCS during the optimisation period which is defined as 2 weeks on the same dose of oral corticosteroids prior to randomisation. The optimised dose must be between 5.0 and 35mg/day of OCS.

2. FEV1: Persistent airflow obstruction as indicated by:

For subjects ≥ 18 years of age at Visit 1, Visit 2, or Visit 3

• a pre-bronchodilator FEV1 <80% predicted

For subjects 12-17 years of age at Visit 1, Visit 2, or Visit 3

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• A pre-bronchodilator FEV1 <90% predicted OR

• FEV1:FVC ratio < 0.8

For predicted FEV1 values NHANES III values will be used and adjustments to these values will be made for race [Hankinson 1999]. If a subject is recorded as having Hispanic or Latino ethnicity, then the Mexican-American equations will be used (irrespective of race). If a subject is recorded as being of African American/African Heritage race, then the African American equations will be used. If a subject is recorded as being of Asian race, then the Asian equations will be used. Otherwise, the Caucasian equations will be used.

3. Eosinophilic Phenotype: Airway inflammation characterized as eosinophilic in nature as indicated by one of the following characteristics:

a. An elevated peripheral blood eosinophil level of ≥300 cells/µL that is related to asthma within the previous 12 months prior to Visit 3

OR

b. Peripheral baseline eosinophil level ≥150 cells/µL between Visit 1 and Visit 3 that is related to asthma

4. Asthma: Evidence of asthma as documented by either:

• Airway reversibility (FEV1≥12% and 200 ml) demonstrated at Visit 1, Visit 2 or Visit 3 OR documented in the previous 12 months OR

• Airway hyperresponsiveness (methacholine: PC20 of <8mg/mL or histamine: PD20 of <7.8 µmol; mannitol: decrease in FEV1 as per the labelled product instructions) documented in the 12 months prior to Visit 3 OR

• Airflow variability in clinic FEV1 ≥20% between two consecutive clinic visits documented in the 12 months prior to Visit 3 (FEV1 recorded during an exacerbation should not be considered for this criteria) OR

• Airflow variability as indicated by >20% diurnal variability in peak flow observed on 3 or more days during the optimisation period

Note: If subjects are unable to demonstrate airway reversibility at Visit 1 or Visit 2 the site should re-iterate the need to withhold SABA and LABA as required in Section 6.1.2 prior to the Visit 3 measurement.

5. OCS Compliance: Compliance with use of OCS dose as instructed during the Optimization Phase on at least 10 of the prior 14 days.

6. eDiary Compliance: Compliance with completion of the eDiary defined as:

• Completion of symptom scores on 4 or more days out of the last 7 days immediately preceding Visit 3

• Completion of information relating to rescue medication use on 4 or more days out of the last 7 days immediately preceding Visit 3.

• Completion of PEF measurements on 4 or more days out of the last 7 days immediately preceding Visit 3.

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7. Laboratory abnormality: No evidence of clinically significant abnormality in the haematological, biochemical or urinalysis screen at Visit 1, as judged by the investigator.

8. Hepatitis status: No diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Visit 1.

9. Liver Function Tests: obtained at Visit 1;

• ALT<2 x ULN (upper limit of normal)

• AST<2 x ULN

• Alk Phos ≤ 2.0 x ULN

• Bilirubin ≤ 1.5 x ULN (isolated bilirubin>1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)

10. ECG over-read: No evidence of significant abnormality in 12-lead ECG (Visit 1) over-read.

4.5. Withdrawal Criteria

A subject will be regarded as having completed study treatment if he/she completes Visit 9 at week 24 and thus completes all phases of the study (Optimisation, Induction, Reduction and Maintenance).

Subjects may be withdrawn (discontinued) from study treatment at anytime by the Investigator if it is considered to be detrimental for them to continue in the study. The reason for withdrawal must be captured in the eCRF.

Subjects are also free to withdraw consent to participate in the study at anytime. Every effort should be made to have them to return to the clinic for an Exit Visit and to return all study related materials. In those instances where the subject specifies the reason for withdrawal of consent, this information will be captured in the eCRF.

Subjects must be discontinued from study treatment if the treatment code is unblinded by the Investigator or treating physician. The primary reason for withdrawal, (the event or condition which led to the unblinding) will be recorded in the eCRF. Additionally, subjects must be discontinued if the subject meets liver chemistry stopping criteria as detailed in Section 6.3.2 or if the subject meets the QT discontinuation criteria listed below.

• QTc(F)>500 msec or uncorrected QT>600 msec

• Bundle branch block: QTc(F)>530 msec

• Change from baseline: QTc > 60ms

Reasons for withdrawal must be captured in the eCRF and can include: an adverse event, lost to follow-up, protocol violation, lack of efficacy, sponsor terminated study, non-compliance, pregnancy, abnormal liver function test, abnormal laboratory results including clinically significant abnormality identified on ECG over-read.

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A subject should only be designated as lost to follow-up only if the site is unable to establish contact with the subject. The site must attempt to contact the subject on multiple occasions and only determine the subject to be ‘lost to follow-up’ after there have been at least 3 documented attempts, via at least 2 different methods (phone, text, e-mail, certified letter, etc), to contact the subject.

An Exit Visit must be conducted at approximately 4 weeks following the last dose received. In the event a subject withdraws early at or during a scheduled visit an Exit Visit is not required. However, all study procedures scheduled at an Exit Visit must be performed at this early withdrawal visit instead. A follow-up visit should be scheduled for approximately12 weeks after the last dose of investigational product.

The primary reason for early withdrawal will be recorded in the electronic case report form (eCRF) and any data collected up until the point of withdrawal will be used in the analyses. For those subjects completing the follow-up visit, any safety data collected post withdrawal through follow-up will be summarised.

4.6. Screening/Run-in Failures

Subjects will be assigned a study number at the time of signing the consent. Subjects who do not progress to the screen visit (Visit 1) will be deemed a Pre-screen Failure. No data will be captured in the eCRF for these subjects.

Those subjects that complete at least one additional procedure at Visit 1 but do not enter the Optimisation Phase will be designated as screen failures. Those subjects who are unable to be maintained on their optimal prednisone/prednisolone dose for the protocol required 2 weeks prior to randomisation (See Randomization criteria Section 4.4), if the will be designated screen failures.

Additionally, those subjects that enter the Optimisation Phase, but do not complete any Visit 3 (randomisation) procedures will be designated as run-in failures.

Information to be collected for screen failure and run-in failure subjects will be detailed in the eCRF completion guidelines.

Re-screening of subjects will be allowed only upon approval by the medical monitor.

5. STUDY TREATMENTS

5.1. Investigational Product and Other Study Treatment

Mepolizumab (SB-240563) is a fully humanised IgG antibody (IgG1, kappa) with human heavy and light chain frameworks. Mepolizumab will be provided as a lyophilised cake in sterile vials for individual use. The vial will be reconstituted with Sterile Water for Injection, just prior to use. Further details of dose preparation and administration can be found in the Clinical Investigator’s Brochure (CIB) [GlaxoSmithKline Document Number CM2003/00010/07], and the Study Procedures Manual (SPM).

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Under normal conditions of handling and administration, investigational product is not expected to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of any unintentional occupational exposure. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be provided to site staff if required by local laws or will otherwise be available from GSK upon request.

Mepolizumab must be stored in a secure area under the appropriate physical conditions for the product. Access to and administration of the mepolizumab will be limited to the investigator’s authorized unblinded site staff. Mepolizumab must be stored under the appropriate physical conditions which includes storage in a refrigerator or at a temperature of 2-8°C and protected from light. Maintenance of a temperature log (manual or automated) is required. Mepolizumab must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.

The contents of the label will be in accordance with all applicable regulatory requirements.

The placebo in this study will be 0.9% sodium chloride solution and will be provided by the study site. Further details on the preparation of the placebo can be found in the SPM and in the Unblinded Site Staff Manual.

Prednisone or prednisolone will be provided to subjects for use in this study through the study site.

Trade label albuterol/salbutamol MDIs will be provided. Subjects will be dispensed an MDI at the time of screening (Visit 1) to be used to treat asthma symptoms on an as needed basis. The MDI should be replaced as needed, and collected at the time of the Exit Visit.

5.2. Dosage and Administration

Subjects in this study will be randomised in a 1:1 ratio to receive 100 mg mepolizumab SC or placebo SC once every 4 weeks.

The unblinded site staff member assigned to the study will be required to prepare the appropriate medication according to the study subject’s treatment assignment (See Section 5.3).

Each vial of mepolizumab will need to be reconstituted in sterile water for injection and swirled gently to enable complete dissolution of the product. Detailed instructions for reconstitution can be found within the pharmacy manual.

To administer mepolizumab 100mg SC, reconstituted mepolizumab for injection will be drawn into a 1.0 ml polypropylene syringe. To administer placebo SC, an equivalent volume of 0.9% sodium chloride will be drawn into a 1.0 ml polypropylene syringe.

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Once prepared the active treatment will be indistinguishable from the placebo. Further details on administration are provided in the pharmacy manual.

A blinded staff member will administer the SC dose into the subject’s upper arm

Procedures must be in place to ensure the blind is maintained by any site staff involved in administration of the drug or clinical care or assessment of the subject, and by the subject themselves.

Safety monitoring of subjects will occur during SC administration and for one hour after the end of injection. Such monitoring will include general safety monitoring including monitoring for both systemic hypersensitivity (i.e., allergic/IgE-mediated and non-allergic) and local site reactions. Trained rescue personnel and rescue medications/equipment must be available for use at all times. See Appendix 8 for additional information.

5.3. Treatment Assignment

A unique Subject Number will be assigned to any subject who is consented. This unique subject number will be used to identify the individual subject throughout the study and will not be re-assigned to any other subject.

Subjects will be assigned to study treatment in accordance with the randomisation schedule. Once a randomisation number has been assigned to a subject, it cannot be reassigned to any other subject in the study.

The randomisation schedule will be generated using the GSK validated randomisation software RandAll. The study will be randomised separately for each country and the randomisation will be stratified by prior use of OCS. Equal numbers of subjects will be allocated to each treatment. The randomisation schedule will be used to create the RAMOS Container Treatment Assignment List (CTAL).

The double-blind treatment will be prepared in accordance with RAMOS Container Treatment Assignment List (CTAL). The RAMOS CTAL will be sent by GSK as a signed, hard copy, controlled document, marked as private, for the attention of the unblinded qualified designee at each centre. The RAMOS CTAL needs to be stored in a secure location.

5.4. Blinding

Subcutaneous preparations of mepolizumab and placebo will be identical in appearance and will be administered by a designated blinded member of the site staff. Investigational product should be prepared by a designated unblinded person, independent of the study assessments. The blindness of those involved in the evaluation of the study i.e., physician/nurse and subject shall be maintained at all times.

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The investigator or treating physician may unblind a subject’s treatment assignment only in the case of an emergency, when knowledge of the study treatment is essential for the appropriate clinical management or welfare of the subject. Whenever possible, the investigator must first discuss options with the GSK Medical Monitor or appropriate GSK study personnel before unblinding the subject’s treatment assignment. If this is impractical, the investigator must notify GSK as soon as possible, but without revealing the treatment assignment of the unblinded subject, unless that information is important for the safety of subjects currently in the study. The date and reason for the unblinding must be recorded in the eCRF. Subjects will be withdrawn if the treatment code is unblinded by the investigator or treating physician. The primary reason for withdrawal, (the event or condition which led to the unblinding) will be recorded in the eCRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for any subject with an SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, identifying the subject’s treatment assignment, may be sent to clinical investigators in accordance with local regulations and/or GSK policy.

5.5. Product Accountability

In accordance with local regulatory requirements, the investigator, designated site staff, or head of the medical institution (where applicable) must document the amount of investigational product dispensed and/or administered to study subjects, the amount returned by study subjects, and the amount received from and returned to GSK, when applicable. Product accountability records must be maintained throughout the course of the study.

5.6. Treatment Compliance

All doses of study treatment will be administered at the study site by designated blinded site staff. Drug dispensing/accountability logs will be maintained by a designated unblinded member of the site staff.

Prednisone/prednisolone use will be captured on a daily basis by a subject through the use of a daily eDiary. Site designated staff should review information to determine if subjects are using prednisone/prednisolone dose instructed by the protocol and follow up with the subject accordingly.

5.7. Concomitant Medications and Non-Drug Therapies

5.7.1. Permitted Medications and Non-Drug Therapies

All concomitant medications taken during the study will be recorded in the electronic case report form (eCRF). The minimum requirement is that drug name and the dates of administration are to be recorded.

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Maintenance OCS is permitted and required per study eligibility criteria (Section 4). OCS dose adjustments that occur during the study must be recorded appropriately in the eCRF.

Additional asthma medications such as theophyllines or anti-leukotrienes will be permitted provided they have been taken regularly in the 3 months prior to randomisation (Visit 3).

Continuous Positive Airway Pressure (CPAP) for the treatment of obstructive sleep apnea is permitted, if initiated prior to the screening visit. This treatment must be captured in the eCRF.

5.7.2. Prohibited Medications and Non-Drug Therapies

Oral corticosteroids (prednisone or prednisolone) will be supplied for use for the treatment of asthma. During this study only the study supplied prednisone/prednisolone should be used for the treatment of asthma.

Prior to screening the following medications are prohibited for the timeframe indicated in Table 4. These medications are also prohibited throughout the study.

Table 4 Medications not allowed prior to the screening visit and throughout the study

Medication

Washout Time

Prior to Screening Visit

Investigational drugs 1 month or 5 half-lives whichever is longer

Omalizumab [Xolair] 130 days Other monoclonal antibodies 5 half-lives Experimental anti-inflammatory drugs (non biologicals) 3 months

Immunosuppressive medications such as those listed below (not all inclusive)

Corticosteroids intramuscular, long-acting depot if used to treat a condition other than asthma

3 months

Methotrexate, troleandomycin, cyclosporin, azathioprine 1 month Oral gold 3 months Chemotherapy used for conditions other than asthma 12 months Regular systemic (oral or parenteral) corticosteroids for the treatment of conditions other than asthma

3 months

Additionally, Bronchial Thermoplasty and Radiotherapy are excluded for 12 months prior to Visit 1 and throughout the study. Neither CPAP nor oxygen therapy may be initiated after Visit 1.

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5.8. Treatment after the End of the Study

The investigator is responsible for ensuring that consideration has been given to the post-study care of the patient’s medical condition whether or not GSK is providing specific post study treatment.

Subjects who complete 24 weeks treatment period, and return for the Exit Visit at week 24, may be recruited into a continuation protocol with open-label mepolizumab.

At the end of the study, subjects who do not enter the OLE study may be prescribed appropriate alternative asthma therapy if needed and as determined by the study Investigator.

5.9. Treatment of Study Treatment Overdose

The dose of mepolizumab considered to be an overdose has not been defined. There are no known antidotes and GSK does not recommend a specific treatment in the event of a suspected overdose. The investigator will use clinical judgment in treating the symptoms of a suspected overdose.

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6. STUDY ASSESSMENTS AND PROCEDURES

Table 5 Time and Events Table

Procedures Pre-Screen1

Screen/ Run-in

(Optimisation Phase)2

Randomisation Treatment (visit window is ± 7days; visit window for

scheduled phone visits is ± 3 days)

Exit visit3

Follow-up4

Visit 1 2 3 4 5 6 7 8

9 10

Week -8 to -3

-7 to -2

0 4 8 12 16 20 4 weeks post last dose ± 7

days5

12 weeks post-last dose ± 7

days Written Informed Consent x x Subject Demography x Medical History x Asthma and Exacerbation History (including triggers)

x

Asthma Therapy History6 x Oral Corticosteroid Therapy History x Smoking History x Cardiovascular History/risk factors x Parasitic Screening7 x Inclusion/Exclusion Criteria x x8 x Randomisation Criteria x Efficacy Assessments Exacerbation review x x x x x x x OCS reduction criteria review10 x x x x x Spirometry including FEV1, FVC x x x x x x x x x Maximum Post Bronchodilator Procedure9

x x x

ACQ-5 review x x x x11 x

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Screen/ Run-in




Exit visit3

Follow-up4

Visit 1 2 3 4 5 6 7 8

9 10

Week -8 to -3

-7 to -2


days5


days Review eDiary data (symptoms, PEF)12

x x x x x x x x

Nasal symptoms VAS x x Health Outcome Assessments Clinician Rated Response to Therapy x x x Subject Rated Response to Therapy x x x Beck Depression Inventory II x x x x St. George’s Respiratory Questionnaire

x x

Steroid Perception Questionnaire x x WPAI-GH x x x x x x x Medical Outcomes Study Sleep Scale

x x

Safety Assessments Concomitant Medication x x x x x x x x x x Physical Examination x x Detailed nasal exam (check for polyps)

x x

Vital Signs x x x x x x x x x x 12 lead ECG x x x x x x Adverse Events x x x x x x x x x x Serious Adverse Events x x x x x x x x x x Steroid withdrawal exam review x x x x x x x x x

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Screen/ Run-in




Exit visit3

Follow-up4

Visit 1 2 3 4 5 6 7 8

9 10

Week -8 to -3

-7 to -2


days5


days Laboratory Assessments13 Haematology with differential x x x x x x x x x Chemistry plus lipoproteins14 x x Clinical Chemistry x x x x x x x x Urinalysis x Pharmacogenetic sample x15 Pregnancy test16 S U U U U U U S U HBsAg and hepatitis C antibody17 x Serum IgE (total) x x Serum IgE (specific) x Immunogenicity x x x x Pharmacokinetic sample x x x x Blood Biomarker x x x Sputum Collection 18 x x x Sub-study blood collection18 x x x Investigational Product (IP) Administer IP x x x x x x OCS dose adjustment19 x x x x x x Oral Corticosteroids dispensed (as needed)

x x x x x x x x

Collect dispensed oral corticosteroid as needed

x x x x x x x x

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Screen/ Run-in




Exit visit3

Follow-up4

Visit 1 2 3 4 5 6 7 8

9 10

Week -8 to -3

-7 to -2


days5


days Albuterol/salbutamol dispensed (as needed)

x x x x x x x x

Collect dispensed albuterol/salbutamol as needed

x x x x x x x

RAMOS/eCRF Call RAMOS to register in clinic visits x x x x x x x x x x Call RAMOS to register scheduled Phone Visits20

x

Complete eCRF x x x x x x x x x x Dispense paper worksheets x x x x x x x x x Dispense eDiary and PEF meter x Collect eDiary and PEF meter x Collect/review paper worksheets x x x x x x x x x x

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Table 5 Time and Events Table 1. Pre-screen visit can occur on the same day as the Visit 1 but must be completed prior to starting Visit 1 procedures. 2. The length of the Optimisation Phase can vary depending on when optimal OCS is achieved. Visit 2 must occur one week following Visit 1. See Section 3.2.1. for details 3. For subjects entering the Open-Label Extension study, Visit 9 will serve as Visit 1 for the Open-Label Extension study. Where procedures overlap, they need only be performed

once, and the data will be used for both studies. 4. For subjects not entering the Open-Label Extension study and who had a positive anti-mepolizumab antibody response at the 12 week follow-up visit (or last study visit at which

immunogenicity was assessed if 12 week follow-up visit immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-mepolizumab antibodies and a blood sample for eosinophils at least 4 months after the last dose of study agent or upon completion and/or un-blinding of the study, whichever is later.

5. Exit visit may be completed upto 6 weeks post last dose. If more than 6 weeks has passed since the last dose, only perform follow-up visit. 6. Therapy history to include a detailed review of prior monoclonal antibodiess received for treatment of asthma, including prior investigational anti-IL5 or anti-IL13 preparations. 7. Parasitic screening is only required in countries with high-risk or for subjects who have visited high-risk countries in the past 6 months. Sites should use local laboratories. 8. Study inclusion/exclusion criteria should be reviewed at Visit 2. The review should include the results of any lab/safety assessments conducted at Visit 1. 9. Maximum Post Bronchodilator Procedure is required to complete reversibility testing. If subject does not reverse ≥12% in FEV1 at Visit 1 (screen), the procedure may be repeated

at Visit 2 or 3 (see Section 6.1.4 for details on procedure). 10. OCS dose adjustments should occur through scheduled phone Visits (or optional in-clinic Visits), but can occur at the scheduled in clinic visits if the in clinic is to occur within +3

days of the scheduled OCS dose adjustment 11. The ACQ-5 should be completed weekly following Visit 1 through the subject’s eDiary. 12. eDiary data must be reviewed on a weekly basis during the Optimisation Phase and prior to OCS dose reduction during the Reduction Phase of the study. 13. During the treatment period, all lab samples should be obtained pre-dose. 14. Subject must be in the fasting state. If subject has not fasted, may return to the clinic to obtain this sample. 15. PGx consent must be obtained prior to collecting optional PGx sample. PGx sample can be taken at any visit post-randomisation. 16. Pregnancy test S = serum, U= urine 17. Hepatitis B Antigen and Hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RIBA immunoblot assay should be reflexively performed on the serum sample to

confirm the result) 18. A sub-study is being conducted in select study centers. Sputum and sub-study specific blood collection are only to be collected at the selected centers. 19. OCS titration during the Optimisation Phase can occur weekly following Visit 2 until optimal OCS dose is determined (see Section 3.2.1) and every 4 weeks during the Reduction

Phase (Section 3.2.3) but do not necessarily need to occur at the scheduled in clinic Visit (see footnote #10). The last OCS dose adjustment can occur at week 20 but not later. 20. Scheduled phone visits for assessing OCS dose adjustment will occur and must be registered in RAMOS

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6.1. Critical Baseline Assessments

All the clinical assessments and blood sampling should be performed prior to administration of study treatment unless otherwise specified. Subjects should be instructed to withhold short acting beta agonist for at least 6 hours prior to in clinic visits and long acting bronchodilators for at least 12 hours prior to in-clinic visits.

Subjects will attend a pre-screening visit and a subject number will be assigned at this time. Sites will review the informed consent with the subject at this Visit and inform them on any study related procedures that must be taken prior to the next visit (i.e. fasting for lab assessments, withholding of SABA for 6 hours and LABA for 12 hours prior to study Visits, etc).

During the OCS Optimisation Phase, which can vary from three to eight weeks, optional in clinic visits can be scheduled per Investigator's discretion for monitoring of changes in clinical signs and symptoms and for providing instruction on OCS dose adjustment. OCS dose adjustments can be managed through scheduled phone Visits. Subjects can proceed with randomisation assessments and procedures once the optimal OCS dose has been determined and maintained for a minimum of two weeks.

6.1.1. Critical Procedures Performed at Screening Visit 1

• Demographic information including gender, ethnic origin, race, date of birth, height, weight and body mass index (BMI)

• Medical history including smoking status, history of diabetes, history of hypertension, history of sinusitis, history of polyposis, history of osteoporosis, history of cataracts, aspirin sensitivity, current treatment, duration of asthma, duration of maintenance use of oral corticosteroid for asthma, courses of rescue corticosteroids (oral and parenteral), history of previous intubations, asthma exacerbation history in previous year, triggers of worsening asthma history of gastrointestinal bleeding, history of myopathy, history of adrenal insufficiency/crisis, history of susceptibility to infections

• Physical exam including an assessment for any clinically significant adverse effects associated with the use of maintenance OCS should be captured as part of the physical exam. Any clinically significant findings, either newly emerged or worsening of pre-existing clinical signs and symptoms identified on physical examinations after randomization will be recorded on the Adverse Event (AE) or Serious Adverse Events (SAE) electronic case report form (eCRF) pages.

• Cardiovascular medical history/risk factors will be assessed at screening. This assessment must include a review of the subject responses to the cardiovascular assessment questions (See Appendix 5) and height, weight, blood pressure, smoking history, medical conditions and family history of premature cardiovascular disease

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• Therapy history should include the duration of prior use of maintenance OCS for the treatment of asthma and a detailed review of prior other investigational or marketed biologics such as Xolair, received for the treatment of asthma including prior investigational anti-IL-5 and anti-IL-13 preparations.

• Subject should be instructed on how to complete the Asthma Control Questionnaire-5 (ACQ-5) through their eDiary. The first ACQ-5 should be completed at Visit 1 and then weekly throughout the study.

• Nasal exam to check for presence or absence of nasal polyps

• Pulmonary function tests and assessment of reversibility (maximum post-bronchodilator value of lung function). See Section 6.1.4

• Vital signs (Section 6.3.11)

• Sputum and blood sample collection at selected centers in Canada (see Appendix 9).

• A serum pregnancy test is required of all females and at the exit visit or early withdrawal visit (See Appendix 1). In addition, a urine pregnancy test will be performed for all females prior to Randomisation. Pregnancy testing will be conducted during each scheduled study visit prior to the administration of investigational product, and during the Exit Visit and Follow-up Visits if conducted

• Resting 12 lead ECG (see Section 6.3.12)

• Laboratory testing as indicated in Table 5 which includes the following:

• Clinical Chemistry including HbA1c

• Chemistry plus lipoprotein panel (subject must have fasted)

• Haematology with differential

• Hepatitis B Surface Antigen and hepatitis C antibody

• FSH will be assessed to confirm child-bearing status

• Parasitic screening (only in countries with a high risk or in subjects who have visited a high risk country)

6.1.2. Critical Procedures Performed at Visit 2

• Review the results from any data collected, including laboratory or safety assessment completed at Visit 1 and re-assess subject eligibility.

• Review ACQ-5 score (see Section 6.2.6) and determine appropriate OCS dose adjustment according to Section 3.2.1 and Table 1.

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6.1.3. Critical Procedures Performed at Visit 3

• Review the results from any data collected, including laboratory or safety assessment completed at Visit 1 and re-assess subject eligibility.

• Conduct pulmonary function tests and assessment of reversibility, if necessary (maximum post-bronchodilator value of lung function).

• Resting 12 lead ECG (see Section 6.3.12)

• Vital signs (Section 6.3.11)

• Review eDiary data including PEF diurnal variability (See Section 6.1.4) and Prednisone/prednisolone use

• Laboratory Tests:

• Serum IgE

• Specific IgE to a perennial allergen (to include house dust mite, cat dander, dog dander, cockroach, and mould)

• Blood for baseline immunogenicity and blood biomarker

• Urine pregnancy test for all females

• Questionnaires including:

• ACQ-5 (completed through eDiary). See Section 6.2.6.

• St. George’s Respiratory Questionnaire (SGRQ). See Section 6.2.4.

• Beck Depression Inventory II. See Section 6.2.5.

• Nasal symptoms visual analog scale (VAS). See Section 6.2.7

• Work Productivity and Activity Impairment Questionnaire. See Section 6.4.3.

• Steroid Perception Questionnaire. See Section 6.4.4.

• Medical Outcomes Study (MOS) Sleep Scale. See Section 6.4.5.

6.1.4. Pulmonary Function Testing including Reversibility using the Maximum Post-Bronchodilator Method

Spirometry will be conducted, using the site’s own equipment at the visits specified in the Time and Events schedule (Table 5). The spirometer should meet American Thoracic Society standards and produce a printout of all data generated, which should be stored in the subject’s notes. The spirometer should be calibrated in accordance with the manufacturer’s instructions and a calibration log maintained. Spirometry must be performed at the same time (±1 hour) of the Visit 1 spirometry. Subjects should withhold short-acting beta-2-agonists (SABAs) for ≥6 hours and LABAs for ≥12 hours prior to clinic visit. Assessments to be recorded will include FEV1, FVC and PEF.

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Pre-bronchodilator measurements will be taken at each in clinic visit. In addition, at visit specified in the Time and Events schedule (Table 5), post bronchodilator values will be recorded following reversibility testing, using the maximum post bronchodilator method. For subjects unable to achieve ≥12% reversibility and 200mL change at Visit 1, reversibility can be repeated at Visit 2 and/or Visit 3. The procedures to achieve the maximum post-bronchodilator are those generated by the Asthma Clinical Research Network. Further details of spirometry and reversibility testing procedures are presented in the Study Procedures Manual.

6.1.5. Cardiovascular Assessment

The cardiovascular assessment (see Appendix 5) will be administered by site personnel assessment and must be completed at the screening visit. Subject responses to each question will must be entered into the eCRF. If the subject responds ‘yes’ to any of the questions a physician must conduct a further evaluation to assess for previously unrecognized and undiagnosed angina. The results of the evaluation should be considered when determining subject eligibility (see exclusion criteria #5).

The cardiovascular assessment questions are provided in Appendix 5.

6.2. Efficacy

6.2.1. Efficacy Endpoints


The primary efficacy endpoint is the percent reduction of OCS dose during weeks 20 – 24, compared to the baseline dose, while maintaining asthma control.

Secondary Efficacy Endpoint

• The proportion of subjects who achieve a reduction of 50% or greater in their daily OCS dose, compared to baseline dose, during weeks 20-24 while maintaining asthma control.

• The proportion of subjects who achieve a reduction of their daily OCS dose to less than or equal to 5.0mg during weeks 20-24, while maintaining asthma control

• The proportion of subjects who achieve a total reduction of OCS dose during weeks 20 – 24, while maintaining asthma control

• Median percentage reduction from baseline in daily OCS dose during weeks 20 -24, while maintaining asthma control

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Other Efficacy Endpoints

• Annualised rate of clinically significant exacerbations

• Annualised rate of exacerbations requiring hospitalization

• Annualised rate of exacerbations requiring hospitalization or ED visits

• Mean change from baseline in St. George’s Respiratory Questionnaire at week 24

• Mean change from baseline in clinic pre-bronchodilator FEV1 at week 24

• Time to first clinically significant exacerbation

• Time to first exacerbation requiring hospitalization

• Time to first exacerbation requiring hospitalization or ED visit

• Mean change in Beck Depression Inventory II (BDI II) score compared to placebo

• Number of days in hospital due to asthma

• Mean number of days with oral corticosteroids taken for exacerbations

• Mean prednisone (or equivalent) exposure for exacerbations

• Mean change from baseline in ACQ-5 score at week 24

• Mean change from baseline in daily salbutamol/albuterol use

• Mean change from baseline in daily asthma symptom scores during weeks 20-24

• Mean change from baseline in awakening at night due to asthma symptoms requiring rescue medication use during weeks 20 – 24

• Mean change in nasal symptoms VAS scores

• Mean change from baseline in morning PEF during weeks 20 - 24

• Mean change from baseline in clinic post-bronchodilator FEV1 at week 24

• Mean change in IgE from baseline compared to placebo

6.2.2. OCS Dose Adjustment and eDiary

The OCS Dose Adjustment through the Reduction Phase of the study will be based on 1) asthma symptom data collected through the subject eDiary, 2) through subject history of clinically significant exacerbation or 3) presence of adrenal insufficiency.

The subject will be asked to record the following parameters daily in the eDiary from Visit 1 onwards:

• Morning peak flow (best of three), before rescue medication usage (L/min)

• Number of puffs of rescue usage over the previous 24-hours

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• Asthma symptom score over the previous 24-hours using a 6-point scale (Appendix 5)

• Frequency of awakening due to asthma symptoms requiring rescue medication use.

• Daily dose of OCS

The subject will be asked to complete the ACQ-5 weekly in the eDiary from Visit 1 onwards.

From Visit 1 to Visit 3 only, subjects will record peak flow twice a day to allow for calculation of PEF diurnal variability (See Randomization Criteria Section 4.4).

Alerts indicative of worsening asthma will be programmed into the eDiary (See Table 3). Sites will view subject data regularly through a study specific web portal. Sites should review the eDiary data prior to adjusting OCS. If the subject meets criteria for not reducing OCS as scheduled the decision should be recorded in the electronic data capture tool.

eDiary data will additionally be reviewed at each clinic visit by the site staff throughout the treatment period to confirm use of OCS as instructed, and an association between any exacerbation event and eDiary data (See Section 6.2.3).

Note: That an alert in itself will not qualify as a clinically significant exacerbation and the site should follow up with the subject as appropriate.

Subjects will also be issued a paper worksheet to record adverse events and concomitant medications during the study. This will be used to assist subject recall in discussions with the investigator, for site staff to then enter as appropriate in the eCRF.

6.2.3. Exacerbation

Clinically significant exacerbations recorded in the eCRF by the Investigator or designee will be verified using data from the eDiary to confirm that the exacerbation was associated with changes in peak flow, rescue medication use, nocturnal awakening due to asthma symptoms requiring rescue medication use or symptoms. In the case that an event described as a clinically significant exacerbation is not associated with deterioration in at least one of these objective eDiary parameters, the investigator will be asked to provide an explanation to support the decision for defining the event as an exacerbation. In those circumstances where the event cannot be supported by any objective assessment, the case will not be included as a protocol defined exacerbation, but will be included as an investigator defined exacerbation. This verification process will be overseen by GSK clinical staff to ensure consistency.

The period of time for which exacerbation information will be included in the endpoint analysis will be from the start of treatment until the week 24 visit. For those subjects that early withdrawal, the time period for endpoint collection will be from the start of treatment until the date of withdrawal (but no greater than approximately 4 weeks post last dose).

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Clinically significant exacerbations of asthma will be defined as the worsening of asthma which requires use of systemic corticosteroids. Exacerbation will be treated per the protocol with the use of oral or parenteral corticosteroids at a dose at least equivalent to double the dose of current maintenance dose of OCS for a minimum of 3 days to a maximum of 7 days, this is to ensure that exacerbations are managed in a timely manner and consistently, when possible, for all subjects participating in this study. If the exacerbation is not resolved after 7 days the treatment of the exacerbation may continue at the discretion of the Investigator. For consistency, exacerbations treated with courses of corticosteroids separated by less than 7 days will be treated as a continuation of the same exacerbation.

Clinically significant exacerbations of asthma also include worsening of asthma that requires hospitalization and/or Emergency Department (ED) visits.

For safety reasons alerts will be programmed into the eDiary to encourage the subject to contact the investigator if their asthma worsens. However, an alert in itself will not be classified as a clinically significant exacerbation.

6.2.4. St. George’s Respiratory Questionnaire

The St. George’s Respiratory Questionnaire is a well established instrument, comprising 50 questions designed to measure Quality of Life in patients with diseases of airway obstruction [Jones 1992]. The questionnaire will be administered at baseline (Visit 3) and at the Exit visit.

Subjects will initially complete the paper questionnaire, and then the study designated site staff will transcribe the information into the eCRF.

The questionnaire should be completed in a quiet area, free from distraction and the patient should ideally be sitting at a desk or table. Explain to the subject why they are completing it, and how important it is for clinicians and researchers to understand how their illness affects them and their daily life. Ask him or her to complete the questionnaire as honestly as they can and stress that there are no right or wrong answers, simply the answer that they feel best applies to them. Explain that they must answer every question and that someone will be close at hand to answer any queries about how to complete the questionnaire. It is designed for supervised self-administration. This means that the subject should complete the questionnaire themselves, but someone should be available to give advice if required. It is designed to elicit the subject’s opinion of his/her health, not someone else’s opinion of it, so family, friends or members of staff should not influence the subject’s responses.

Once the patient has finished, it is very important that site staff check the questionnaire to make sure a response has been given to every question. If they have missed an item return it to the subject for completion, before proceeding to the next activity.

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6.2.5. Beck Depression Inventory II (BDI II)

Patients who have uncontrolled or severe persistent asthma are more likely to report feeling depressed or anxious. [Demoly 2012; Carvalho-Pinto, 2012; Clienti, 2011]. It is important to assess depressive and anxiety symptoms in this population, as mood disorders can influence other QoL assessments [Carvalho-Pinto, 2012]. The BDI-II is a 21 item, self- administered questionnaire designed to assess the intensity of depression in clinical and normal patients. Individual questions of the BDI assess mood, pessimism, sense of failure, self-dissatisfaction, guilt, punishment, self-dislike, self-accusation, suicidal ideas, crying, irritability, social withdrawal, body image, work difficulties, insomnia, fatigue, appetite, weight loss, bodily preoccupation, and loss of libido over the prior two weeks. Items 1 to 13 assess symptoms that are psychological in nature, while items 14 to 21 assess more physical symptoms. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. The BDI–II is in alignment with the Diagnostic and Statistical Manual of Mental Disorders (DSM–IV) criteria.

The sum of all BDI-II item scores indicates the severity of depression. The test is scored differently for the general population and for individuals who have been clinically diagnosed with depression. For the general population, a score of 21 or over represents depression [Beck 1984; Beck 1988].

The BDI-II will be completed at several time points during the study in subjects who are 13 years of age an older, as listed in the Time and Events table (Table 5). The questionnaire should be completed in a quiet area, free from distraction and the patient should ideally be sitting at a desk or table. Explain to the subject why they are completing it, and how important it is for clinicians and researchers to understand how their illness affects their mental wellbeing. Ask him or her to complete the questionnaire as honestly as they can and stress that there are no right or wrong answers, simply the answer that they feel best applies to them. Explain that they must answer every question.

The questionnaire will be completed on paper and then designated study site staff will transcribe the responses into the eCRF.

6.2.6. Asthma Control Questionnaire -5 (ACQ-5)

The ACQ-5 is a five-item questionnaire, which has been developed as a measure of subject’ asthma control that can be quickly and easily completed in clinical practice. [Juniper 2005] The questions are designed to be self-completed by the subject. The five questions enquire about the frequency and/or severity of symptoms (nocturnal awakening on waking in the morning, activity limitation, and shortness of breathe, wheeze). The response options for all these questions consist of a zero (no impairment/limitation) to six (total impairment/ limitation) scale. The ACQ-5 score is a mean of the values recorded for the individual questions.

Throughout the study subjects should complete the ACQ-5 on a weekly basis using their eDiary. The results from the ACQ-5 will be used as a part of the assessment to determine subject eligibility for OCS dose adjustment.

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The subject should complete the questionnaire within the eDiary. The subject should be instructed to complete the questions as accurately as possible. The subject should be reassured that there are no right or wrong answers. If the subject requests help or clarification with any of the questions, he/she will be asked to re-read the instructions and give the answer that best reflects how he/she felt over the previous week. The investigator should not provide the subject with any answer or attempt to interpret any portion of a question.

If the ACQ-5 is completed through the eDiary while the subject is at a scheduled in clinic Visit, it is recommended that the ACQ be administered at the same time during the visit. To avoid biasing responses, the subjects should not be told the results of diagnostic tests prior to completing the questionnaire and should be completed before any procedures are performed on the subject to avoid influencing the subject’s response. Adequate time should be allowed to complete all items on the ACQ.

6.2.7. Nasal Symptoms Individual Analogue Scale (VAS)

Subjects will be asked to indicate on a VAS (0 – 10 cm) the severity of four nasal symptoms (one VAS for each symptom) at the time points listed in the Time and Events table (Table 5). Prior to using the scale subjects will be instructed on how to use it. All scales to be used in the study will be printed by the sponsor and investigators should not use any scales besides those provided by the sponsor and specifically not use any Xeroxed or photocopied scales. Further instruction is provided in the SPM.

6.3. Safety

6.3.1. Safety Endpoints

• Adverse Events, including both systemic (i.e., allergic/IgE-mediated and non-allergic) and local site reactions reported throughout the 24-week treatment period.

NOTE: Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis as outlined by the 2006 Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson 2006; Appendix 6]. Information will be also collected to assess localised site reactions.

• Adverse Events typical of and associated with the chronic use maintenance OCS.

• Haematological and clinical chemistry parameters throughout the 24-week treatment period.

• Vital signs (pulse rate and systolic and diastolic blood pressure) throughout the24-week treatment period.

• Blood glucose and body weight throughout the 24-week treatment period

• HbA1c throughout the 24-week treatment period

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The following endpoints will be derived:

• Change from baseline in systolic blood pressure

• Change from baseline diastolic blood pressure

• Change from baseline in pulse rate

• 12-lead ECG to derive the following endpoints:

• Mean change from baseline in the QTc(F) (QT interval corrected by Fridericia's method)

• Mean change from baseline in QTc(B) (QT interval corrected by Bazett's method)

• Maximum change from baseline for QTc(F) and QTc(B).

6.3.2. Liver chemistry stopping and follow up criteria

Phase III-IV liver chemistry stopping and follow up criteria have been designed to assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance).

Phase III-IV liver chemistry stopping criteria 1-5 are defined below and in Appendix 4:

1. ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT ≥ 3xULN and INR>1.5, if INR measured)

NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug for that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 2. ALT ≥ 8xULN.

3. ALT ≥ 5xULN but <8 x ULN persists for ≥2 weeks

4. ALT ≥ 3xULN if associated with symptoms (new or worsening) believed to be related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).

5. ALT ≥ 5xULN but <8 x ULN and cannot be monitored weekly for ≥2 weeks

When any of the liver chemistry stopping criteria 1-5 is met, do the following:

• Immediately withdraw investigational product for that subject

• Report the event to GSK within 24 hours of learning its occurrence

• Complete the liver event CRF and SAE data collection tool if the event also meets the criteria for an SAE. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) (or ALT ≥ 3xULN and INR>1.5, if INR measured); INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).

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NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug for that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.

• Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

• Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilize, or return to baseline values as described below.

• Withdraw the subject from the study after completion of the liver chemistry monitoring (unless further safety follow up is required).

• Do not restart investigational product unless written approval is granted by GSK Medical Governance

• Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat liver chemistries, liver event follow up assessments (see below), and close monitoring

• A specialist or hepatology consultation is recommended

• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values

For criteria 2, 3, 4 and 5:

• Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for repeat liver chemistries and liver event follow up assessments (see below)

• Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects should be monitored as frequently as possible.

Subjects with ALT ≥5xULN and <8xULN which exhibit a decrease to ALT x≥3xULN, but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be monitored weekly for 4 weeks:

• Notify the GSK medical monitor within 24 hours of learning of the abnormality to discuss subject safety

• Can continue investigational product

• Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) until they resolve, stabilize or return to within baseline

• If at any time these subjects meet the liver chemistry stopping criteria, proceed as described above

• If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor subjects twice monthly until liver chemistries normalize or return to within baseline values.

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For criteria 1-5, make every attempt to carry out the liver event follow up assessments described below:

• Viral hepatitis serology including:

• Hepatitis A IgM antibody;

• Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);

• Hepatitis C RNA;

• Cytomegalovirus IgM antibody;

• Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);

• Hepatitis E IgM antibody

• Blood sample for PK analysis, obtained within 4 weeks of last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the SPM.

• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

• Fractionate bilirubin, if total bilirubin ≥2xULN

• Obtain complete blood count with differential to assess eosinophilia

• Record the appearance or worsening of clinical symptoms of hepatitis or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or eosinophilia as relevant on the AE report form

• Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins, on the concomitant medications report form.

• Record alcohol use on the liver event alcohol intake case report form

The following are required for subjects with ALT ≥3xULN and bilirubin ≥2xULN (>35% direct) but are optional for other abnormal liver chemistries:

• Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies.

• Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in subjects with definite or likely acetaminophen use in the preceding week (James 2009).

• Only in those with underlying chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta antibody. NOTE: if hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus (where needed) – as outlined in: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/

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• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.

6.3.3. Adverse Events

The subject will be provided with a AE worksheet on which they may record any adverse events during the study.

The investigator or site staff will be responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

6.3.3.1. Definition of an AE

Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

Events meeting the definition of an AE include:

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

• New conditions detected or diagnosed after study treatment administration even 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 either study

treatment or a concomitant medication (overdose per se will not be reported as an AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-harming intent. This should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfil the definition of an AE or SAE.

Events that do not meet the definition of an AE include:

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

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

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

• The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition

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6.3.3.2. Definition of a SAE

A serious adverse event is any untoward medical occurrence that, at any dose:

a. Results in death

b. Is life-threatening

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the 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 hospitalization or prolongation of existing hospitalization

NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 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 conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect

f. Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also 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, or development of drug dependency or drug abuse.

g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) (or ALT ≥ 3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants).

NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick indicating

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direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a subject meets the criterion of total bilirubin ≥ 2xULN, then the event is still reported as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver injury.

6.3.4. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator are to be recorded as AEs or SAEs.

However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition, are not to be reported as AEs or SAEs.

6.3.5. Cardiovascular Events

Investigators will be required to fill out event specific pages in the eCRF for the following AEs and SAEs:

• Myocardial infarction/unstable angina

• Congestive heart failure

• Arrhythmias

• Valvulopathy

• Pulmonary hypertension

• Cerebrovascular events/stroke and transient ischemic attack

• Peripheral arterial thrombosis

• Deep Venous Thrombosis

• Revascularization

Cardiovascular events information should be recorded on the corresponding eCRF pages within one week of when the AE/SAE(s) are first reported. Please refer to Section 6.3.10 for timelines for reporting AE/SAEs.

6.3.6. Death Events

In addition, all deaths will require completion of a specific death data collection page in the eCRF. The death data collection page in the eCRF includes questions regarding cardiovascular (including sudden cardiac death) and non-cardiovascular death.

Death information should be recorded on the death eCRF page within one week of when the death is first reported.

Please refer to Section 6.3.10 for timelines for reporting SAEs.

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6.3.7. Pregnancy

Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child. Pregnancy complications and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE.

Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the study treatment, must be promptly reported to GSK.

6.3.8. Medical Devices

Medical devices are being provided by GSK for use in this study. GSK medical device incidents, including those resulting from malfunctions of the device, must be detected, documented, and reported by the investigator throughout the study.

Medical Device – this is any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of:

• diagnosis, prevention, monitoring, treatment or alleviation of disease;

• diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;

• investigation, replacement or modification of the anatomy or of a physiological process;

• control of conception

and which does not achieve its principle action in or on the human body by pharmacological, immunological or metabolic means, but may be assisted in its function by such means.

Note: if these means fulfill the main purpose of the product, it is a Medicinal Product. The term medical device includes in vitro diagnostic (IVD) devices.

The detection and documentation procedures described in this protocol apply to all GSK medical devices provided for use in the study.

Incident – Any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly might lead to or might have led to the death of a patient, or user or of other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health. The non-occurrence of such a result might have been due to other fortunate circumstances or to the intervention of health care personnel.

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It is sufficient that

• An incident associated with a device happened and

• The incident was such that, if it occurred again, it might lead to death or serious deterioration in health

A serious deterioration in state of health can include:

• A life-threatening illness (a)

• Permanent impairment of body function or permanent damage to a body structure (b)

• A condition necessitating medical or surgical intervention to prevent (a) or (b)

• Any indirect harm as a consequence of an incorrect diagnostic or IVD test results when used within the manufacturer’s instructions for use

• Fetal distress, fetal death or any congenital abnormality or birth defects

Incidents include, for example:

• inhalation of an object that has accidentally entered a spacer device and resulted in tracheal obstruction.

Incidents do not include for example:

• medical occurrences associated with metered-dose inhalers that do not fulfill the definition of a medical device (such events will be reported as medicinal product AEs)

• non-serious medical occurrences which have no further safety implications for the subject or the device

Malfunction – A failure of a device to perform in accordance with its intended purpose when used in accordance with the manufacturer’s instructions.

Remedial Action – Any action other than routine maintenance or servicing of a device where such action is necessary to prevent recurrence of a reportable incident. [This includes any amendment to the design to prevent recurrence.]

6.3.9. Time Period and Frequency of Detecting AEs and SAEs

The investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

AEs will be collected from the start of study treatment and until the Exit Visit/follow up contact.

SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be recorded from the time a subject consents to participate in the study

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up to and including any follow up contact. All SAEs will be reported to GSK within 24 hours, as indicated in Section 6.3.10.

6.3.10. Prompt Reporting of Serious Adverse Events and Other Events to GSK

SAEs, pregnancies, medical device incidents, and liver function abnormalities meeting pre-defined criteria will be reported promptly by the investigator to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event.

Initial Reports Follow-up Information on a Previous Report Type of Event Time Frame Documents Time Frame Documents All SAEs 24 hours “SAE” data collection

tool

24 hours Updated “SAE” data collection tool “CV events” and/or “death” data collection tool(s)

Device Incident 24 hours “Medical Device Incident Report Form”

24 hours Updated “Medical Device Incident Report Form”

Pregnancy 2 weeks “Pregnancy Notification Form”

2 weeks “Pregnancy Follow-up Form”

Liver chemistry abnormalities for Phase I to IV: ALT≥3xULN and Bilirubin≥2xULN (>35% direct) (or ALT≥3xULN and INR>1.5, if INR measured)1

24 hours2 “SAE” data collection tool. “Liver Event CRF” and “Liver Imaging” and/or “Liver Biopsy” CRFs, if applicable3

24 hours Updated “SAE” data collection tool/“Liver Event” Documents3

Remaining liver chemistry abnormalities Phase III to IV: ALT≥8xULN; ALT≥3xULN with hepatitis or rash or ≥3xULN and <5xULN that persists≥4 weeks

24 hours2 “Liver Event” Documents (defined above) 3

24 hours Updated “Liver Event” Documents3

ALT≥5xULN plus bilirubin <2xULN

24 hours2 “Liver Event” Documents (defined above) do not need completing unless elevations persist for 2 weeks or subject cannot be monitored weekly for 2 weeks3

24 hours Updated “Liver Event” Documents, if applicable3

ALT≥5xULN and bilirubin <2xULN that persists ≥2 weeks

24 hours2 “Liver Event” Documents (defined above) 3

24 hours Updated “Liver Event” Documents3

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Initial Reports Follow-up Information on a Previous Report Type of Event Time Frame Documents Time Frame Documents ALT≥3xULN and <5x ULN and bilirubin <2xULN

24 hours2 “Liver Event” Documents (defined above) do not need completing unless elevations persist for 4 weeks or subject cannot be monitored weekly for 4 weeks3

24 hours Updated “Liver Event” Documents, if applicable3

1. INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving anticoagulants.

2. GSK must be contacted at onset of liver chemistry elevations to discuss subject safety 3. Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as

applicable) should be completed as soon as possible.

The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided in the SPM. Procedures for post-study AEs/SAEs are provided in the SPM.

Procedures for documenting, transmitting and follow-up of medical device incidents along with the regulatory reporting requirements for medical devices are provided in the SPM.

6.3.10.1. Regulatory reporting requirements for SAEs

Prompt notification of SAEs by the investigator to GSK is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.

GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and investigators.

Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.

6.3.11. Vital Signs

Sitting pulse rate and blood pressure measurements will be performed by the investigator or qualified site staff, as outlined in Time and Events schedule (Table 5) Measurements will be done pre-infusion/injection with the subject sitting, having rested in this position for at least 5 minutes before each reading. They will be taken before measurement of any clinic lung function tests or ECGs at the specified time point.

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6.3.12. Twelve-lead electrocardiogram (ECG)

Twelve-lead ECGs will be performed at the visits specified in the Time and Events schedule (Table 5).

Electrocardiogram measurements will be made after the subject has rested in the supine position for 5 minutes. The ECG should be obtained before lung function testing followed by other study procedures. Collection shortly after a meal or during sleep should be avoided since QT prolongation can occur at these times.

Investigators will be provided with ECG machines by GSK through a designated central laboratory. Paper ECG traces will be recorded at a standard paper speed of 25mm/sec and gain of 10mm/mV, with a lead II rhythm strip. There will be electronic capture and storage of the data by a validated method, with subsequent transferral to the central laboratory for manual reading and calculation of the electrocardiographic parameters.

Subjects with evidence of significant abnormality in the 12-lead ECG or a QTc(F) ≥ 450msec or QTc(F) ≥ 480 msec for patients with Bundle Branch Block at screening will be excluded from randomisation.

Paper traces are required to be maintained at the site with other source documents.

6.3.13. Clinical Laboratory Parameters

Clinical laboratory tests will be conducted at the visits specified in the Time and Events schedule (Table 5).

All blood samples which will be taken pre-infusion, will be sent to a central laboratory for analysis (details provided in the SPM). Standard reference ranges will be used. For the chemistry plus lipoprotein sample at scheduled visits, the subject must be fasting. If a subject has not fasted at an Early Withdrawal Visit, the subject does not need to return for the chemistry plus lipoproteins. The laboratory requisition should be marked that the subject did not fast.

Full details of the collection and shipping requirements for the central laboratory are provided in the Central Laboratory Investigator Manual. The central laboratory will fax laboratory results to the Investigator and will transmit the results electronically to GlaxoSmithKline. To maintain the treatment blind, the site will not be sent information on haematology differential from any visits post-randomisation either from the central laboratory or from GSK.

6.4. Health Outcomes

6.4.1. Health Outcome Endpoints

• Percent of subjects evaluated as having a favourable treatment response compared to placebo as measured by the Clinician Rated Response to Therapy

• Percent of subjects recording a favourable treatment response as measured by the Subject Rated Response to Therapy

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• Mean Work Productivity and Activity Impairment Index – General Health (WAPI-GH) version 2

• Steroid Perception Questionnaire

• Change from baseline Medical Outcomes Study (MOS) Sleep Scale

• Mean days of school/work missed

6.4.2. Clinician/Subject Rated Response to Therapy

The clinician and the subject will be asked to rate the response to therapy at the visits specified in the Time and Events schedule (Table 5). This is an overall evaluation of response to treatment, conducted separately by the investigator and the subject using a rating scale. In this rating scale, a seven-point scale score is used with the following definitions:

• 1 = significantly improved

• 2 = moderately improved

• 3 = mildly improved

• 4 = no change

• 5 = mildly worse

• 6 = moderately worse

• 7 = significantly worse.

The subject will indicate their response on a paper questionnaire which will be transcribed into the eCRF by study designated site staff.

6.4.3. Work Productivity and Activity Impairment Questionnaire: General Health (WAPI-GH)

Asthma has a substantial effect on lost days of works, with millions of days being lost each year [Catley 2011]. Furthermore, asthma results in lost productivity due to decreased effectiveness while working [Wilson 2012]. The WPAI-GH is a self or interviewer administered tool comprised of 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated tool captures data from the past 7 days. WPAI-GH outcomes are scored as impairment percentages, with a higher percentage indicating greater impairment and less productivity [Reily Associates 2012].


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6.4.4. Steroid Perception Questionnaire

The use of maintenance oral corticosteroids can have many and diverse adverse effects. The steroid perception questionnaire was developed to better assess the subjects perception of the adverse effects associated with the use of daily OCS. Specifically, weight gain, infections, muscle weakness, making bone brittle or prone to fracture, gastrointestinal bleeding, skin atrophy or striae, diabetes, hypertension, mood changes, difficulty sleeping, and cataracts or eye problems.


6.4.5. Medical Outcomes Study (MOS) Sleep Scale

The MOS Sleep Scale is a 12-item questionnaire (MOS-12). The questionnaire is intended to assess the extent of sleep problems, the MOS Sleep Scale measures six dimensions of sleep, including initiation, maintenance (e.g. staying asleep), quantity, adequacy, somnolence (e.g. drowsiness), and respiratory impairments (e.g. shortness of breath, snoring). The scale has a 4-week recall period and reliability and validity of the MOS Sleep Scale has been evaluated in a number of disease areas. Disturbed sleep has a major impact on quality of life and is often a common symptom of many other chronic conditions, such as chronic pain and mood disorders and is an adverse event noted with chronic use of OCS.


6.4.6. Missed Days of School/Work

As the WPAI-GH only captures the prior 7 days of work and does not capture missed days of school, the eDiary will be programmed to capture missed days of work/school.

6.5. Pharmacokinetics

Blood samples for analysis of mepolizumab plasma concentration will be obtained as per the Time and Events table (Table 5). Samples should be obtained prior to dosing. The date and exact time of collection for each sample will be documented in the eCRF.

Details for collection and processing of samples may be found in the SPM.

6.6. Pharmacodynamics

Blood eosinophil counts will be recorded as part of the standard haematological assessments performed at the visits specified in the Time and Events table (Table 5). From Visit 3 onwards, blood eosinophil counts will not be communicated to investigators, in order to maintain the blind.

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6.7. Immunogenicity

Blood samples will be collected for the determination of anti-mepolizumab antibodies, prior to dosing, at randomisation (Visit 3), week 16 (Visit 7), at the Exit Visit and at the Follow-up Visit for those not entering the open-label extension study.

Details for sample collection and processing may be found in the SPM.

6.8. Pharmacogenetic Research

Information regarding genetic and pharmacogenetic (PGx) research is included in Appendix 2. The IEC/IRB and, where required, the applicable regulatory agency must approve the genetic or PGx assessments before these can be conducted at the site. The approval(s) must be in writing and will clearly specify approval of the genetic or PGx assessments (i.e., approval of Appendix 2). In some cases, approval of the genetic or PGx assessments can occur after approval is obtained for the rest of the study. If so, then the written approval will clearly indicate approval of the genetic or PGx assessments is being deferred and the study, except for genetic or PGx assessments, can be initiated. When genetic or PGx assessments will not be approved, then the approval for the rest of the study will clearly indicate this and therefore, genetic or PGx assessments will not be conducted.

6.9. Exploratory Biomarkers

After completion of the clinical trial, investigations may be performed on serum samples collected during the course of the trial to detect factors or profiles that correlate with other measures of response to treatment with mepolizumab or with asthma status. The results gained may also be of application for medically related conditions.

A sub-study will be conducted at selected centers in Canada to investigate the role of eosinophil progenitor cells and markers of eosinophilic inflammation in blood and sputum samples, as indicated in Table 5 and in Appendix 7.

All samples will be retained for a maximum of 15 years after the last subject completes the trial.

7. DATA MANAGEMENT

For this study subject data will be entered into GSK defined electronic case report forms (eCRFs), transmitted electronically to GSK or designee and combined with data provided from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data. Adverse events and concomitant medications terms will be coded using MedDRA and an internal validated medication dictionary, GSKDrug. eCRFs (including queries and audit trails) will be retained by GSK, and copies will be sent to the investigator to maintain as the investigator copy In all cases, subject initials will not be collected or transmitted to GSK according to GSK policy..

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8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

8.1. Hypotheses

The study is designed to show superiority of mepolizumab vs. placebo.

This will be tested at a two-sided 5% significance level.

8.2. Study Design Considerations

8.2.1. Sample Size Assumptions

Sample size is based on the primary efficacy endpoint of percentage reduction of daily prednisone dose during weeks 20-24 compared to the baseline dose, using the categories specified in Section 8.4.4.1. The sample size calculation uses the method of Whitehead [Whitehead 1993] for analysis based on a proportional odds model.

A study with 60 subjects randomised to each treatment arm is estimated to have 90% power to detect a difference in the proportion of subjects achieving at least 50% reduction in oral corticosteroid dose of 48% on placebo, compared to 73% on mepolizumab, using a two sided 5% significance level. This is equivalent to an odds ratio of 2.9

These assumptions are based on a number of previous corticosteroid-tapering studies, as summarised below in Table 6.

Table 6 Sample Size Assumptions

Study Investigational Product Response Rate* Placebo Active

Bateman 2006 Ciclesonide 33% 64% (low dose) 77% (high dose)

Nair 2009 Mepolizumab 48%** 84%** Noonan 1995 Fluticasone proprionate 26% 84% (low dose)

97% (high dose) Nelson 1999 Fluticasone proprionate 39% 85% (low dose)

97% (high dose) 1. *Proportion of subjects with corticosteroid reduction of 50% or greater. 2. **Estimated values, based on published mean (±SD) percentage reduction

The response rate of 48% was the highest placebo rate observed in the above studies, i.e. a conservative estimate was assumed. The minimum treatment effect at which the study was to be powered was considered to be a mepolizumab rate 25% greater than placebo, i.e. a mepolizumab rate of 73% was assumed.

For a proportional odds model, the sample size estimate is also dependent on assumptions about the proportion of subjects in each category [Whitehead 1993]. Table 7 below shows the assumptions have been used:

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Table 7 Sample Size Assumptions by Category

Percentage reduction in prednisone daily dose compared to baseline

Placebo SC Mepolizumab 100mg SC

≥90 - 100% 12% 28% ≥75-< 90% 16% 25% ≥50 < 75% 20% 20% >0 -< 50% 24% 16%

No decrease in prednisone, lack of control during weeks 20-24, or withdrawal from treatment

28% 12%

8.2.2. Sample Size Sensitivity

If the actual odds ratio observed in the study is different from the value assumed in Section 8.2.1, the power to detect the planned different in prednisone daily dose reduction will be affected. Table 8 illustrates the estimated power which would be obtained given different values of the odds ratio, assuming the sample size remains at 60 subjects per arm. It also shows the estimated sample size per arm which would be required for 90% power.

Table 8 Estimated Power

Response Rate Odds Ratio Power N per arm required for 90% power Placebo Mepolizumab

48% 67% 2.2 68% 106 48% 70% 2.5 82% 76 48% 73% 2.9 90% 60 48% 76% 3.4 97% 43

8.2.3. Sample Size Re-estimation

No sample size re-estimation is planned.

8.3. Data Analysis Considerations

All pre-specified analyses will be described in a full Reporting and Analysis Plan (RAP) which will be finalised prior to unblinding.

The study will be unblinded once the final subject has completed their final visit (i.e. Exit Visit at week 24, or the follow-up visit if not going into the open-label study), all queries for data collected up to this time are resolved and the clinical study database is frozen.

8.4. Analysis Populations

Intent-to-Treat Population

The Intent-to-Treat (ITT) population will consist of all subjects randomised to treatment and who received at least one dose of trial medication.

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The ITT Population will be used for tables of efficacy, safety, demography and health outcomes measures, and all relevant listings. This is the primary population for the analysis of the primary endpoint.

Per Protocol Population

The Per Protocol (PP) population will consist of those patients in the Intent-to-Treat population who do not have a protocol deviation considered to potentially have an effect on the assessment of efficacy. These deviations will be determined prior to unblinding, and will be fully documented. The PP population will be used for a supplementary analysis of the primary endpoint.

All decisions regarding definition of analyses populations will be made prior to unblinding.

8.4.1. Analysis Data Sets

All analyses will be performed using all available data as outlined in the Reporting and Analysis Plan.

8.4.2. Treatment Comparisons

All treatment comparisons are between mepolizumab and placebo.

8.4.2.1. Primary Comparisons of Interest

For those subjects randomized to mepolizumab, 6 doses will provide therapeutic coverage for 24 weeks (4 weeks following the last dose). For those subjects who complete the study the primary efficacy endpoint will be measured from week 20 to the week 24 (Visit 9). Subjects who early withdraw or do not exhibit asthma control will be considered as non-responders in the endpoint analysis (i.e. assigned to the lowest efficacy category).

8.4.3. Interim Analysis An Independent Data Monitoring Committee (IDMC) will be utilized in this study to ensure external objective review of safety issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study (see Section 9.8). The schedule of any planned interim analysis and the analysis plan for IDMC review is described in the charter, which is available upon request.

Only members of the IDMC and the independent statistical center responsible for preparing results for the IDMC will have access to unblinded randomisation codes and the interim results. The study statistician, investigators, and GSK personnel involved in monitoring of the study will not be unblinded until the study completes as planned or is terminated.

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8.4.4. Key Elements of Analysis Plan It is anticipated that approximately 10 countries will participate in the study. The study will be centrally randomized separately within each country. It is envisaged that centres for this study will be in Australia, Canada, Czech Republic, France, Germany, Mexico, Netherlands, Poland, UK and US. A grouping system based on geographical region will be defined in the RAP and used for all analyses. As the study will be stratified by number of years on OCS (< 5 years versus ≥ 5 years), a factor for this will be included in the statistical analysis. In addition terms for other baseline covariates will be included in some models to improve precision. Further detail for the following sections will be fully described in the RAP.

8.4.4.1. Efficacy Analyses


The primary efficacy endpoint is the percentage reduction of daily prednisone dose during weeks 20 - 24 compared to the baseline dose, while maintaining asthma control, categorised as follows:

1. 90 - 100%

2. 75 - <90%

3. 50 - <75%

4. >0 - <50%

5. No decrease in prednisone dose, or withdrawal from treatment

The comparison of mepolizumab with placebo will be expressed as an odds ratio. All subjects in the ITT population will be included in the primary analyses; subjects who withdraw prematurely from treatment will be included in the lowest efficacy category (category 5 in the above list).

The percentage reduction of daily prednisone dose will be analyzed using a proportional odds model with the categories of percentage reduction of daily prednisone dose shown above. Covariates will include treatment group, number of years on OCS (< 5 years versus ≥ 5 years), region, and dose of OCS at baseline. The odds ratio, p-value and 95% confidence intervals will be presented.

The analysis will be performed on the Intent-to-Treat (ITT) population. Supporting analysis will be performed using the PP population.

Secondary Efficacy Endpoint

Secondary endpoints are defined as follows:

• A reduction of OCS dose of at least 50% compared to baseline dose during weeks 20-24, while maintaining asthma control

• A reduction of OCS dose to less than or equal to 5.0 mg during weeks 20-24, while maintaining asthma control

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• A total reduction of OCS dose during weeks 20-24, while maintaining asthma control

• Median percentage reduction in daily OCS dose during weeks 20 – 24, while maintaining asthma control

Reduction of OCS dose of at least 50% compared to baseline and reduction of OCS dose to less than or equal to 5.0mg, and total reduction in OCS dose, will be analysed using logistic regression. Covariates will be as for the primary analysis.

Median percentage reduction in OCS dose at week 24 will be analysed using the Wilcoxon test with adjustment for randomisation stratum. A p-value will be presented.

Other efficacy endpoints are defined as follows:





• Mean change from baseline in clinic pre-bronchodilator FEV1

• Time to first exacerbation requiring hospitalization

• Time to first exacerbation requiring hospitalization or ED visit

• Mean change in Beck Depression Inventory II (BDI II) score compared to placebo

• Number of days in hospital due to asthma

• Mean number of days with oral corticosteroids taken for exacerbations

• Mean prednisone (or equivalent) exposure for exacerbations

• Mean change from baseline in ACQ score at week 24

• Mean change from baseline in daily salbutamol/albuterol use

• Mean change from baseline in daily asthma symptom scores during weeks 20 -24

• Mean change from baseline in awakening at night due to asthma symptoms requiring rescue medication use during weeks –20 - 24

• Mean change from baseline in morning PEF during weeks –20 - 24


• Mean change in IgE from baseline compared to placebo

• Mean change in nasal symptoms VAS scores

Details of analyses of other efficacy endpoints will be described in the RAP.

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8.4.4.2. Safety Analyses

Safety endpoints are as follows:

• Serious adverse events

• All adverse events

• Withdrawals

• Pregnancy

• Haematological and clinical chemistry parameters

• ECG

• Vital signs (pulse rate and systolic and diastolic blood pressure)

• Immunogenicity

• Assessment of steroid toxicity (e.g. patient history of osteoporosis, diabetes, blood glucose, hypertension, cataract formation, gastrointestinal bleeding, myopathy, adrenal insufficiency, susceptibility to infections, weight gain, and skin thinning)

• Assessment of steroid withdrawal (i.e. the signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension).

The number of treatments administered will be summarised by treatment group as a measure of exposure to study drug. A summary will be produced of the number of days from the start of treatment until 4 weeks after the last dose of study drug (or study discontinuation for those subjects withdrawing prematurely).

AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary and summarised by preferred term and treatment group. Adverse events and serious adverse events (SAEs) occurring pre-treatment, during active treatment and post-treatment will be summarised separately. The number and percentage of subjects experiencing at least one AE of any type, AEs within each body system and AEs within each preferred term will be presented for each treatment group. Separate summaries will be provided for all AEs, investigational product-related AEs, SAEs, events of special interest (including systemic infusion [non-IgE-mediated] and hypersensitivity [IgE-mediated] reactions and local site reactions) and for AEs leading to permanent discontinuation of investigational product or withdrawal from the study.

All laboratory parameters for clinical chemistry and haematology will be summarised and tabulated.

Each ECG parameter at every assessed time point will be summarised using summary statistics. Summary statistics of QT interval corrected for heart rate according to Fridericia’s formula (QTcF) and QT interval corrected for heart rate according to Bazett’s formula (QTcB) as well as change from baseline value will be presented by visit.

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Summary statistics of pulse rate and systolic and diastolic blood pressure will be presented by visit.

Immunogenicity will be summarised using appropriate descriptive statistics.

Full details of the analyses to be performed on all safety endpoints will be given in the RAP.

8.4.4.3. Health Outcomes Analyses

Health outcomes endpoints are as follows:

• Percent of subjects evaluated as having a favourable treatment response compared to placebo as measured by the Clinician Rated Response to Therapy

• Percent of subjects recording a favourable treatment response as measured by the Subject Rated Response to Therapy

• Mean Work Productivity and Activity Impairment Index

• Steroid Perception Questionnaire

• Change from baseline Medical Outcomes Study Sleep Scale

• Mean days of school/work missed

Full details of the analyses to be performed on all health outcomes endpoints will be given in the RAP.

8.4.4.4. Pharmacokinetic Analyses

The plasma mepolizumab levels from this study will be evaluated using the population pharmacokinetics model developed based on previous mepolizumab data from healthy and asthmatics subjects. Population and/or individual mepolizumab systemic exposure, clearance and volume of distribution as well as the associated between- and within-subject variability will be estimated. The effects of subjects’ characteristics (such as gender, weight, age, race, creatinine clearance, etc.) on mepolizumab systemic exposure will be explored in order to account for potential sources of inter-individual variability.

Further details on the analysis will be described in the RAP.

8.4.4.5. Pharmacodynamic Analyses

Full details of the analyses to be performed on all pharmacodynamic endpoints will be given in the RAP.

8.4.4.6. Pharmacogenetic Analyses

Any genetic or pharmacogenetic analyses will be described in a separate PGx Reporting and Analysis Plan and will be reported separately from the main clinical study report. See Appendix 2 for details about potential genetic or pharmacogenetic analyses.

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8.4.4.7. Exploratory Biomarker(s) Analyses

The results of these biomarker investigations will be reported separately from the main clinical study report. All endpoints of interest from all comparisons will be descriptively and/or graphically summarised as appropriate to the data.

9. STUDY CONDUCT CONSIDERATIONS

9.1. Posting of Information on Publicly Available Clinical Trial Registers

Study information from this protocol will be posted on publicly available clinical trial registers before enrolment of subjects begins.

9.2. Regulatory and Ethical Considerations, Including the Informed Consent Process

Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical Practice (GCP) and applicable country-specific regulatory requirements.

The study will be conducted in accordance with all applicable regulatory requirements.

The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to:

• Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and favourable opinion/approval of study protocol and any subsequent amendments.

• Subject informed consent.

• Investigator reporting requirements.

GSK will provide full details of the above procedures, either verbally, in writing, or both.

Written informed consent must be obtained from each subject prior to participation in the study.

In approving the clinical protocol the IEC/IRB and, where required, the applicable regulatory agency are also approving the optional assessments e.g., PGx assessments described in Appendix 2, unless otherwise indicated. Where permitted by regulatory authorities, approval of the optional PGx assessments can occur after approval is obtained for the rest of the study. If so, then the written approval will clearly indicate approval of the optional PGx assessments is being deferred and the study, except for the optional PGx assessments, can be initiated. When the optional PGx assessments are not approved, then the approval for the rest of the study will clearly indicate this and therefore, the optional PGx assessments will not be conducted.

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9.3. Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will include identification, agreement and documentation of data items for which the CRF will serve as the source document.

GSK will monitor the study to ensure that the:

• Data are authentic, accurate, and complete.

• Safety and rights of subjects are being protected.

• Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents.

9.4. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study. In the event of an assessment, audit or inspection, the investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to implement any corrective and/or preventative actions to address any findings/issues identified.

9.5. Study and Site Closure

The completion of the study will be defined as completion of the last subject last visit for the study.

Upon completion or termination of the study, the GSK monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and GSK Standard Operating Procedures.

GSK reserves the right to temporarily suspend or terminate the study at any time for reasons including (but not limited to) safety issues, ethical issues, or severe non-compliance. If GSK determines that such action is required, GSK will discuss the reasons for taking such action with the investigator or head of the medical institution (where applicable). When feasible, GSK will provide advance notice to the investigator or head of the medical institution of the impending action.

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If a study is suspended or terminated for safety reasons, GSK will promptly inform all investigators, heads of the medical institutions (where applicable),and/or institutions conducting the study. GSK will also promptly inform the relevant regulatory authorities of the suspension/termination along with the reasons for such action. Where required by applicable regulations, the investigator or head of the medical institution must inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination.

9.6. Records Retention

Following closure of the study, the investigator or head of the medical institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere) in a safe and secure location. The records must be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff.

Where permitted by local laws/regulations or institutional policy, some or all of the records may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution must be exercised before such action is taken. The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original. In addition, they must meet accessibility and retrieval standards, including regeneration of a hard copy, if required. The investigator must also ensure that an acceptable back-up of the reproductions exists and that there is an acceptable quality control procedure in place for creating the reproductions.

GSK will inform the investigator of the time period for retaining the site records in order to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK standard operating procedures, and/or institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to archival of records at an off-site facility or transfer of ownership of the records in the event that the investigator is no longer associated with the site.

9.7. Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers and Publication

Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

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GSK will provide the investigator with the randomisation codes for their site only after completion of the full statistical analysis.

GSK aims to post a results summary to the GSK Clinical Study Register and other publicly available registers no later than 8 months after the last subject’s last visit (LSLV) [this applies to each data analysis phase for studies with multiple phases, e.g., primary analysis, follow up analysis etc]. In addition, the aim is to submit a manuscript to a peer-reviewed journal for publication within 18 months of LSLV. GSK also aims to publish the full study protocol on the GSK Clinical Study Register at the time the results of the study are published as a manuscript in the scientific literature.

When manuscript publication in a peer-reviewed journal is not feasible, further study information will be posted to the GSK Clinical Study Register to supplement the results summary.

9.8. Independent Data Monitoring Committee (IDMC)

An IDMC will be utilized in this study to ensure external objective medical and/or statistical review of safety and/or efficacy issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study. The schedule of any planned interim analysis and the analysis plan for IDMC review is described in the charter, which is available upon request.

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10. REFERENCES

American Heart Association. Classes of Heart Failure. Available at: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jsp. Accessed14 August 2012

Bateman E, Karpel, J, Casale, T, et al. Ciclesonide reduces the need for oral steroid use in adult patients with severe, persistent asthma. Chest 2006;129:1176-1187

Beck, AT, Steer RA. Internal consistencies of the original and revised Beck Depression Inventory. J Clin Psych 1984;40:1365-1367.

Beck, AT., Steer RA, Garbin GM. Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation. Clin Psych Rev 1988;8:77-100.

BelEH, Sousa A, Fleming L et al. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI). Thorax 2011;66:910-917.

Carvalho-PintoRM, Cukier A, Angelini L et al. Clinical characteristics and possible phenotypes of an adult severe asthma population. Resp Med 2012;106:47-56.

CatleyMC, Coote J, Bari M, et al. Monoclonal antibodies for the treatment of asthma. Pharmacol Ther 2011;333-351.

ClientiS, Morjaria MB, Basile E, et al. Monoclonal antibodies for the treatment of severe asthma. Curr Allergy Asthma Rep. 2011;11:253-260.

Demoly P, Annunziata K, Gubba E et al. Repeated cross-sectional survey of patient-reported asthma control in Europe in the past 5 years. Eur Resp Rev 2012;123:66-74.

GlaxoSmithKline Document Number CM2003/00010/07 Compound ID SB-240563. Investigator’s brochure for Mepolizumab. Report date 23-MAY-2012.

Hankinson, JL, Odencrantz, JR, Feden, KB. Spirometric Reference Values from a Sample of the General U.S. Population. AM J Respir Crit care Med. 1999;159:179-187.

Hashimoto S, A. T. Brinke, Roldaan, A. C., et al, Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial. Thorax 2011; 66: 514-20

Hashimoto S, Bel EH. Current treatment of severe asthma. Cin Exp Allergy 2012;42:693-705.

HuscherD, Thiele K, Gromnica-Ihle E, et al. Dose-related patterns of glucocorticoidinduced side effects. Ann Rheum Dis 2009;68:1119e24

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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos 2009;37(8):1779-84.

Jarjour N., S. C. Erzurum, Bleecker, E. R., et al. Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Am J Respir Crit Care Med 2012; 185: 356-62.

Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure for chronic airflow limitation - the St George's Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321-1327.

Juniper EF, O’Byrne PM, Guyatt GH, et al. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14: 902–907.

Juniper EF, Svensson K, Mőrk AC, Ståhl E. Measurement properties and interpretation of three-shortened versions of the asthma control questionnaire. Resp Med 2005;99:553-558.

Karpel, J. P., A. Nayak, Lumry, W. et al. Inhaled mometasone furoate reduces oral prednisone usage and improves lung function in severe persistent asthma. Respir Med 2007; 101(3): 628-37.

Korn S., J. Both, Matthias, J. et al. Prospective evaluation of current asthma control using ACQ and ACT compared with GINA criteria. Ann Allergy Asthma Immunol. 2011 107(6): 474-9

Marjoria JB, Polosa R. Recommendation for management of severe refractory asthma. J Asthma Allerg 2010;3:43-56.

McDonaldVM, Gibson PG. Exacerbations of Severe Asthma. Clin Exp Allergy 2012; 42:670-677.

Nair P, Pizzichini MMM, Kjarsgaard M et al. Mpolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985-993.

National Institutes of Health. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. August 2007. NIH publication no. 07-4051

Nelson H. S., W. W. Busse, deBoisblanc, B. et al. Fluticasone propionate powder: oral corticosteroid-sparing effect and improved lung function and quality of life in patients with severe chronic asthma. J Allergy Clin Immunol. 1999; 103: 267-75.

NoonanM., P. Chervinsky, Busse, W.W. et al. Fluticasone propionate reduces oral prednisone use while it improves asthma control and quality of life. Am J Respir Crit Care Med 1995; 152: 1467-73.

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Polosa R, Casale T. Monoclonal antibodies for chronic refractory asthma and pipeline developments. Drug Disc Today 2012;00:1-9.

Reily Associates. Scoring of WPAI. Available at: http://www.reillyassociates.net/WPAI_Scoring.html. Accessed on May 16, 2012.

Sampson HA, Munoz-Furlong A, Campbell RL, et. al. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391-397.

Sumitas K, Radinger M and Bossios A. Current update on eosinophilic lung diseases and anti-IL-5 treatment. Recent Patents Anti-inf Drug Disc 2011;6:189-205

Wadsworth SJ, Sin DD, Dorscheid DR. Clinical update on the use of biomarkers of airway inflammation in the management of asthma. J Asthma Allergy 2011;4:77-86.

Walsh LJ, Wong CA, Oborne J, et al. Adverse effects of oral corticosteroids in relation to dose in patients with lung disease. Thorax 2001; 56:279e84

Walsh GM. An update on emerging drugs for asthma. Expert Opin Emerging Drugs 2012;17:37-42.

Wilson SR, Rand CS, Cabana MD. Asthma Outcomes: Quality of life. J Allergy Clin Immunol 2012; 129:S89-123.

WhiteheadJ. Sample size calculations for ordered categorical data. Stat. Med. 1993; 12(24): 2257-71.

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11. APPENDICES

11.1. Appendix 1: Acceptable Birth Control

To be eligible for entry into the study, females of childbearing potential (FCBP) must commit to consistent and correct use of an acceptable method of birth control from the time of consent, for the duration of the trial, and for 4 months after the last study drug administration.

• Male partner who is sterile prior to the female subject’s entry into the study and is the sole sexual partner for that female subject

• Abstinence from penile-vaginal intercourse

• Implants of levonorgestrel or etonogestrel

• Injectable progestogen

• Oral contraceptive (either combined or progestogen alone)

• Estrogenic vaginal ring

• Percutaneous contraceptive patches

• Any intrauterine device (IUD) with a documented failure rate of less than 1% per year.

• Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository)

• Male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository)

Females of childbearing potential are defined as females with functioning ovaries (i.e., post-menarche, premenopausal women with no documented impairment of oviductal or uterine function that would cause sterility). This category includes females with oligomenorrhea, females who are peri-menopausal, and young females who have begun to menstruate (adolescents). The information on the lack of impairment of oviductal or uterine function that would cause sterility can come from the site personnel’s:

• Review of subject’s medical records

• Medical examination of the subject

• Interview with the subject on her medical history.

Females of non-childbearing potential are defined as females with functioning ovaries and with a documented tubal ligation or hysterectomy; or females who are postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile, e.g. age appropriate, >45 years, in the absence of hormone replacement therapy (HRT).

In questionable cases a blood sample for follicle stimulating hormone (FSH) and estradiol will be obtained and analyzed to confirm childbearing potential.

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Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed above for females of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

Based on the absence of an identified reproductive hazard from preclinical studies, absence of a genotoxic potential, and very low levels of mepolizumab that might be present in semen, there is no recognized risk for mepolizumab to affect human sperm or the fetus if transferred to a female partner via semen. Therefore, the use of condoms or other methods of contraception in the male study subject is not required.

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11.2. Appendix 2: Genetics and Pharmacogenetic Research

Genetics and Pharmacogenetics – Background

Genetics is the study of variability in traits due to hereditary factors in populations. Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors in populations. There is increasing evidence that an individual's genetic background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, and elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of PGx associations with safety/adverse events include:

Drug Disease Gene Variant Outcome Abacavir HIV

[Hetherington, 2002; Mallal, 2002; Mallal, 2008]

HLA-B* 5701 Carriage of the HLA-B*5701 variant has been shown to increase a patient's risk for experiencing hypersensitivity to abacavir. Prospective HLA-B*5701 screening and exclusion of HLA-B*5701 positive patients from abacavir treatment significantly decreased the incidence of abacavir hypersensitivity. Treatment guidelines and abacavir product labeling in the United States and Europe now recommend (US) or require (EU) prospective HLA-B*5701 screening prior to initiation of abacavir to reduce the incidence of abacavir hypersensitivity. HLA-B*5701 screening should supplement but must never replace clinical risk management strategies for abacavir hypersensitivity.

Carbamazepine

Seizure, Bipolar disorders & Analgesia Chung, 2010; Ferrell, 2008

HLA-B*1502 Independent studies indicated that patients carrying HLA-B*1502 are at higher risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis and that this marker is prevalent in some populations, particularly with Asian ancestry. Regulators, including the US FDA and the Taiwanese TFDA, have updated the carbamazepine drug label to indicate that patients with ancestry in genetically at risk populations should be screened for the presence of HLA-B*1502 prior to initiating treatment with carbamazepine.

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Drug Disease Gene Variant Outcome Irinotecan Cancer

[Innocenti, 2004; Liu, 2008; Schulz, 2009]

UGT1A1*28 Variations in the UGT1A1 gene can influence a patient’s ability to break down irinotecan, which can lead to increased blood levels of the drug and a higher risk of side effects. A dose of irinotecan that is safe for one patient with a particular UGT1A1 gene variation might be too high for another patient without this variation, raising the risk of certain side-effects, that include neutropenia following initiation of Irinotecan treatment. The irinotecan drug label indicates that individuals who have two copies of the UGT1A1*28 variant are at increased risk of neutropenia. A genetic blood test is available that can detect variations in the gene.

A key component to successful PGx research is the collection of samples during the conduct of clinical studies.

For example, PGX research recently led to the identification of an association between genetic variants in the gene GLCCI1and response to glucocorticoid therapy in asthma [Tantisira 2011].

Collection of whole blood samples, even when no a priori hypothesis has been identified, may enable genetic or PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in asthma status or response to mepolizumab or study treatment.

Genetic or Pharmacogenetic Research Objectives

The objective of the potential Genetic research (if suggested by variation in asthma status in subjects enrolled in this clinical study) is to investigate a possible genetic relationship to asthma status.

The objective of the potential PGx research (if there is a potential unexpected or unexplained variation) is to investigate a relationship between genetic factors and response to mepolizumab or study treatment If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with mepolizumab, the following objectives may be investigated – the relationship between genetic variants and study treatment with respect to:

• Pharmacokinetics and/or pharmacodynamics of study treatment

• Safety and/or tolerability

• Efficacy

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Study Population

Any subject who is enrolled in the clinical study, can participate in genetic or PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the genetic or PGx research.

Subject participation in the genetic or PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study or result in any penalty or loss of benefits to which the subject would otherwise be entitled.

Study Assessments and Procedures

Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in genetic or PGx assessments.

In addition to any blood samples taken for the clinical study, a whole blood sample (~6ml) will be collected for the genetic or PGx research using a tube containing EDTA. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized (Visit 3) and provided informed consent for genetic or PGx research, but may be taken at any time while the subject is participating in the clinical study.

• The genetic or PGx sample is labelled (or “coded”) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample is taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample.

The DNA extracted from the blood sample may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed.

The need to conduct genetic or PGx analysis may be identified after a study (or a set of studies) of mepolizumab has been completed and the clinical study data reviewed. In some cases, the samples may not be studied. e.g., no questions are raised about how people respond to mepolizumab or study treatment.

Samples will be stored securely and may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples sooner. GSK or those working with GSK (for example, other researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form.

Subjects can request their sample to be destroyed at any time.

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Subject Withdrawal from Study

If a subject who has consented to participate in genetic or PGx research and has had a sample taken for PGx research withdraws from the clinical study for any reason other than lost to follow-up, the subject will be given the following options:

• Retain the sample for genetic or PGx research

• Destroy the genetic or PGx sample

If a subject withdraws consent for genetic or PGx research or requests sample destruction for any reason, the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records.

Screen and Baseline Failures

If a blood sample for genetic PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, then the investigator should instruct the participant that their genetic or PGx sample will be destroyed. No forms are required to complete this process as it will be completed as part of the consent and sample reconciliation process. In this instance a sample destruction form will not be available to include in the site files.

Genetic or Pharmacogenetics Analyses

Specific genes may be studied that encode the drug targets, or drug mechanism of action pathways, drug metabolizing enzymes, drug transporters or which may underpin adverse events, disease risk or drug response.

• These candidate genes may include a common set of ADME (Absorption, Distribution, Metabolism and Excretion) genes that are studied to determine the relationship between gene variants or treatment response and/or tolerance.

• In addition, continuing research may identify other enzymes, transporters, proteins or receptors that may be involved in response to mepolizumab or study treatment. The genes that may code for these proteins may also be studied.

Genome-wide scans involving a large number of polymorphic markers (e.g., single nucleotide polymorphisms) at defined locations in the genome, often correlated with a candidate gene, may be studied to determine the relationship between genetic variants and treatment response or tolerance. This approach is often employed when a definitive candidate gene(s) does not exist and/or the potential genetic effects are not well understood.

If applicable, and genetic or PGx research is conducted, appropriate statistical analysis methods will be used to evaluate pharmacogenetic data in the context of the other clinical data. Results of genetic or PGx investigations will be reported either as part of the main clinical study report or as a separate report. Endpoints of interest from all comparisons will be descriptively and/or graphically summarized as appropriate to the data. A detailed description of the analysis to be performed will be documented in the study reporting and analysis plan (RAP) or in a separate pharmacogenetics RAP, as appropriate.

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Informed Consent

Subjects who do not wish to participate in the genetic or PGx research may still participate in the clinical study. Genetic or PGx informed consent must be obtained prior to any blood being taken for genetic or PGx research.

Provision of Study Results and Confidentiality of Subject’s Genetic or PGx Data

GSK may summarize the genetic or PGx research results in the clinical study report, or separately, or may publish the results in scientific journals.

GSK does not inform the investigator, subject, or anyone else (e.g., family members, study investigators, primary care physicians, insurers, or employers) of individual genotyping results that are not known to be relevant to the subject’s medical care at the time of the study, unless required by law. This is due to the fact that the information generated from genetic or PGx studies is generally preliminary in nature, and therefore the significance and scientific validity of the results are undetermined.

References

Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-induced skin reactions. Expert Opin. Drug Saf. 2010; 9: 15-21.

Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics. 2008; 9: 1543-46.

Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121-2.

Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22: 1382-1388.

Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Wang WS. UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma. Cancer. 2008; 112: 1932-40.

Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359:727-32.

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Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78

Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer. World J. Gastroenterol. 2009; 15: 5058-66.

Tantisira KG, Lasky-Su J, Harada M, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med 2011; 365: 1173-83.

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11.3. Appendix 3: Country Specific Requirements

Country-Specific Requirements

No country-specific requirements exist.

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11.4. Appendix 4: Liver Chemistry Stopping and Follow up Criteria

Phase III -IV Liver Safety Algorithms

ALT>3xULN

plus bilirubin >2x ULN (or

plus INR >1.5, if measured)*

No

Yes

Yes

•Instruct subject to stop investigational product (IP) •Notify GSK + arrange clinical followup within 24- 72h •Perform liver chemistries and liver event follow up assessments (serology, PK sample etc as in protocol) •Complete liver event CRF, SAE data collection tool if appropriate, + liver imaging +/or biopsy CRFs if tests performed.•Obtain weekly liver chemistries [**as far as possible] until resolved, stabilised or returned to baseline •Withdraw subject from study after liver chemistry monitoring complete + do not re-challenge with IP

• Instruct subject to stop investigational product (IP)• Notify GSK + arrange clinical followup within 24h• Perform liver chemistries and liver event follow up assessments (serology, PK sample etc as in protocol) • Report as SAE (excl. hepatic impairment or cirrhosis studies)+ complete liver event CRF, SAE data collection tool, + liver imaging +/or biopsy CRFs if tests performed.• Obtain twice weekly liver chemistries until resolved, stabilised or returned to baseline values• Consultation with hepatologist/specialist recommended• Withdraw subject from study after liver chemistry monitoring complete + do not re- challenge with IP

Hepatitis symptomsor rash?

No

Able to monitor

weekly for 4 weeks?

Yes

No**Yes

Continue IPObtain twice monthly liver

chemistries until normalised or

back to baseline values

Yes

Yes

ALT<3xULN + bilirubin<2xULN after ? 4

wks?

Yes

ALT >5xULN

but <8xULN

NoALT > 8xULN

Yes

ALT >5 and

<8xULN for > 2 wks

Yes No

ALT>3xULN but <5xULN + bilirubin

<2xULN+no symptoms

NoAble to monitor

weekly for > 2 wks?

No

No

Notify GSK within 24h to discuss subject

safetyContinue IP

Check liver chemistry weekly for 4 weeks

YesNo

*INR value not applicable to patients on anticoagulants

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11.5. Appendix 5: Cardiovascular Screening Questions

At screening subjects should be asked the following:

Unrelated to the symptoms you experience with your asthma:

1. Do you have any pain or discomfort (such as pressure) in your chest? a. If yes, does this pain/discomfort/pressure go to other areas of your body such as

neck, jaw, throat, or down your arms (including a numbness feeling in your arm) when it occurs?

2. When you walk at an ordinary pace on a level surface does this produce chest pain? If yes, respond to a and b:

a. Does this chest pain or discomfort occur when you are not doing any activities such as resting in bed or sitting in a chair?

b. Has this chest pain/discomfort been more frequent or more intense or last longer or come on with less exertion lately?

3. When you walk uphill or hurry does this produce chest pain/discomfort?

4. Do you use or have you been previously prescribed nitroglycerine to relieve the discomfort? a. If yes, have you needed to increase the number of pills or frequency of using the

pills recently?

If the subject responds “yes” to any of the above questions a study physician should further assess for the presence of undiagnosed or unrecognized angina when evaluating Exclusion Criterion 5.

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11.6. Appendix 6: New York Heart Association Functional Classification of Congestive Heart Failure

Class Patient Symptoms Class I (Mild) No limitation of physical activity. Ordinary physical activity does not cause undue fatigue,

palpitation, or dyspnea (shortness of breath). Class II (Mild) Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in

fatigue, palpitation, or dyspnea. Class III (Moderate)

Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.

Class IV (Severe) Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.

Adapted from American Heart Association, 2012

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11.7. Appendix 7: Daily Asthma Symptom Score

Each morning subjects will record an asthma symptom score using the following scale:

• Daily Symptom Score:

• 0 = No symptoms during the previous 24-hours.

• 1 = Symptoms for one short period during the previous 24-hours.

• 2 = Symptoms for two or more short periods during the previous 24-hours.

• 3 = Symptoms for most of the previous 24-hours which did not affect my normal daily activities.

• 4 = Symptoms for most of the previous 24-hours which did affect my normal daily activities.

• 5 = Symptoms so severe that I could not go to work/school or perform normal daily activities.

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11.8. Appendix 8: Anaphylaxis Criteria

Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson 2006]. The criteria do not make a distinction based on underlying mechanism. These criteria are summarized as follows:

1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula), and at least one of the following:

a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)

b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence)

2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):

a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-tongue-uvula)

b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)

c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)

d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)

3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):

a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP

b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline

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11.9. Appendix 9: Eosinophil Progenitor Sub-study

In chronic airways disease such as severe asthma, local maturation rather than new systemic recruitment of mature cells may contribute to the ongoing airway eosinophilia. Controlling cellular differentiation at the local level may lead to better control of symptoms in severe asthmatics.

Considerable evidence purports a role of bone marrow-derived progenitor cells in allergic asthmatic responses [Sehmi, 2009]. The prevailing view is that that bone marrow-derived progenitor cells traffic to the lung where they undergo in situ differentiation under the influence of local growth factors to provide an ongoing source of either pro-inflammatory cells (eosinophils, basophils or mast cells) or tissue structural cells (fibrocytes or vascular endothelial cells). Whilst the lung-homing of progenitors is a prominent feature of acute inflammatory responses, studies in mice show that in chronic allergen exposure models lung progenitor levels are increased while bone marrow activation returns to baseline [Doyle, 2011]. These findings suggest that in chronic inflammatory processes, local differentiation of progenitor cells may play a more prominent role in the development of local inflammation.

In human studies performed by Menzies-Gow et al., it was observed that anti-IL-5 treatment in subjects with asthma significantly reduced numbers of eosinophil progenitors in the lung mucosa (but not in blood or bone marrow) strongly indicating that local differentiative events rather than recruitment of mature inflammatory cells from the peripheral circulation may contribute to airway eosinophilia [Menzies-Gow, 2003]. In order to investigate this further samples will be collected to study progenitor cell levels in subjects enrolled in MEA115575 (i.e. prednisone-dependent asthmatics with eosinophilia).

The objective of this sub-study is to assess 1) eosinophil progenitor cells in blood and sputum samples at baseline and 2) to study the effect of anti-IL-5 treatment on these progenitor cells levels in sputum and blood.

References:

Sehmi, R., J. V. Thomson, and A. E. Catalli 2009. Allergy and the bone marrow: transmigration pathways of hemopoietic progenitor cells from the bone marrow. In P. Pawankar, S. Holgate, and L. J. Rosenwasser, editors Allergy Frontiers: Classification and Pathomechanisms,Part 1 ed. Springer, Japan, 421-432.

Doyle, T. M., R. Ellis, H. J. Park, K. Peng, M. D. Inman, and R. Sehmi. 2011. Modulating progenitor cell accumulation attenuates lung angiogenesis in a mouse model of asthma. Eur.Respir.J. 38:679-687.

Menzies-Gow, A. N., P. T. Flood-Page, R. Sehmi, J. Burman, Q. Hamid, D. S. Robinson, A. B. Kay, and J. A. Denburg. 2003. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. J.Allergy Clin.Immunol. 111:714-719.

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11.10. Appendix 10: Protocol Changes

Protocol Amendment Number 01 SCOPE: This amendment applies to all sites

Protocol Changes specified in Amendment No. 1 are summarised below:

• To add further clarification regarding the assessment of the primary efficacy endpoint in the Summary Section, Section 6.2 and Section 8.4.4.1.

• To reduce the number of secondary efficacy endpoints in the Summary Section, Section 6.2 and Section 8.4.4.1. Endpoints removed from the secondary endpoint section were added to other efficacy endpoints. In making this correction a duplicate secondary efficacy endpoint was remove from the list in the Summary Section

• To add clarification regarding the treatment of exacerbations during the various study phases (Section 3.2.1.1, 3.2.2.1, 3.2.3.1 and 6.2.3). In Section 3.2.3.1 additional wording was added to clarify that following exacerbation subjects must maintain a new maintenance OCS dose for 4-weeks before being assessed for an OCS dose reduction.

• Item #4 in Table 3 was clarified to indicate that the ACQ-5 score during baseline would be compared with the ACQ-5 score obtained during the previous OCS dose assessment and the footnote was modified to clarify the data that would be used to calculate baseline values.

• Inclusion criteria #6 was amended to reference the correct randomisation criteria.

• Further guidance was added to exclusion criterion 5 regarding cardiovascular disease. This includes the addition of Section 6.1.5 and Appendix 5and Appendix 6, and amending of Section 6.1.1.

• To clarify exclusion criterion 12, to note that only other monoclonal antibodies are excluded. Also corrected Table 1 and footnote #6 (Table 5).

• Amended randomisation criterion 4, to allow for airway hyperresponsiveness testing with mannitol (bullet 2) and to correct the “≥” to “>” in bullet 4.

• Added normal saline as the placebo to the Investigational Product Section 5.1

• Clarified Table 5 to indicate that all scheduled phone visits should be called into RAMOS

• Section 6.2.3 was amended to make it clear that clinically significant exacerbations include worsening of asthma requiring hospitalization and/or Emergency Department visits.

• Added Section 6.3.5 and Section 6.3.6 to document the additional data to be collected and the timeframe of collection for cardiovascular AE/SAEs and for death, to be consistent with a new GSK wide initiative using standard protocol language

• Clarified that subjects to not have to be in the fasted state for an unscheduled Early Withdrawal Visit (Section 6.3.13)

• Minor typographical errors were corrected throughout the document.

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Protocol Changes:

Regulatory Agency Identifying Number(s):

Original Text

EudraCT: 2102-001497-29

Revised Text

EudraCT: 2012-001497-29

Section 3.2.1.1, 3.2.2.1, 3.2.3.1 and 6.2.3

Original Text

Anytime during the study when a subject experiences an exacerbation the exacerbation should be treated according to the protocol with the use of oral [or parenteral (IV or intramuscular (IM))] corticosteroids at a dose at least equivalent to double the dose of current maintenance dose of OCS for a minimum of 3 days and a maximum of 7 days.

Revised Text

Anytime during the study when a subject experiences an exacerbation the exacerbation should be treated according to the protocol with the use of oral [or parenteral [IV or intramuscular (IM)] corticosteroids at a dose at least equivalent to double the dose of current maintenance dose of OCS for a minimum of 3 days and a maximum of 7 days, this is to ensure that exacerbations are managed in a timely manner and consistently, where possible, for all subjects participating in this study. If the exacerbation is not resolved after 7 days the treatment of the exacerbation may continue at the discretion of the Investigator.

Table 3

Original Text

Section 3.2.3 Table 3



the baseline mean 3 Rescue medication use requiring 4 or more puffs/day above the mean baseline value for any 2 consecutive

days in the prior week, or 12 puffs or more on any one day in the prior week 4 Change in ACQ-5 ≥ +0.5 from previous assessment 5 Symptoms of adrenal insufficiency 1. Baseline means for AM PEF, night time awakenings, and rescue medication use are calculated on a per night or

per day basis using subject diary information from the 7 days prior to Randomisation Visit (Visit 3)

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Revised Text



the baseline mean 3 Rescue medication use requiring 4 or more puffs/day above the mean baseline value for any 2

consecutive days in the prior week, or 12 puffs or more on any one day in the prior week 4 Change in ACQ-5 ≥ +0.5 from the prior month OCS dose assessment 5 Symptoms of adrenal insufficiency 1. Baseline means for AM PEF, night time awakenings, and rescue medication use are calculated on a per night or

per day basis using subject diary information from the 7 completed eDiary records prior to Randomisation Visit (Visit 3)

Section 3.2.3 OCS Reduction Phase and Maintenance Phase (5th paragraph)

Original Text

During the OCS Reduction Phase subjects on lower doses of OCS at baseline may be completely weaned from OCS, while subjects on relativity higher doses of OCS at baseline (25mg/day and higher) will not be weaned 2.5mg/day. This is to protect the subject from potentially experiencing adrenal crisis. Throughout the Reduction Phase subjects should be monitored for the signs and symptoms of adrenal insufficiency.

Revised Text

During the OCS Reduction Phase subjects on lower doses of OCS at baseline may be completely weaned from OCS, while subjects on relativity higher doses of OCS at baseline (25mg/day and higher) will not be weaned completely. This is to protect the subject from potentially experiencing adrenal crisis. Throughout the Reduction Phase subjects should be monitored for the signs and symptoms of adrenal insufficiency.

Section 3.2.3.1.Exacerbation Management during Reduction and Maintenance Phases

Original Text

If an exacerbation occurs during the Reduction or Maintenance Phase the exacerbation should be treated with the use of oral or parenteral corticosteroids at a dose at least equivalent to double the dose of current maintenance dose of OCS for a minimum of 3 days to a maximum of 7 days.

Following resolution the subject should be placed on the OCS dose one step higher than that which they were on when the exacerbation occurred (according to Table 2) and continue as scheduled with the Reduction Phase of the study. If a subject experience 2 exacerbations they should be maintained for the remaining duration of the treatment period at the OCS dose which asthma control was maintained.

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Revised Text

If an exacerbation occurs during the Reduction or Maintenance Phase the exacerbation should be treated with the use of oral or parenteral corticosteroids at a dose at least equivalent to double the dose of current maintenance dose of OCS for a minimum of 3 days to a maximum of 7 days, this is to ensure that exacerbations are managed in a timely manner and consistently, when possible, for all subjects participating in this study. If the exacerbation is not resolved after 7 days the treatment of the exacerbation may continue at the discretion of the Investigator.

Following resolution the subject should be placed on the OCS dose one step higher than that which they were on when the exacerbation occurred (according to Table 2) for 4-weeks and continue as scheduled with the Reduction Phase of the study. If a subject experience 2 exacerbations they should be maintained for the remaining duration of the treatment period at the OCS dose which asthma control was maintained.

Section 4.2 Inclusion Criteria #6

Original Text

Eosinophilic asthma: Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma as per Randomisation Criteria 1 and 2.

Revised Text

Eosinophilic asthma: Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma as per Randomisation Criteria 2 and 3.

Section 4.3 Exclusion Criteria #5

Original Text

Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment.

Revised Text

Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment. Including but not limited to:

• known ejection fraction of <30% OR

• severe heart failure meeting New York Heart Association Class IV (see Appendix 6) OR

• hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III (see Appendix 6) OR

• angina diagnosed less than 3 months prior to Visit 1 or at Visit 1

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Original Text:

Other Biologics: Subjects who have received any biological (other than Xolair) to treat inflammatory disease within 5 half-lives of visit 1

Revised Text:

Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of visit 1.


Original Text

Previous participation: Subjects who have previously any study of mepolizumab and received Investigational Product.

Revised Text

Previous participation: Subjects who have previously participated in any study of mepolizumab and received Investigational Product (including placebo).

Section 4.4 Randomization Criteria #4 (2nd and 4th bullet)

Original Text

Asthma: Evidence of asthma as documented by either:


• Airway hyperresponsiveness (PC20 of <8mg/mL or PD20 of <7.8 µmol methacholine/histamine) documented in the 12 months prior to Visit 3 OR


• Airflow variability as indicated by ≥20% diurnal variability in peak flow observed on 3 or more days during the optimisation period

Revised Text

Asthma: Evidence of asthma as documented by either:


• Airway hyperresponsiveness (methacholine: PC20 of <8mg/mL or histamine: PD20 of <7.8 µmol; mannitol: decrease in FEV1 as per the labelled product instructions) documented in the 12 months prior to Visit 3 OR

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• Airflow variability as indicated by >20% diurnal variability in peak flow observed on 3 or more days during the optimisation period

Section 4.6 Screening/Run-in Failures (2nd paragraph)

Original Text

Those subjects that complete at least one additional procedure at Visit 1 but do not enter the Optimisation Phase will be designated as screen failures. Those subjects who are unable to be maintained on their optimal prednisone/prednisolone dose for the protocol required 2 weeks prior to randomisation (See Randomization criteria Section 4.4), if the will be designated screen failures.

Revised Text

Those subjects that complete at least one additional procedure at Visit 1 but do not enter the Optimisation Phase will be designated as screen failures. Those subjects who are unable to be maintained on their optimal prednisone/prednisolone dose for the protocol required 2 weeks prior to randomisation (See Randomization criteria Section 4.4), if the will be designated run-in failures.

Section 5.1 Investigational Product and Other Study Treatment (2ndthrough 5th paragraph)

Original Text

Under normal conditions of handling and administration, investigational product is not expected to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of any unintentional occupational exposure. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be provided to site staff if required by local laws or will otherwise be available from GSK upon request.

Investigational Product must be stored in a secure area under the appropriate physical conditions for the product. Access to and administration of the investigational product will be limited to the investigator’s authorized unblinded site staff. Mepolizumab must be stored under the appropriate physical conditions which includes storage in a refrigerator or at a temperature of 2-8°C and protected from light. Maintenance of a temperature log (manual or automated) is required. Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.

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Revised Text

Under normal conditions of handling and administration, mepolizumab is not expected to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of any unintentional occupational exposure. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be provided to site staff if required by local laws or will otherwise be available from GSK upon request.

Mepolizumab must be stored in a secure area under the appropriate physical conditions for the product. Access to and administration of the mepolizumab will be limited to the investigator’s authorized unblinded site staff. Mepolizumab must be stored under the appropriate physical conditions which includes storage in a refrigerator or at a temperature of 2-8°C and protected from light. Maintenance of a temperature log (manual or automated) is required. Mepolizumab must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.

Added Text

The placebo in this study will be 0.9% sodium chloride solution and will be provided by the study site. Further details on the preparation of the placebo can be found in the SPM and in the Unblinded Site Staff Manual.

Table 5 Footnote #3

Original Text

For subjects entering the Open-Label Extension study, Visit 10 will serve as Visit 1 for the Open-Label Extension study. Where procedures overlap, they need only be performed once, and the data will be used for both studies.

Revised Text

For subjects entering the Open-Label Extension study, Visit 9 will serve as Visit 1 for the Open-Label Extension study. Where procedures overlap, they need only be performed once, and the data will be used for both studies.

Table 5 Footnote #20

Original Text

A maximum of 5 scheduled phone visits for assessing OCS dose adjustment will occur and must be registered in RAMOS

Deleted Text

A maximum of 5

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Section 6.1.1 Critical Procedures Performed at Screening Visit 1 (4th bullet)

Original Text

Cardiovascular medical history/risk factors will be assessed at baseline (including height, weight, blood pressure, smoking history, medical conditions and family history of premature cardiovascular disease)

Revised Text

Cardiovascular medical history/risk factors will be assessed at screening. This assessment must include a review of the subject responses to the cardiovascular assessment questions (See Appendix 5) and height, weight, blood pressure, smoking history, medical conditions and family history of premature cardiovascular disease

Section 6.1.5 Cardiovascular Assessment

Added Text

The cardiovascular assessment (see Appendix 5) will be administered by site personnel assessment and must be completed at the screening visit. Subject responses to each question will must be entered into the eCRF. If the subject responds ‘yes’ to any of the questions a physician must conduct a further evaluation to assess for previously unrecognized and undiagnosed angina. The results of the evaluation should be considered when determining subject eligibility (see exclusion criteria #5).

The cardiovascular assessment questions are provided in Appendix 5.

Section 6.2.1 Efficacy Endpoint – Primary Efficacy Endpoint

Original Text

The primary efficacy endpoint is the percent reduction of OCS dose at week 24 compared to the baseline dose.

Revised Text

The primary efficacy endpoint is the percent reduction of OCS dose during weeks 20 – 24, compared to the baseline dose, while maintaining asthma control.

Section 6.2.1 Efficacy Endpoint – Secondary Efficacy Endpoint (4th bullet)

Original Text

• Median percentage reduction from baseline in daily OCS dose during weeks 20 -24

Revised Text

• Median percentage reduction from baseline in daily OCS dose during weeks 20 -24, while maintaining asthma control

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Section 6.2.1 Efficacy Endpoint – Secondary Efficacy Endpoint

Deleted Text






Section 6.2.1 Efficacy Endpoint – Other Efficacy Endpoint

Additional Text






Section 6.2.1 Efficacy Endpoint – Other Efficacy Endpoint

Original Text

• Mean change from baseline in clinic post-bronchodilator FEV1

Revised Text


Section 6.2.3 Exacerbation

Original Text

Exacerbation will be treated per the protocol with the use of oral or parenteral corticosteroids at a dose at least equivalent to double the dose of current maintenance dose of OCS for a minimum of 3 days to a maximum of 7 days. For consistency, exacerbations treated with courses of corticosteroids separated by less than 7 days will be treated as a continuation of the same exacerbation.

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Revised Text

Clinically significant exacerbations of asthma will be defined as the worsening of asthma which requires use of systemic corticosteroids. Exacerbation will be treated per the protocol with the use of oral or parenteral corticosteroids at a dose at least equivalent to double the dose of current maintenance dose of OCS for a minimum of 3 days to a maximum of 7 days, this is to ensure that exacerbations are managed in a timely manner and consistently, when possible, for all subjects participating in this study. If the exacerbation is not resolved after 7 days the treatment of the exacerbation may continue at the discretion of the Investigator. For consistency, exacerbations treated with courses of corticosteroids separated by less than 7 days will be treated as a continuation of the same exacerbation.

Additional Text

Clinically significant exacerbations of asthma also include worsening of asthma that requires hospitalization and/or Emergency Department (ED) visits.

Section 6.3.5 Cardiovascular Events:

Additional text:

Investigators will be required to fill out event specific pages in the eCRF for the following AEs and SAEs:

• Myocardial infarction/unstable angina

• Congestive heart failure

• Arrhythmias

• Valvulopathy

• Pulmonary hypertension

• Cerebrovascular events/stroke and transient ischemic attack

• Peripheral arterial thrombosis

• Deep Venous Thrombosis

• Revascularization

Cardiovascular events information should be recorded on the corresponding eCRF pages within one week of when the AE/SAE(s) are first reported. Please refer to Section 6.3.10 for timelines for reporting AE/SAEs.

Section 6.3.6 Death Events:

Additional text:

In addition, all deaths will require completion of a specific death data collection page in the eCRF. The death data collection page in the eCRF includes questions regarding cardiovascular (including sudden cardiac death) and non-cardiovascular death.

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Death information should be recorded on the death eCRF page within one week of when the death is first reported.

Please refer to Section 6.3.10 for timelines for reporting SAEs.

Section 6.3.10 Prompt reporting of Serious Adverse Events and Other Events to GSK

Original Text:

Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame Documents All SAEs 24 hours “SAE” data

collection tool

24 hours Updated “SAE” data collection tool

Revised Text:

Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame Documents All SAEs 24 hours “SAE” data

collection tool

24 hours Updated “SAE” data collection

tool “CV events”

and/or “death” data collection

tool(s)

6.3.13 Clinical Laboratory Parameters:

Original Text:

All blood samples which will be taken pre-infusion, will be sent to a central laboratory for analysis (details provided in the SPM). Standard reference ranges will be used. For the chemistry plus lipoprotein sample, the subject must be fasting.

Revised Text

All blood samples which will be taken pre-infusion, will be sent to a central laboratory for analysis (details provided in the SPM). Standard reference ranges will be used. For the chemistry plus lipoprotein sample at scheduled visits, the subject must be fasting. If a subject has not fasted at an Early Withdrawal Visit, the subject does not need to return for the chemistry plus lipoproteins. The laboratory requisition should be marked that the subject did not fast.

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Section 8.2.1 Sample Size Assumptions

Original Text

Sample size is based on the primary efficacy endpoint of percentage reduction of daily prednisone dose at week 24 compared to the baseline dose.

Revised Text

Sample size is based on the primary efficacy endpoint of percentage reduction of daily prednisone dose during weeks 20-24 compared to the baseline dose, using the categories specified in Section 8.4.4.1. The sample size calculation uses the method of Whitehead [Whitehead 1993] for analysis based on a proportional odds model.

Section 8.2.1 Table 7

Original Text



≥90 - 100% 12% 28% ≥75-< 90% 16% 25% ≥50 < 75% 20% 20% ≥0 -< 50% 24% 16%

No decrease in prednisone or withdrawal from treatment 28% 12%

Revised Text



≥90 - 100% 12% 28% ≥75-< 90% 16% 25% ≥50 < 75% 20% 20% >0 -< 50% 24% 16%

No decrease in prednisone, lack of control during weeks 20-24, or withdrawal from treatment

28% 12%

Section 8.4.2.1 Primary Comparison of Interest

Original Text

For those subjects randomized to mepolizumab, 6 doses will provide therapeutic coverage for 24 weeks (4 weeks following the last dose). For those subjects who complete the study the primary efficacy endpoint will be measured from week 20 to the week 24 (Visit 9). For subjects who early withdraw they will be considered as non-responders in the endpoint analysis

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Revised Text

For those subjects randomized to mepolizumab, 6 doses will provide therapeutic coverage for 24 weeks (4 weeks following the last dose). For those subjects who complete the study the primary efficacy endpoint will be measured from week 20 to the week 24 (Visit 9). Subjects who early withdraw or do not exhibit asthma control will be considered as non-responders in the endpoint analysis (i.e. assigned to the lowest efficacy category).

Section 8.4.4.1 Efficacy Analysis

Original Text

The primary efficacy endpoint is the percentage reduction of daily prednisone dose during weeks 20 - 24 compared to the baseline dose, categorised as follows:

1. 90 - 100%

2. 75 - <90%

3. 50 - <75%

4. 0 - <50%

5. No decrease in prednisone dose, or withdrawal from treatment

Revised Text

The primary efficacy endpoint is the percentage reduction of daily prednisone dose during weeks 20 - 24 compared to the baseline dose, while maintaining asthma control, categorised as follows:

1. 90 - 100%

2. 75 - <90%

3. 50 - <75%

4. >0 - <50% 5. No decrease in prednisone dose, or withdrawal from treatment

Section 8.4.4.1 Secondary Efficacy Endpoint

Original Text

• Median percentage reduction in daily OCS dose at week 24

Revised Text

• Median percentage reduction in daily OCS dose during weeks 20 – 24, while maintaining asthma control

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Deleted Text






The rate of clinically significant exacerbations will be analysed using a generalized linear model, assuming the Negative Binomial distribution, with the logarithm of time on treatment as an offset variable. Covariates will be as for the primary analysis of reduction in OCS dose. The adjusted mean rates per year, rate ratio for mepolizumab versus placebo, p-value and 95% confidence intervals will be presented.

Rates of exacerbations requiring hospitalization and rate of exacerbations requiring hospitalization or ED visits will be analysed as for clinically significant exacerbations described above.

Mean change from baseline in St. George’s Respiratory Questionnaire at week 24 will be analysed using mixed models repeated measures. Covariates will include treatment group, number of years on OCS (< 5 years versus ≥ 5 years), region, dose of OCS at baseline, baseline value and interaction terms for visit by baseline and visit by treatment group. Pre-bronchodilator FEV1 will be analysed in the same way.

Section 8.4.4.1 Other Efficacy Endpoint

Additional Text






Section 8.4.4.1 Other Efficacy Endpoint

Original Text

• Mean change from baseline in clinic post-bronchodilator FEV1

Revised Text


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Section 10 References

Additional Text

American Heart Association. Classes of Heart Failure. Available at: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jsp. Accessed14 August 2012

Section 11 Appendices

Additional Text

Appendix 5 (Cardiovascular Screening Questions) and Appendix 6 (New York Heart Association Functional Classification of Congestive Heart Failure) were added.

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