protocol cr0012 an open-label, multicenter study to … · ucb 08 may 2012 clinical study protocol...

UCB 08 May 2012Clinical Study Protocol Certolizumab pegol CR0012

Confidential of 119

PROTOCOL CR0012

AN OPEN-LABEL, MULTICENTER STUDY TO ASSESS THE SAFETY OF CERTOLIZUMAB PEGOL IN CHILDREN AND ADOLESCENTS WITH ACTIVE CROHN’S DISEASE WHO

COMPLETED C87035 OR WERE TERMINATED FROM C87035 WHEN THE STUDY WAS STOPPED BY UCB

PHASE 2B

IND Number: 11197

Sponsor:

UCB BIOSCIENCES, INC.

8010 Arco Corporate Drive

Raleigh, NC 27617

UNITED STATES

Protocol/Amendment Number Date Type of amendment

Final Protocol 07 May 2010 N/A

Amendment 1 29 Jun 2010 Substantial

Amendment 2 08 May 2012 Substantial

Confidential Material

Confidential

This document is the property of UCB and may not – in full or in part – be passed on, reproduced, published or otherwise used without the express permission of UCB.

REDACTED rporrpo

h, NCh, NC

NITENITE

RE

COPY ES, INES, IN

oratorat

This do

cumen

t t can

nots docdoc

, reprreprc

be us

ed

usto

supp

ort rt

sup

any m

arketi

ng DDgggng

ket

m

autho

rizati

on N

te Drive Driv

C 276276

D STAD ST

appli

catio

n

NC.C.

and a

ny ex

tensio

ns or

varia

tions

there

of.


Confidential of 119

SPONSOR DECLARATIONI confirm that I have carefully read and understand this protocol and agree to conduct this clinical study as outlined in this protocol and according to current Good Clinical Practice.

EDACCCCCCCCCCCCCCCCCCCCCCTTTTTTTTTTTTTTTTTTTTTTTEEEEEETED OPYYYYYYYYYYYY OP

CO

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

auauthhhhhhhhhhhhhhhhhooooooooooooooooooooooooo

rrrrrrrrrrrrrrrrriiiiiiiiiiiiizzn

rizati

on ap

plica

apca

tion

a

d an

d annnnyny

ions

ensio

exten

or orva

riatio

ns

vv

thereo

f.


Confidential of 119

STUDY CONTACT INFORMATIONSponsorUCB BIOSCIENCES, INC.


Raleigh, NC 27617

UNITED STATES

Sponsor Study PhysicianName: , MD

Address: 8010 Arco Corporate DriveRaleigh, NC 27617, USA

Phone:

Fax:

Clinical Project ManagerName:


Phone:

Fax:

Clinical Study Biostatistician Name: , PhD


Phone:

Fax:

REDACTED rate Drate Dr

276172761

ED

EDRE

COPY

CO

This do

cumen

t can

not

nobe

be

used

se

to su

pport

ststpo

upsuuuupp

oan

y ticiaici

mararrketi

ng

tintiark

etau

thoriz

ation

on

riveve7, USA, USA

za

a

appli

catio

n tio

and

anan

y a

exten

sions

io

ten

or va

riatio

ns th

ereof.


Confidential of 119

Medical MonitorName: , MD

Address: 5610 Point West DriveOakwood, GA 30566

Phone:

Fax:

Clinical Monitoring Contract Research OrganizationName: PRA International

Address: Glen Lake 64130 Parklake AvenueRaleigh, NC 27612

Phone: 919-786-8200

Fax: 919-786-8201

COPY YOP

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on n ap

plica

tion

tio

plia

and a

ny

nyex

tensio

ns s

xt

or ova

riatio

ns th

ereof.


Confidential of 119

SERIOUS ADVERSE EVENT REPORTING

Serious adverse event reporting (24h), safety related issues, and emergency unblinding

Fax Europe and Rest of the World (except Japan): +32 2 386 24 21

USA: +1 800 880 6949

Canada: +1 877 582 8842

Phone During business hours: Outside business hours:

Europe and Rest of the World (except Japan): +32 2 386 24 68

USA & Canada:

+1 770 970 2709

Europe and Rest of the World (except Japan): +32 2 386 24 68

USA & Canada:

+1 678 799 4007

REDACTED COPY

COOPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on n ap

plica

tionanadnad

8 799 48 799

andn):): +3+3

any of theof th

2

y exten

sions

rs:s:ns

e

or orva

riatio

ns th

ereof.


Confidential of 119

TABLE OF CONTENTSLIST OF ABBREVIATIONS.................................................................................................. 101 SUMMARY..................................................................................................................... 122 INTRODUCTION ........................................................................................................... 133 STUDY OBJECTIVES.................................................................................................... 144 STUDY VARIABLES..................................................................................................... 14

4.1 Safety variables...................................................................................................... 144.2 Efficacy variables................................................................................................... 154.3 Pharmacokinetic and immunological variables ..................................................... 16

5 STUDY DESIGN............................................................................................................. 165.1 Study description ................................................................................................... 16

5.1.1 Study duration per subject ........................................................................... 175.1.2 Planned number of subjects and sites .......................................................... 175.1.3 Anticipated regions and countries................................................................ 17

5.2 Schedule of study assessments............................................................................... 185.3 Schematic diagram................................................................................................. 225.4 Rationale for study design and selection of dose................................................... 23

6 SELECTION AND WITHDRAWAL OF SUBJECTS................................................... 236.1 Inclusion criteria .................................................................................................... 236.2 Exclusion criteria ................................................................................................... 236.3 Withdrawal criteria ................................................................................................ 23

7 STUDY TREATMENTS................................................................................................. 257.1 Description of investigational medicinal product(s).............................................. 257.2 Treatments to be administered ............................................................................... 257.3 Packaging............................................................................................................... 277.4 Labeling ................................................................................................................. 277.5 Handling and storage requirements ....................................................................... 277.6 Drug accountability................................................................................................ 287.7 Procedures for monitoring subject compliance...................................................... 287.8 Concomitant medication(s)/treatment(s) ............................................................... 29

7.8.1 Permitted concomitant treatments (medications and therapies) .................. 297.8.2 Prohibited concomitant treatments (medications and therapies) ................. 307.8.3 Rescue therapy............................................................................................. 30

7.9 Enrollment and numbering of subjects .................................................................. 308 STUDY PROCEDURES BY VISIT ............................................................................... 31

8.1 Entry Week 0 ......................................................................................................... 318.2 Week 2 Visit .......................................................................................................... 31

REDACTEDSUBSUB...........

....................

COPY ............n of dn of dBJ

This do

cumen

t can

not 7.8.17.8.1

77

beConConus

edaccoacco

oceducedu

to anouou

supp

ort ..........

............nd stnd st

any minismini mark

eting

..........................

ationaltionaste

autho

rizati

on doseose

JECTECT..........

...........

appli

catio

n ............................

.............

and

............

any ...

........ex

tensio

ns.........................

................

.

or 14111

varia

tions

44

thereo

f.


Confidential of 119

8.3 Phone call (home administration) or visit (clinic administration) (every 4 weeks and in between regular clinic visits beginning at Week 6) ......................... 32

8.4 Regular clinic visits................................................................................................ 328.4.1 Assessments every 12 weeks beginning at Week 14................................... 328.4.2 Assessments at Weeks 14, 26, 38, 50 and then every 12 months

thereafter: ..................................................................................................... 338.5 Completion/Early Termination Visit ..................................................................... 338.6 Reinduction visits................................................................................................... 348.7 Unscheduled Visit .................................................................................................. 348.8 Safety Follow-Up Visit .......................................................................................... 35

9 SAFETY ASSESSMENTS.............................................................................................. 359.1 Adverse events ....................................................................................................... 35

9.1.1 Definition of adverse event.......................................................................... 359.1.2 Procedures for reporting and recording adverse events............................... 369.1.3 Description of adverse events ...................................................................... 369.1.4 Follow-up on adverse events ....................................................................... 369.1.5 Rule for repetition of an adverse event ........................................................ 369.1.6 Pregnancy..................................................................................................... 379.1.7 Overdose of investigational medicinal product ........................................... 379.1.8 Safety signal detection ................................................................................. 38

9.2 Serious adverse events ........................................................................................... 389.2.1 Definition of serious adverse event ............................................................. 389.2.2 Procedures for reporting serious adverse events.......................................... 399.2.3 Follow-up of serious adverse events............................................................ 39

9.3 Adverse events of interest...................................................................................... 399.4 Immediate reporting of adverse events .................................................................. 409.5 Laboratory measurements...................................................................................... 409.6 Other safety measurements .................................................................................... 41

9.6.1 Demographics .............................................................................................. 419.6.2 Assessment of childbearing potential .......................................................... 419.6.3 Pregnancy test .............................................................................................. 419.6.4 Physical examination ................................................................................... 419.6.5 Tuberculin test ............................................................................................. 41

9.6.5.1 Mantoux tuberculin skin test (PPD test) ............................................ 419.6.6 Evaluation of signs and symptoms of TB.................................................... 429.6.7 Vital signs .................................................................................................... 439.6.8 Concomitant medications ............................................................................ 439.6.9 Medications for CD ..................................................................................... 43

REDACTED medicmedi

........................

us adus ad

COPY ventvent .

........

This do

cumen

t can

not 6.36.

9.6.9.6.be

33

usedDemDem

AA

tofetyfetysupp

ortorting tingmeasumeasumm

any nteresnteremark

eting

.dverse dverse

orting srting ious aous

autho

rizati

on ............

cinal pcinal p..........

........

appli

catio

n ent

..........................

...........

and ........

nts...ts...an

y ............

exten

sions..........

...............................

or. 34.34varia

tions

34

thereo

f.


Confidential of 119

9.6.10 Autoantibodies ............................................................................................. 4310 EFFICACY ASSESSMENTS ......................................................................................... 43

10.1 Disease activity/PCDAI......................................................................................... 4310.2 Erythrocyte sedimentation rate .............................................................................. 4410.3 C-reactive protein................................................................................................... 4410.4 Tanner stage ........................................................................................................... 44

10.4.1 Bone markers ............................................................................................... 4410.5 Height..................................................................................................................... 4410.6 Weight.................................................................................................................... 4510.7 IMPACT-III ........................................................................................................... 4510.8 Days missed from school/work (WPAI:CD for children and for working

individuals with CD).............................................................................................. 4510.9 Effect on the caregiver's work (WPAI:CD for caregivers).................................... 4610.10 Concurrent medical procedures ............................................................................. 46

11 PHARMACOKINETICS AND IMMUNOLOGICAL ASSESSMENTS....................... 4712 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 47

12.1 Adherence to protocol............................................................................................ 4712.2 Monitoring ............................................................................................................. 47

12.2.1 Definition of source data.............................................................................. 4712.2.2 Source data verification ............................................................................... 48

12.3 Data handling ......................................................................................................... 4812.3.1 Case report form completion ....................................................................... 4812.3.2 Database entry and reconciliation................................................................ 4812.3.3 Subject Entry and Enrollment log/Subject Identification Code list............. 49

12.4 Termination of the study........................................................................................ 4912.5 Archiving and data retention.................................................................................. 4912.6 Audit and inspection .............................................................................................. 5012.7 Good Clinical Practice ........................................................................................... 50

13 STATISTICS ................................................................................................................... 5013.1 Definition of analysis sets...................................................................................... 5013.2 General statistical considerations........................................................................... 5113.3 Planned safety analyses.......................................................................................... 5113.4 Planned efficacy analyses ...................................................................................... 5213.5 Pharmacokinetics and immunological analyses..................................................... 5313.6 Handling of protocol deviations............................................................................. 5313.7 Handling of dropouts or missing data.................................................................... 5313.8 Planned interim analysis and data monitoring ....................................................... 5413.9 Determination of sample size................................................................................. 54

................

.........................

mpm

COPY TIOI.............

....

This do

cumen

t 1 cann

otGG3.33.3

1313

be Defef

GeGeus

ed

ICSCSfinifin

toinicinicsupp

ort

data rdata rinspectnspect

al

any ndd

studstudymark

eting

....pletionpletion

d reconrecond Enrd En

autho

rizati

on .

........................

....................

appli

catio

n ......ESSSSMM

......................

and ..........

.

any............ex

tensio

ns ...

................................

rkingking

or .. 44.44va

riatio

ns

444

thereo

f.


Confidential of 119

14 ETHICS AND REGULATORY REQUIREMENTS...................................................... 5414.1 Informed consent ................................................................................................... 5414.2 Subject identification cards.................................................................................... 5514.3 Institutional Review Boards and Independent Ethics Committees........................ 5514.4 Subject privacy....................................................................................................... 5614.5 Protocol amendments............................................................................................. 56

15 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 5616 REFERENCES ................................................................................................................ 5617 APPENDICES ................................................................................................................. 58

17.1 Tuberculosis questionnaire .................................................................................... 5817.2 Pediatric Crohn’s Disease Activity Index.............................................................. 5917.3 IMPACT III ........................................................................................................... 7217.4 Work Productivity and Activity Impairment Questionnaire for children with

CD (WPAI:CD for children).................................................................................. 8017.5 Work Productivity and Activity Impairment Questionnaire for working

individuals with CD (WPAI:CD for working individuals with CD) ..................... 8217.6 Work Productivity and Activity Impairment Questionnaire for caregivers of

children with CD (WPAI:CD for caregivers of children with CD) ....................... 8417.7 Protocol amendment #1 ......................................................................................... 8617.8 Protocol Amendment 2 .......................................................................................... 89

18 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 119

LIST OF TABLESTable 5-1. Schedule of study assessments ............................................................................. 18

Table 7-1. Doses of CZP in CR0012 ..................................................................................... 26LIST OF FIGURES

Figure 5-1: Schematic Diagram............................................................................................... 22

REDACTED ......................

URE OURE

ISTIST

COPY gent Quent Q

givers ivers

This do

cumen

t can

not b

e use

d to s

uppo

rt Diagramiagra

any00100Lmark

eting

T OF T OF

smentsmen

1212

autho

rizati

ons of chof c...........

............OF INOF IN

appli

catio

n ......nnaire naire

vidualsidualuestionestio

hih

andfor chor c

.

any ............

hi

exten

sions

...................

.............................

or .. 56.56va

riatio

ns

566

thereo

f.


Confidential of 119

LIST OF ABBREVIATIONS

AE adverse event

ANA antinuclear antibody

CD Crohn’s disease

CDAI Crohn’s Disease Activity Index

CDP870 certolizumab pegol

CI confidence interval

CDMS clinical data management system

CRF Case Report Form

CRO contract research organization

CRP C-reactive protein

CZP certolizumab pegol

dsDNA double-stranded deoxyribonucleic acid

DSMB Data and Safety Monitoring Board

ELISA enzyme-linked immunosorbent assay

ESR erythrocyte sedimentation rate

ET Early Termination

EU European Union

Fab′ antigen-binding fragment

FDA Food and Drug Administration

GCP Good Clinical Practice

GCSP Global Clinical Safety and Pharmacovigilance

HIPAA Health Insurance Portability and Accountability Act

HRQOL health-related quality of life

IBD inflammatory bowel disease

ICH International Conference on Harmonization

IEC Independent Ethics Committee

IMP investigational medicinal product

INH isonicotinic acid hydrazide (isoniazid)

IRB Institutional Review Board

REDACTEDring Bring

unosornoso

mentamenta

tiontion

COPY ucleic clei

BB

This do

cumen

t C

IECIECca

nnot

HH

be us

ed to

GGsupp

orand and

Good Cood

GloGl

anyndinndi

d Dd D

marketi

ng

n

ionon

inging

autho

rizati

on acac

Boardoard

orbent rbent

tion ron r

appli

catio

n

cidid

and a

ny ex

tensio

ns or

varia

tions

there

of.


Confidential of 119

ITT Intention-To-Treat

iv intravenous

IVRS Interactive Voice Response System

MedDRA® Medical Dictionary for Regulatory Activities®

PCDAI Pediatric Crohn’s Disease Activity Index

PEG polyethylene glycol

PFS prefilled syringe

PK pharmacokinetics

PPD purified protein derivatives

PT Preferred Term

Q2W every 2 weeks

Q4W every 4 weeks

QFT-GOLD QuantiFERON®-TB GOLD

RBC red blood cell

SAE serious adverse event

SAP Statistical Analysis Plan

sc subcutaneous

SD standard deviation

SFU Safety Follow-Up

SOC System Organ Class

SOP Standard Operating Procedures

TB tuberculosis

TNF human tumor necrosis factor alpha

US United States

WBC white blood cell

WPAI:CD Work Productivity and Activity Impairment Questionnaire for CD

WHODrg World Heath Organization Drug

lanlan

tiontion

COPY

This do

cumen

t can

not :CDCD

HODHOD

be us

ed to

hhsupp

ortdard ard

berculbercu

humhu

anyrganga

d Opd O

marketi

ng

UpUp

an Can

autho

rizati

on ap

plica

tion a

nd an

y exte

nsion

s or v

ariati

ons t

hereo

f.


Confidential of 119

1 SUMMARYThis is a Phase 2b, open-label, multicenter study to assess the safety of certolizumab pegol (CDP870, CZP) in children and adolescents with active Crohn’s disease (CD) who completed C87035 or were terminated from C87035 when the study was stopped by UCB.

C87035 was a Phase 2, open-label, multicenter study to assess the safety, efficacy, pharmacokinetics (PK), and immunogenicity of CZP in children and adolescents ages 6 to 17 with moderately to severely active Crohn’s disease. The study was performed as a postapproval commitment following the Food and Drug Administration (FDA) approval of CZP for the treatment of adults with moderately to severely active CD.

the decision was made to stop C87035 after determining it was inadequate to address the efficacy of CZP for labeling in pediatric subjects. Subjects ongoing in the study were given the opportunity to enter CR0012 without having completed C87035.

Certolizumab pegol, the investigational medicinal product (IMP) is a humanized antibody fragment antigen binding (Fab′), with specificity for human tumor necrosis factor alpha (TNF), conjugated to polyethylene glycol (PEG). The drug intended for use in this study is the liquid formulation of CZP in a prefilled syringe (PFS).

All subjects who complete Week 62 of C87035 or were terminated from C87035 when the study was stopped by UCB (and completed all assessments required for Week 62/Visit 23 at the time of termination) are eligible to enter this open-label extension study.

Following entry, subjects may continue on the CZP dose they were receiving at the end of C87035 (Low-Dose Group or High-Dose Group [weight adjusted in kg]) every 4 weeks (Q4W). The first clinic visit of this study should coincide with the last visit of C87035(Week 62/Visit 23). Home administration of CZP by the subject/caregiver/appropriate designee as determined by the Investigator will be permitted following appropriate training at clinic visits. For subjects performing home administration, a phone call to the subject and/or the parents/caregiver will be performed by the Investigator (or designee) every 4 weeks between regular clinic visits. A Safety Follow-Up (SFU) Visit will be conducted 12 weeks after the last dose of study medication.

If a subject has not been previously reinduced in C87035, the subject is eligible for 1 reinduction due to loss of response in CR0012 (defined as an increase in Pediatric Crohn’s Disease Activity Index [PCDAI] ≥15 points compared to Week 6 of C87035 at 2 consecutive visits at least 1 week apart or an overall PCDAI >30 points at any time).

A Data and Safety Monitoring Board (DSMB) will periodically review all emerging safety data.

The primary objective of the study is to assess the longterm safety and tolerability of CZP in children and adolescents with moderately to severely active CD. As secondary objectives, this study further assesses the longterm efficacy, PK, and immunogenicity of CZP treatment in this population.

REDACTED asseassethis opthis op

on the on theose Gose G

tudytudy

COPY FS)FS

were twereessmess

This do

cumen

t The The chch

cann

ot a andanda..

bevi

ast 1 st 1 us

edue to e to ityty IIyy

tobeenbee supp

ort pep

its. ts. A A udydy memyy

n p

anymingmin

erformerformmark

eting

Groroy shoulshouy

ation oftion oestigatostiga

g hg

autho

rizati

on termer

mentsmentspenen--lala

e CZP CZP oup up

appli

catio

nnecronecrnded fnded

rminmin

and humahuma

any ubjub

omplempleex

tenining ning bjecbjec

ions oval ofval of

ensio

or 177 va

riatio

ns

77

thereo

f.


Confidential of 119

Safety variables to be evaluated are adverse events (AEs), laboratory parameters (hematology, biochemistry, urinalysis), vital signs, and autoantibodies (anti-nuclear antibody [ANA] and anti-double-stranded deoxyribonucleic acid [dsDNA] antibody).

The main efficacy variable is the proportion of subjects in clinical remission.

Other efficacy variables include: absolute score and change in PCDAI scores, proportion of subjects maintaining clinical response, absolute and change in both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and change in growth scores (Tanner stage), absolute and change in bone marker values, absolute and change in IMPACT-III scores, days missed from school/work, absolute and change in Work Productivity and Activity Impairment Questionnaire for CD (WPAI:CD) scores, and concurrent medical procedures required during the study.

Pharmacokinetic and immunological variables include measurement of plasma concentrations of CZP and detection of anti-CZP antibodies.

2 INTRODUCTIONTumor necrosis factor alpha is a key proinflammatory cytokine with a central role in the immune response. In CD, TNF activates similar processes, with gut epithelial tissue injury resulting from induction of proteases, prostaglandins, leukotrienes, eicosanoids, and other products, some of which (eg, prostaglandin E2) may also directly cause diarrhea by promoting mucosal secretion of chloride and potassium. In addition, both intestinal and peripheral phagocytes from subjects with active CD have the capacity to secrete increased amounts of TNF.

Several large double-blind, randomized clinical studies of biological products targeted at neutralizing TNF have demonstrated marked clinical benefit in subjects with active CD (Targan et al, 1997; Rutgeerts et al, 1999; Sandborn et al, 2001). Furthermore, it has been shown that sustained clinical benefit over a year can be achieved in subjects who respond to a first dose of anti-TNF therapy (Hanauer et al, 2002).

Several TNF-antagonists (including CZP [Cimzia®], adalimumab [Humira®], and infliximab [Remicade®]) have been approved for the treatment of CD.

Use of anti-TNF agents has been studied in pediatric patients suffering from CD. Infliximab has been approved in the United States (US) and the European Union (EU) for pediatric use (Hyams J et al, 2007) and adalimumab is currently under investigation in this population.

It is widely recognized that there exists an unmet need for new therapies for children and adolescents with active CD. The primary goal of treatment is to provide longterm reduction or remission in the signs and symptoms of their disease.

Certolizumab pegol is an engineered, humanized antigen-binding fragment (Fab' fragment) conjugated to PEG with specificity for human TNF. Certolizumab pegol (CIMZIA) has been approved in the US, Switzerland, Russia, Brazil, and Chile for reducing the signs and symptoms of CD and maintaining the clinical response in adult subjects with moderately to severely active disease who have had an inadequate response to conventional therapy.

REDACTED tastasive CDive CD

ed clined clinmarmar

COPYleukleukayay alsoalsyyssiussiu

This do

cumen

tCertoCertoconcon

cann

oty

ents ents missiomissio

ll

bey recoy recus

ed d inin

, 20072007to

entsin thn th

supp

orncludclu

approvappr

tss hasha

anyHanaHan

udinudi

marketi

ng nicic

arked crked c999; Sa999; S

fit overt ovenauenau

autho

rizati

on o did

um. Im. InnD havD hav

cal sal s

appli

catio

n with a cith a th gut eth gut

otrienesrienedirecirec

and a

ny ma a ex

tensio

ns

eduresdure

a conco

or ays ays varia

tions

there

of.


Confidential of 119

Single intravenous (iv) and subcutaneous (sc) doses of CZP in healthy volunteers have been shown to have a predictable dose-related response with an approximately linear relationship between the dose administered and the maximum serum concentration (Cmax) and the area under the CZP plasma concentration versus time curve (AUC). The terminal elimination phase half-life (t1/2) was approximately 14 days for all dosage levels tested and the bioavailability of CZP when administered subcutaneously was approximately 80%. A similar PK profile was found in healthy Japanese and Caucasian subjects. The metabolism and route of excretion of CZP have not yet been fully elucidated.

The safety of CZP has been assessed in 2518 adult subjects with CD representing over 2837 patient years of exposure. Certolizumab pegol is well tolerated. The incidence of injection site reactions and hypersensitivity-type reactions was low. There were no reports of anaphylaxis or anaphylactoid-type reactions with CZP. All available data in CD show the safety of CZP is consistent with the known risks of anti-TNF therapies.

The risks of the present study are essentially those of experiencing an adverse effect following administration of CZP and for loss of response. As a therapeutic class, currently available TNF-antagonists are known to be associated with serious infections, particularly reactivation of tuberculosis (TB) and opportunistic fungal infections. An association has also been reported with TNF-antagonist therapy and the development of lymphoma and leukemia especially in children and adolescents, although it is not clear whether there is a causal relationship as confounding factors exist (eg, the increased risk of lymphoma and leukemia associated with autoimmune diseases and immunosuppression) themselves. Other cancer types also have been reported in association with TNF-antagonist use, but the causal relationship for these is unclear as well. Other serious AEs that have been infrequently reported in subjects treated with currently available TNF-antagonists (including CZP) include congestive heart failure, drug-induced lupus, new-onset psoriasis, seizures, demyelinating disorders, and pancytopenia.

For more information, please refer to the Investigator’s Brochure.

3 STUDY OBJECTIVESThe primary objective of this open-label, multicenter study is to assess the longterm safety and tolerability of CZP in children and adolescents with moderately to severely active CD who completed C87035 or were terminated from C87035 when the study was stopped by UCB. The secondary objectives of this study are to assess the longterm efficacy, PK, and immunogenicity of CZP treatment on this population.

4 STUDY VARIABLES4.1 Safety variables• AEs

• Laboratory parameters (hematology, biochemistry, urinalysis)

• Vital signs

• Autoantibodies (ANA and anti-dsDNA antibody)

REDACTEDmunosmunon withn with

Other Otherentlyently aayyd lud lu

COPY velove not cnot c

ncreancrea

This do

cumen

t •• AAca

nnot

be ci us

ed8787

ndaryndarytty oy o

to7035035su

pport

BJBJf this othis

P in chP in c

any

r r

JECJECmark

eting

avavaupus, npus, n

to thto th

autho

rizati

onased rased ruppreuppre

h TNFTNFr serioserioailabilab

appli

catio

np

s infes infetions. Aions.

ment ofment oear whear w

i

and dverver

eutic eutic an

y rse erse

exten

sions

of of

o reporepoD showshow

or va

riatio

ns th

ereof.


Confidential of 119

4.2 Efficacy variablesMain efficacy variable:

• Proportion of subjects in clinical remission (clinical remission is defined as a PCDAI score ≤10)

Other efficacy variables:

• Disease activity variables:

− Absolute PCDAI scores

− Change from Baseline (Week 0 of C87035) in PCDAI scores

− Proportion of subjects maintaining clinical response (clinical response is defined as a decrease from Baseline (Week 0 of C87035) in PCDAI score of ≥15 points and a total PCDAI score ≤30 points)

− CRP levels

− Change from Baseline (Week 0 of C87035) in CRP levels

− ESR values

− Change from Baseline (Week 0 of C87035) in ESR values

− Change from Baseline (Week 0 of C87035) in growth scores (Tanner stage [assessing puberty])

− Bone marker values

− Changes from Baseline (Week 0 of C87035) in bone marker values

• Subject-reported outcome variables:

− Absolute IMPACT-III scores

− Change from Baseline (Week 0 of C87035) in IMPACT-III score

− Actual scores of WPAI:CD for children and for working individuals with CD

− Change from Baseline (Week 0 of C87035) in scores of WPAI:CD for children and for working individuals with CD)

− Concurrent medical procedures

• Caregiver-reported outcome variables:

− Actual scores of WPAI:CD for caregivers

− Change from Baseline (Week 0 of C87035) in scores of WPAI:CD for caregivers

REDACTED 35

8703587035COPY

5) in ) in

This do

cumen

t can

not onon

CareCare

be

ncurrncurus

edfrom omrkingrking

to o

BBsu

pport

eline (Wline

of WPf WP

any scorescoremark

eting

0 of C0 of C

ables:ables

autho

rizati

on

ESR ESR

5) in g) in g

appli

catio

n velsvels

and a

ny5 poin5 poiex

tensio

ns

is des de

or va

riatio

ns th

ereof.


Confidential of 119

4.3 Pharmacokinetic and immunological variables• Plasma concentrations of CZP

• Detection of anti-CZP antibodies

5 STUDY DESIGN5.1 Study descriptionThis is a Phase 2, open-label, multicenter study in children and adolescents with moderately to severely active CD who completed C87035, or were terminated from C87035 when the study was stopped by UCB, to assess the longterm safety and tolerability of CZP.

All subjects who complete Week 62 of C87035 or were terminated from C87035 when the study was stopped by UCB (and completed all assessments required for Week 62/Visit 23 at the time of termination) are eligible for entry.

Subjects may continue on CZP at the dose they were receiving at the end of C87035 (Low-Dose Group or High-Dose Group [weight adjusted in kg; see Section 7.2 and Table 7-1])every 4 weeks until the subject reaches the age of 18 years or CZP is approved for use in the US by pediatric subjects with CD. The first clinic visit should coincide with the last visit of C87035 (Week 62/Visit 23). First study drug administration occurs 2 weeks later (Week 2) and subsequent clinic visits for safety and efficacy assessments are scheduled at 12-week intervals. After Week 2, subjects or parents/caregivers/appropriate designee as determined by the Investigator have the option of home administration of CZP upon appropriate training during a previous clinic visit(s) or continuing to have CZP administered every 4 weeks at the clinic. For subjects performing home administration, a phone call to the subject and/or the parents/caregiver will be performed by the Investigator (or designee) every 4 weeks between regular clinic visits in order to capture potential AEs and changes in concomitant medications, and to check compliance with home dosing. An SFU Visit will be conducted 12 weeks after the last dose of study medication for subjects.

Please refer to Study Schedule of Assessments in Section 5.2 for visit-specific procedures and to Section 5.3 for a schematic representation of the study.

A DSMB will periodically review all emerging safety data (see Section 13.8). Based on the safety data, the DSMB can recommend modifying or stopping the study.

Loss of response/reinduction

• Subjects who were reinduced in C87035 are not eligible for reinduction in CR0012. Should loss of response occur in CR0012, the subject must be withdrawn.

• If there was no reinduction in C87035, 1 reinduction only is permitted in CR0012. If response is lost a second time in CR0012, the subject must be withdrawn.

REDACTED acy acyaregivaregiv

adminidmininuinginuing

admadm

COPYt shoshnistratnistra

y assas

This do

cumen

t•• cann

otSubjeSubjeShoSh

beponon us

edDSMDSM

nsense

todicadicB

supp

ortdule oule oematicemati

alll

anystudystudymark

etingministrnist

y the Invthe Iure potee ponce wnce

autho

rizati

on tionion

sessmessmvers/apers/a

istratioistratig to hato ha

t

appli

catio

n e ention ion 7.7

CZP isCZP ild coind co

n ocn oc

and

end nd an

yek 6ek 6exten

sions

ten the n the

35 wh35 wh622

or ly yva

riatio

ns th

ereof.


Confidential of 119

Loss of response, defined as an increase in PCDAI ≥15 points compared to Week 6 of C87035 at 2 consecutive visits at least 1 week apart, or an overall PCDAI >30 points at any time, will result in reinduction and dosing as follows:

• The reinduction dose will be adjusted to the subject’s weight: 400mg for subjects ≥40kg or 200mg for subjects 20 to <40kg sc Q2W for a total of 3 doses

• Continue dosing with CZP administered sc Q4W as 400mg for subjects ≥40kg or 200mg for subjects 20 to <40kg, regardless of the subject’s previous randomized dose group

Summary of visits related to loss of response

1. Loss of response must be confirmed at a clinic visit where assessments and labs are performed to determine PCDAI score. Scores cannot be confirmed until lab results are received by central lab a few days after the clinic visit. Once loss of response is confirmed, sites must contact the subject to return for the first Reinduction Visit.

2. Reinduction Week 0 - subjects will receive the first dose for reinduction at the clinic.

3. Reinduction Week 2 occurs 2 weeks later for second dose at the clinic.

4. Reinduction Week 4 occurs 2 weeks later for third dose at the clinic.

5. Subject resumes the original schedule of clinic visits after reinduction. The clinic should contact the Study Monitor to determine the most appropriate way to resume the original schedule of clinic visits.

5.1.1 Study duration per subjectThe maximum study duration of CZP treatment may be until the subject reaches the age of 18 years or CZP is approved for use in the US by pediatric subjects with CD. An SFU visit will be conducted 12 weeks following the last dose of study drug.

The end of the study is defined as the date of the last SFU visit of the last subject in the study.

5.1.2 Planned number of subjects and sitesIt is anticipated that the approximately 30 to 40 centers which participated in C87035 will participate in this study. Those subjects who completed Week 62 of C87035 or were terminated from C87035 when the study was stopped by UCB (and completed all assessments required for Week 62/Visit 23 at the time of termination) may be enrolled in this study.

• First subject first visit: Jul 2010

• Last subject first visit: Jun 2012

• Last subject last visit: to be determined (including the SFU Visit)

5.1.3 Anticipated regions and countriesThis study will be conducted in the US, Canada, Australia, and New Zealand.

REDACTED ectect

reatmreatmin thein the

COPYsits asits aost appost app

This do

cumen

t L

5

cann

ot ast subst sub

LasLas

bebjecbjecus

ediredred to

7030d fod fo

supp

ortpproxiproxiy. Thos Tho35 w35 w

anyber ober mark

etinge US e US

the lasthe la

the dathe da

autho

rizati

onpropprop

ent mnt mb

appli

catio

n e clincli

he clinhe cli

fter reinter repriari

andctionction

nii

any on Von V

n a

exten

sions

are re

esults sultsnse is se is

VV

or va

riatio

ns th

ereof.

UC

B08

May

2012

Clin

ical

Stu

dy P

roto

col

Cer

toliz

umab

peg

olC

R00

12

Con

fiden

tial

Page

18

of 1

19

5.2

Sche

dule

of s

tudy

ass

essm

ents

Tabl

e5-

1.Sc

hedu

le o

f stu

dy a

sses

smen

ts

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic a

dmin

istr

atio

nb

Reg

ular

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

2E

very

4 w

eeks

beg

inni

ng

at W

eek

6 an

d in

bet

wee

n re

gula

r cl

inic

vis

its

Eve

ry 1

2 w

eeks

be

ginn

ing

at W

eek

14+1

2 w

eeks

af

ter

last

do

se o

f st

udy

drug

Writ

ten

info

rmed

con

sent

X

Ass

essm

ent o

f inc

lusi

on/

excl

usio

n cr

iteria

X

Dem

ogra

phy

X

Life

styl

eC

8703

5

Cro

hn’s

dis

ease

his

tory

C87

035

Med

ical

and

surg

ical

his

tory

C87

035

Ass

essm

ent o

f chi

ldbe

arin

g po

tent

ial

C87

035

XX

Preg

nanc

y te

ste

C87

035

XX

X

Phys

ical

exa

min

atio

nC

8703

5X

XX

TB te

stX

TB q

uest

ionn

aire

XX

XX

Tann

er st

age

C87

035

XX

Hei

ght

C87

035

XX

Wei

ght

C87

035

XX

Vita

l sig

nsf

C87

035

XX

XX

X

REDACTED DTE

DARE

COPY PY

CCC

This do

cumen

t can

not Cot

annnnn

be

C87

0C

870eus

ed d

035

035

edu

to tosu

pport

oooor po

up

any

anmark

eting

get

m

autho

rizati

on

tiori rri riz ori

uth

appli

catio

n

ek 1

4k

14

capp

and dddd

andan

y Ear

Ea

Ter

mT

erm

exten

sions

ns

mpl

etio

plet

iote

or va

riatio

ns

onthe

reof.

08 M

08 M

UC

B08

May

2012

Clin

ical

Stu

dy P

roto

col

Cer

toliz

umab

peg

olC

R00

12

Con

fiden

tial

Page

19

of 1

19

Tabl

e5-

1.Sc

hedu

le o

f stu

dy a

sses

smen

ts

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic a

dmin

istr

atio

nb

Reg

ular

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

2E

very

4 w

eeks

beg

inni

ng

at W

eek

6 an

d in

bet

wee

n re

gula

r cl

inic

vis

its

Eve

ry 1

2 w

eeks

be

ginn

ing

at W

eek

14+1

2 w

eeks

af

ter

last

do

se o

f st

udy

drug

Adv

erse

eve

ntsa

C87

035

XX

XX

XX

Con

com

itant

med

icat

ions

aC

8703

5X

XX

XX

X

Con

curr

ent m

edic

al p

roce

dure

sC

8703

5X

XX

XX

X

PCD

AI

C87

035

XX

ESR

/hem

atoc

rit/a

lbum

in fo

r PC

DA

IC

8703

5X

X

CR

PC

8703

5X

X

Hem

atol

ogy/

chem

istry

/urin

alys

isC

8703

5X

XX

IMPA

CT

III

C87

035

Xl

X

WPA

I:CD

gC

8703

5X

lX

Cer

toliz

umab

peg

ol p

lasm

a co

ncen

tratio

nhC

8703

5X

XX

Ant

i-CZP

ant

ibod

y pl

asm

a co

ncen

tratio

niC

8703

5X

XX

Aut

oant

ibod

ies (

AN

A a

nd a

nti-

dsD

NA

)C

8703

5X

XX

Bon

e m

arke

rs (o

steo

calc

in,

bone

spec

ific

alka

line

phos

phat

ase,

n-te

lope

ptid

es)

C87

035

Xl

X

REDACTED D

ACED

COPY YCCCOC

This do

cumen

t can

not

nnnnnnnnbe

C87

0C

87

used

5

dus

to tosu

pport

popopopop

any ny

marketi

ng

kema

autho

rizati

on n

atori th

a

appli

catio

n on

XX

at

XXpp a

and

andan

y yexten

sions

ion/

n/

ar

ly

ly

min

ati

inat

ioooooor r

varia

tions

on

v

thereo

f.

08 M

08 M

UC

B08

May

2012

Clin

ical

Stu

dy P

roto

col

Cer

toliz

umab

peg

olC

R00

12

Con

fiden

tial

Page

20

of 1

19

Tabl

e5-

1.Sc

hedu

le o

f stu

dy a

sses

smen

ts

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic a

dmin

istr

atio

nb

Reg

ular

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

2E

very

4 w

eeks

beg

inni

ng

at W

eek

6 an

d in

bet

wee

n re

gula

r cl

inic

vis

its

Eve

ry 1

2 w

eeks

be

ginn

ing

at W

eek

14+1

2 w

eeks

af

ter

last

do

se o

f st

udy

drug

Stud

y dr

ug a

dmin

istra

tionj

XX

X

Rei

nduc

tionk

Loss

of r

espo

nse

mus

t be

conf

irmed

at a

clin

ic v

isit

whe

re a

sses

smen

ts a

nd la

bs a

re p

erfo

rmed

to d

eter

min

e PC

DA

I sco

re.

Scor

es c

anno

t be

conf

irmed

unt

il la

b re

sults

are

rece

ived

by

cent

ral l

ab a

few

day

s afte

r the

clin

ic v

isit.

Onc

e lo

ss o

f re

spon

se is

con

firm

ed, s

ites m

ust c

onta

ct th

e su

bjec

t to

retu

rn fo

r the

firs

t Rei

nduc

tion

Vis

it.R

eind

uctio

n W

eek

0 (f

irst r

eind

uctio

n do

se) i

s fol

low

ed b

y R

eind

uctio

n W

eek

2 (s

econ

d do

se, 2

wee

ks a

fter f

irst d

ose)

, and

R

eind

uctio

n W

eek

4 (th

ird d

ose,

2 w

eeks

afte

r sec

ond

dose

). Su

bjec

ts sh

ould

retu

rn to

the

clin

ic fo

r eac

h R

eind

uctio

n.

Subj

ect r

esum

es th

e or

igin

al sc

hedu

le o

f clin

ic v

isits

afte

r rei

nduc

tion.

The

clin

ic sh

ould

con

tact

the

Stud

y M

onito

r to

dete

rmin

e th

e m

ost a

ppro

pria

te w

ay to

resu

me

the

orig

inal

sche

dule

of c

linic

vis

its.

Rei

nduc

tion

Wee

k 0

asse

ssm

ents

: PC

DA

I: ES

R, h

emat

ocrit

, and

alb

umin

; IM

PAC

T-II

I; W

PAI:C

DR

eind

uctio

n W

eek

2 as

sess

men

ts: P

CD

AI:

ESR

, hem

atoc

rit, a

nd a

lbum

inR

eind

uctio

n W

eek

4 as

sess

men

ts: P

CD

AI:

ESR

, hem

atoc

rit, a

nd a

lbum

in; W

PAI:C

D

AN

A=a

ntin

ucle

ar a

ntib

ody;

CR

P=C

-rea

ctiv

e pr

otei

n; C

ZP=c

erto

lizum

ab p

egol

; dsD

NA

=dou

ble-

stra

nded

deo

xyrib

onuc

leic

aci

d (a

ntib

ody)

; ES

R=e

ryth

rocy

te se

dim

enta

tion

rate

; ET=

Early

Ter

min

atio

n; P

CD

AI=

Pedi

atric

Cro

hn’s

Dis

ease

Act

ivity

Inde

x; S

FU=S

afet

y Fo

llow

-Up;

TB

=tub

ercu

losi

s;

WPA

I:CD

=Wor

k Pr

oduc

tivity

and

Act

ivity

Impa

irmen

t Que

stio

nnai

re fo

r CD

a Wee

k 0

of C

R00

12 is

equ

ival

ent t

o th

e la

st v

isit

(Wee

k 62

; sta

tus e

valu

atio

n) o

f C87

035

with

the

follo

win

g ex

cept

ions

: writ

ten

info

rmed

con

sent

, as

sess

men

t of i

nclu

sion

/exc

lusi

on c

riter

ia, d

emog

raph

y, T

B te

stin

g, a

nd T

B q

uest

ionn

aire

. Ong

oing

AEs

and

con

com

itant

med

icat

ions

from

C87

035

will

co

ntin

ue to

be

follo

wed

in C

R00

12. O

ther

ass

essm

ents

will

be

take

n fr

om th

e C

8703

5 da

taba

se b

y U

CB

.Sub

ject

s who

wer

e te

rmin

ated

from

C87

035

whe

n th

e st

udy

was

stop

ped

by U

CB

com

plet

ed a

ll as

sess

men

ts re

quire

d fo

r Wee

k 62

/Vis

it 23

at th

e tim

e of

term

inat

ion.

b Afte

r Wee

k 2,

subj

ects

or p

aren

ts/c

areg

iver

s hav

e th

e op

tion

of h

ome

adm

inis

tratio

n of

CZP

upo

n ap

prop

riate

trai

ning

dur

ing

apr

evio

us c

linic

vis

it(s)

or

can

cont

inue

to h

ave

CZP

adm

inis

tere

d ev

ery

4 w

eeks

at t

he c

linic

. For

subj

ects

per

form

ing

hom

e ad

min

istra

tion,

a p

hone

cal

l to

the

subj

ect a

nd/o

r the

pa

rent

s/ca

regi

ver w

ill b

e pe

rfor

med

by

the

Inve

stig

ator

(or d

esig

nee)

eve

ry 4

wee

ks b

etw

een

regu

lar c

linic

vis

its in

ord

er to

capt

ure

pote

ntia

l AEs

and

ch

ange

s in

conc

omita

nt m

edic

atio

ns, a

nd to

che

ck c

ompl

ianc

e w

ith h

ome

dosi

ng. S

ubje

cts w

ill h

ave

the

optio

n to

eith

er sw

itch

to h

ome

dosi

ng o

r sw

itch

REDACTED

cond

dco

nd

visi

ts a

visi

ts a

me

the

oe

the

CD

AI:

EC

DA

I: : P

CD

A: P

CD

APCP

COPY

y ce

nty

cen

etur

n fo

etur

ned

by

Red

by

dod

This do

cumen

t can

not

nis

nifo

rmed

orm

eded

icat

idi

cati

be

/car

eca

rst

ere

ster

e

used

r asas

eted

all

ed a

llre

gire

g

to

emo

mo

sses

sses

supp

ort

inat

ina

tm

ent Q

men

t it

((Wee

Wee

ogra

pog

r

any

P=ce

rtP=

cer

tion;

io

n

marketi

ng

AI:

E: EC

DA

I: E

DA

I: E

ket

autho

rizati

onoR

eind

uR

eind

use

). Su

be)

. Sub

fter r

ein

ter r

ein

orig

inal

orig

inal

ESR

, he

SR, h

ESR

ESR

appli

catio

n on

ts a

nd la

s and

ll l

ab a

fela

b a

fth

e fir

the

fir

cat

and

andan

y yexten

sions

ion/

n/

ar

ly

ly

min

ati

inat

ioooooor r

varia

tions

on

v

thereo

f.

08 M

08 M

UC

B08

May

2012

Clin

ical

Stu

dy P

roto

col

Cer

toliz

umab

peg

olC

R00

12

Con

fiden

tial

Page

21

of 1

19

Tabl

e5-

1.Sc

hedu

le o

f stu

dy a

sses

smen

ts

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic a

dmin

istr

atio

nb

Reg

ular

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

2E

very

4 w

eeks

beg

inni

ng

at W

eek

6 an

d in

bet

wee

n re

gula

r cl

inic

vis

its

Eve

ry 1

2 w

eeks

be

ginn

ing

at W

eek

14+1

2 w

eeks

af

ter

last

do

se o

f st

udy

drug

back

to si

te a

dmin

istra

tion

at a

nytim

e du

ring

the

stud

y.c V

ital s

igns

, con

com

itant

med

icat

ion,

and

AEs

mus

t be

asse

ssed

at e

very

Uns

ched

uled

Vis

it. O

ther

safe

ty a

nd P

K a

sses

smen

ts (e

g,C

ZP p

lasm

a sa

mpl

e) m

ay

be p

erfo

rmed

at t

he d

iscr

etio

n of

the

Inve

stig

ator

as r

elat

ed to

the

natu

re o

f the

vis

it.d Th

e SF

U V

isit

shou

ld b

e pe

rfor

med

12

wee

ks a

fter t

he fi

nal d

ose

of st

udy

med

icat

ion.

For

subj

ects

con

tinui

ng d

irect

ly o

nto

com

mer

cial

CZP

, a S

FU V

isit

shou

ld b

e co

mpl

eted

prio

r to

the

first

dos

e of

com

mer

cial

dru

g ad

min

istra

tion.

e For a

ll fe

mal

es p

ost m

ense

s, a

urin

e pr

egna

ncy

test

will

be

cond

ucte

d at

all

regu

larly

sche

dule

d cl

inic

vis

its e

xcep

t Wee

k 2.

f Vita

l sig

ns w

ill b

e co

llect

ed 1

5 m

inut

es p

rior t

o do

sing

with

a ±

5 m

inut

e w

indo

w.

g Day

s mis

sed

from

scho

ol w

ill b

e as

sess

ed u

sing

the

WPA

I:CD

for c

hild

ren.

The

tim

e m

isse

d fr

om w

ork

will

be

asse

ssed

usi

ng th

eW

PAI:C

D fo

r wor

king

in

divi

dual

s with

CD

. The

eff

ect o

f the

chi

ld’s

CD

on

the

care

give

r’s p

rodu

ctiv

ity w

ill b

e as

sess

ed u

sing

the

WPA

I:CD

for c

areg

iver

s of c

hild

ren

with

CD

.h Pl

asm

a sa

mpl

es w

ill b

e co

llect

ed to

det

erm

ine

the

conc

entra

tion

of C

ZP e

very

12

wee

ks st

artin

g at

Wee

k 14

, and

at t

he C

ompl

etio

n/Ea

rly T

erm

inat

ion

and

SFU

Vis

its. S

ampl

es w

ill b

e co

llect

ed b

efor

e do

sing

(exc

ept f

or th

e C

ompl

etio

n/ET

and

SFU

Vis

its w

hen

ther

e is

no

dosi

ng).

i Ant

i-CZP

ant

ibod

y co

ncen

tratio

ns in

pla

sma

will

be

colle

cted

eve

ry 1

2w

eeks

star

ting

at W

eek

14, a

nd a

t the

Com

plet

ion/

ET a

nd S

FU V

isits

(ant

i-CZP

an

tibod

y m

easu

rem

ents

will

be

mad

e us

ing

the

sam

ples

take

n fo

r PK

mea

sure

men

ts a

t the

se ti

me

poin

ts, s

o ad

ditio

nal b

lood

dra

ws w

ill n

ot b

e re

quire

d).

j If h

ome

adm

inis

tratio

n is

per

form

ed, s

uffic

ient

stud

y dr

ug w

ill b

e di

spen

sed

at th

e sc

hedu

led

ever

y 12

-wee

k cl

inic

vis

it to

last

unt

il th

e ne

xt sc

hedu

led

clin

ic

visi

t.k If

a su

bjec

t has

not

bee

n pr

evio

usly

rein

duce

d in

C87

035,

the

subj

ect i

s elig

ible

for 1

rein

duct

ion

due

to lo

ss o

f res

pons

e in

CR

0012

.l M

easu

red

at W

eeks

14,

26,

38,

50

and

then

eve

ry 1

2 m

onth

s the

reaf

ter.

REDACTED

ll re

gull

regu

ute

win

ute

win

r chi

ldr

r chi

lder

’s

er’s

pp

COPY

catio

n.

catio

n

This do

cumen

t can

not b

e use

d

en n

to

n ev

eev

e

supp

ort

y dr

ugdr

ug

in C

87in

C8

any edd

aken

foak

en f

gw

marketi

ng

rodu

ctro

duc

of C

ZP e

of C

ZPr t

he C

oth

e C

d ev

erev

e

autho

rizati

on

For

For

larly

scar

ly sc

ndow

.do

w.

en. T

hn.

Th

appli

catio

n

Oth

er sa

fth

er sa

r subsu

b

non an

d an

dany yex

tensio

ns

ion/

n/

ar

ly

ly

min

ati

inat

ioooooor r

varia

tions

on

v

thereo

f.

08 M

08 M

UC

B08

May

2012

Clin

ical

Stu

dy P

roto

col

Cer

toliz

umab

peg

olC

R00

12

Con

fiden

tial

Page

22

of 1

19

5.3

Sche

mat

ic d

iagr

am

Figu

re5-

1:Sc

hem

atic

Dia

gram

CZP

=cer

toliz

umab

peg

ol; Q

4W=e

very

4 w

eeks

RRRRRRRRRRRREDACCCTTTTTTTTTTTTTTTTTTTTTEEEEEEEEEEEEEEEEEEED COPY

This do

cumen

t can

not b

e

ry 4y 4

used

4w

4w

dto su

pport

annnnnnyyyyyyy mmmmmmmmmmm

aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaarrrrrrkkkkkketi

ngg aaaaaaauu

thoriiiiiiiiiiiiiiizzzzzzzzzzzzz

aaaaaaaation

appli

catio

n aaaaaaaaaaaaaaand

aaaaannnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy

nsion

s

exxtttttttttteeeeeeeeeeeeeeen

s

or va

riatio

ns

onthe

reof.

08 M

08 M


Confidential of 119

5.4 Rationale for study design and selection of doseFollowing the Food and Drug Administration (FDA) approval of CZP for the treatment of CD in adults, C87035 was a postapproval commitment to investigate the administration of CZP administration in children and adolescents with moderately to severely active CD. This study will provide continued treatment of CZP to subjects who completed C87035 or were terminated from C87035 when the study was stopped by UCB and who, in the Investigator’s opinion, would benefit from continued administration of CZP.

The primary objective of this open-label study is to assess the longterm safety and tolerability of CZP in children and adolescents with moderately to severely active CD who completed C87035 or were terminated from C87035 when the study was stopped by UCB. The secondary objectives of this study are to assess the longterm efficacy, PK, and immunogenicity of CZP treatment on this population. Subjects may continue on CZP at the dose they were receiving at the end of C87035.

6 SELECTION AND WITHDRAWAL OF SUBJECTS6.1 Inclusion criteriaTo be eligible to participate in this study, all of the following criteria must be met:

1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent form is signed and dated by the subject or by the parent(s) or legally acceptable representative. The Consent form or a specific Assent form, where required, will be signed and dated by minors.

2. Subject/parent(s)/legally acceptable representative is considered reliable and capable of adhering to the protocol, visit schedule or medication intake according to the judgment of the Investigator.

3. Subject completed the C87035 study (Week 62 Visit) or was terminated from C87035 when the study was stopped by UCB and completed all assessments required for Week 62/Visit 23 at the time of termination.

4. Subject’s current or recent regimen of concomitant medication(s) for CD should be stable through the study period (see Section 7.8.1).

6.2 Exclusion criteriaSubjects are not permitted to enroll in the study if the following criterion is met:

1. Subject did not complete the C87035 study (Week 62 Visit) or was terminated from C87035 when the study was stopped by UCB but did not complete all assessments required for Week 62/Visit 23 at the time of termination.

6.3 Withdrawal criteriaSubjects (or represented by their parent[s]/legally acceptable representative[s]) are free to withdraw from the study at any time, without prejudice to their continued care. Whenever possible, cases should be discussed with the UCB Study Physician or designee prior to withdrawing the subject. All subjects withdrawn due to an AE must be followed until resolution of the event or until subject is stable.

REDACTEDnsent fsent minors.inors.

e repree reprehedulehedule

COPY nt Ethnt Eth

dateddatedf

This do

cumen

t 6.36.3ca

nnot

ect dct d870357035

requirequi

be

diddidus

ed xclcl

ot peot pe

to luslussu

pport

imim

recent recentperiodperiod

any by by U

me ofme ofmark

etinge or me or m

studystudyUCU

autho

rizati

ond byd by ththyyform oform o

esentasenta

appli

catio

n

criteriacriteri

ics Cocs Coh

andBJEJE an

y

C

exten

sions

eted ed e

on CZn CZ

olitylity varia

tions

there

of.


Confidential of 119

The Investigator may withdraw a subject from the study if in the opinion of the Investigator:

• The subject develops a clinically relevant medical condition that, in the opinion of the Investigator, jeopardizes or compromises the subject’s ability to participate in this study.

• The subject develops an intolerable AE, as determined by the subject and/or Investigator, which cannot be controlled by appropriate therapy.

• The subject fails to comply with the protocol.

• Other safety issues arise during the course of the study.

• Subjects who require any of the following therapies must be withdrawn from study participation:

− Anti-TNF therapy (other than CZP) or any biologic therapy for CD (eg, natalizumab)

− Immunosuppressants (eg, azathioprine/6-mercaptopurin, or methotrexate)

− Surgery related to exacerbation of CD (seton insertion per se is not to be considered surgery)

− Inpatient hospitalization for exacerbation of CD

• The subject becomes pregnant (as evidenced by a positive pregnancy test) or plans to become pregnant during the study.

• The Investigator feels that it is in the subject’s best interest to be withdrawn.

• Subjects must be withdrawn if requested by the Sponsor or a regulatory agency.

• Subjects who were reinduced once in C87035 cannot be reinduced in CR0012 and must be discontinued from CZP treatment at the time of loss of response.

• Subjects can undergo only 1 reinduction in this study; if response is lost a second time, the subject must be withdrawn from the study (see Section 5.1).

Any subject withdrawn from the study will be treated at the Investigator’s discretion as per standard clinical practice.

Investigators should attempt to obtain information on subjects, in the case of withdrawal or discontinuation. For subjects considered as lost to follow-up the Investigator should make an effort (at least 1 phone call and 1 written message to the subject), and document his/her effort (date and summary of the phone call and copy of the written message in the source documents) to complete the final evaluation. All results of these evaluations and observations, together with a narrative description of the reason(s) for removing the subject, must be recorded in the source documents. The case report form (CRF) must document the primary reason for withdrawal or discontinuation.

Investigators should contact the Medical Monitor whenever possible to discuss the withdrawal of a subject in advance.

REDACTED ect’s bect’s

sted bsted b

ce in Cce in C

COPY a posia pos

This do

cumen

tmustmustprimprim

cann

ot susu

ments) ents) ervatirvatit bt b

be ast 1st

ummummus

ed uldld

n. For For 1 p1 p

od attd attsu

pport

rom theom th

ice.ce.

anywn frwn f m

arketi

ng C870C870

nt at thet at th

inductinducfromfro

autho

rizati

on

best inbest i

y the the

0303

appli

catio

n

tive prive p

and s not not

any rexaterexatex

tensio

ns

dy dy

, natanata

or va

riatio

ns th

ereof.


Confidential of 119

7 STUDY TREATMENTS7.1 Description of investigational medicinal product(s)The investigational product will be supplied under the responsibility of the Sponsor. The frequency at which the investigational product will be supplied to each individual site will be adapted to the availability of the investigational product, and expiry date of the investigational product. Study drug will be managed by the Interactive Voice Response System (IVRS) in order to ensure all sites have sufficient quantities of study drug available.

Drug supplies will consist of the following (allocated based on dosing Table 7-1):

• 1mL syringes with 25G needles of CZP, containing an injectable volume of 1mL (equivalent to a dose of 200mg)

• 0.5mL syringes with 25G needles of CZP, containing an injectable volume of 0.5mL(equivalent to a dose of 100mg)

Certolizumab pegol (acetate pH 4.7) is an anti-TNF, humanized antibody Fab′ fragment conjugated with PEG.

7.2 Treatments to be administeredDetails on drug dispensing and administration will be provided in the Pharmacy Manual.

Certolizumab pegol will be administered by the Investigator/designee during clinic visits. After Week 2, home administration of CZP by the subject or parent/caregiver/appropriate designee as determined by the Investigator will be permitted between scheduled clinic visits. Subjects/caregivers who do not choose home administration will continue to have CZP administered every 4 weeks at the clinic.

All Investigators and designees will be given instructions on the administration of study drug.

The PFS should be allowed to reach room temperature for a minimum of 30 minutes before injection. The acclimatization time must be followed very strictly. The maximum time for the product at room temperature is 2 hours.

Injections will be given sc; suitable areas include upper arm, lateral abdominal wall, and upper outer thigh. Each injection should be administered at a separate injection site and a rotation between the injection sites should be observed for each injection. Treatment of the injection site with an anesthetic cream (containing lidocaine and prilocaine; eg, EMLA®) prior to dosing is permissible. Dosing will be administered based on the subject’s weight as specified in Table 7-1.

Following study drug administration, the used PFS must be disposed appropriately (eg, using a sharps container).

Subjects will be observed for possible AEs for 30 minutes after each dose of study drug (1 or 2 injections) is administered, whether at clinic visits or at home, and subjects and/or parents/caregivers will be asked to contact the Investigator in case any reactions occur within the 2 hours following study drug injection.

REDACTEDhe Invhe InvP byby ththy

ator wiator wse homse homnicni

COPY l be pl be p

This do

cumen

tolllla shaa sha

SS

cann

ot osios

ied in ed in

lowiowi

be e ww

sing sing us

ed EaE

en the n the withwith

ove

Eachachsu

pport

on tin titure is 2ure is

n sc; n sc; i

anyeacheach

timeim

marketi

ngme ame a

c.

l be givbe g

r

autho

rizati

onprovidprovi

vestigaestigahe subhe sub

ill be ll beadad

appli

catio

nntibodntibo

ded

and

dd

anyolumolu ex

tensio

ns

f 1mL 1mL

umeme

or va

riatio

ns th

ereof.


Confidential of 119

The concentration of CZP is 200mg/mL. Depending on the dose, injections will be given sc as 1 or 2 injections of 1mL each resulting in doses of 200 and 400mg, respectively, or as 1 injection of 0.5mL resulting in a dose of 100mg. To achieve the appropriate doses, injections are administered as follows:

For subjects in the High-Dose Group (weight adjusted) CZP 400mg/200mg Q4W:

• Subjects weighing 20 to <40kg (44 to <88lbs): 1 injection of 1mL

• Subjects weighing ≥40kg (≥88lbs): 2 injections of 1mL each

For subjects in the Low-Dose Group (weight adjusted) CZP 200mg/100mg CZP Q4W:

• Subjects weighing 20 to <40kg (44 to <88lbs): 1 injection of 0.5mL

• Subjects weighing ≥40kg (≥88lbs): 1 injection of 1mL

Dosages and injections needed to achieve this dose are also presented in Table 7-1.

A subject should only change dosing category during the course of the study if his/her weight increases by >2kg (4.4lbs) (measured at a clinic visit only) AND crosses the 40kg/88lb boundary (eg, a subject’s weight increases from 39 to 41kg (from 85.8 to 90.2lbs). No dose adjustment is made for a weight decrease. In the event of a dose increase, the first injection of the higher dose must be administered at a clinic visit for all subjects, including those subjects performing home administration.

Table 7-1. Doses of CZP in CR0012

CZP dose (mg) injectionsa

Treatment group High-Dose Group Low-Dose GroupDose frequency Q4W Q4W

Subject weight20 to <40kg (44 to <88lbs) 1x1mL PFS/200mg 1x0.5mL PFS/100mg≥40kg (≥88lbs) 2x1mL PFS/400mg 1x1mL PFS/200mg

CZP=certolizumab pegol; PFS=prefilled syringe; Q4W=once every 4 weeks

Prior to CZP administration at home, subjects/caregivers/appropriate designee as determined by the Investigator will be trained by the site staff and provided written instructions on the schedule and fixed dose for injection, and the correct sc injection technique including 0.5ml and 1ml injections, as appropriate. Starting at Week 2, subjects/caregivers/appropriate designee as determined by the Investigator may administer the study medication under the supervision of the site staff to ensure that the study medication is being properly and safely injected. Once subjects/caregivers/appropriate designee as determined by the Investigator have been trained, the study medication may be administered at home. If administered at home, the subject/caregiver/appropriate designee as determined by the Investigator is requested to document the container number, date, and time point of administration of study

REDACTED visvis

01212ED

COPY41kg41kvent ofvent oisit fsit

This do

cumen

t nd d desigdesigsusu

cann

otnvesnvesdule adule a1m1m

beZP adZP adtiti

used

toegol;gol; su

pport

8lbs)lbs)tpo

PFPsu

any yynyamark

eting

HighHigeti

n

arm

autho

rizati

onf a da

for allfor all

a

appli

catio

n of the sof theND croND cr

g (from(fromdosdos

and in in TaTa

any e

xtens

ions

W:W:or

varia

tions

there

of.


Confidential of 119

medication. All used PFSs will be disposed of by subjects/caregivers/appropriate designee as determined by the Investigator in an acceptable disposal (sharps) container directly after the administration. The subjects/caregivers return the documentation together with any used/unused containers at the next scheduled clinic visit. Subjects who are unable to selfadminister the study treatment, those without a caregiver who can help, or those who choose not to self-inject, will continue to visit the clinic for study treatment administration between regular scheduled visits. In addition, subjects will have the option to either switch to home dosing or switch back to clinic administration at anytime during the study.

7.3 PackagingEach site will receive uniquely numbered PFSs. The PFSs will be packaged in individual protective containers with a uniquely numbered carton.

7.4 LabelingClinical drug supplies will be labeled in accordance with the current International Conference on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing Practice and will include any locally required statements. If necessary, labels will be translated into the local language.

Each PFS will be inserted into a labeled individual container. Only the tear-off section (left section) of the label will be attached to the CRF at the time of administration (or dispensing to the subject/caregiver/appropriate designee as determined by the Investigator for home administration) to the subject, and the main section which will remain affixed to the individual container.

Prefilled syringes used for administration will be labeled with the same unique identifier (MED ID) as on the individual container.

Name, address and phone number of the Investigator will be included on the subject identification card (see Section 14.2).

7.5 Handling and storage requirementsThe Investigator (or designee) is responsible for the safe and proper storage of IMP at the site. Investigational medicinal product stored by the Investigator is to be kept in a secured area with limited access. All investigational products must be stored refrigerated at 2 to 8ºC (35 to 46°F) and protected from light.

Appropriate storage conditions must be ensured either by controlled room temperature (2 to 8ºC [35.6 to 46.4°F]), or by completing a temperature log in accordance with local requirements but at least once a day during the business week, with minimum and maximum temperatures reached over the time interval.

In case an out-of-range temperature is noted, it must be immediately communicated to the Sponsor before further use of the IMP.

The Clinical Project Manager (or designee) will transmit the out-of-range temperature (copy of the temperature log, duration of the out-of-range temperature, if available) to the Drug Supply Coordinator. Based on discussion with Quality Assurance, the Drug Supply

REDACTEDdetdesectionection

tion wtion wineriner

COPYntainntaithe timthe ti

etermter

This do

cumen

t In caIn caSS

cann

otC [35[35

remenemenperatperat

bee stosto5 65

usedd protprot

oraora

tocessces supp

ort andn

ignee) gnee)edicinedicins

any .

d std stmark

eting

will illr.

f the the InI22).).

autho

rizati

onme me

rminedminedn whicwhi

l bebe

appli

catio

n)

ementsment

er. Onlr. Onofof

andernarna

and Gand an

y atioati

exten

sions

vidualidual

or va

riatio

ns th

ereof.


Confidential of 119

Coordinator will then provide the Clinical Project Manager (or designee) with instructions for the site regarding use of the IMP.

For IMP dispensed to the subject/caregiver/appropriate designee as determined by the Investigator for home dosing, the Investigator (or designee) will instruct the subject/caregiver/appropriate designee as determined by the Investigator to store the IMP following the instructions on the label. Cooler bags with freezer packs will be provided to transport home dosing supplies.

7.6 Drug accountabilityA Drug Accountability form will be used to record IMP dispensing and return information on a by-subject basis and will serve as source documentation during the course of the study. Details of any IMP lost (due to breakage or wastage), not used, disposed of at the study site, or returned to the Sponsor or designee must also be recorded on the appropriate forms. All supplies and pharmacy documentation must be made available throughout the study for UCB (or designee) to review.

Copies of completed dispensing records will be collected. Periodically and at the end of the study, all unused and expired investigational product (PFSs and container) will be collected and sent to the Sponsor (or designee) for destruction. All used PFSs will be disposed of by site staff in an acceptable disposal (sharps) container directly after the administration. All containers of the used PFSs must be kept until the accountability is checked by the monitor and can be destroyed afterwards.

The Investigator (or designee) is responsible for retaining all used and unused containers of IMP until returned or destroyed.

For home administration, any used/unused containers should be stored in provided containers and returned at the next clinic visit.

The Investigator may assign some of his/her duties for drug accountability at the study site to an appropriate pharmacist/designee.

Investigational medicinal product intended for the study cannot be used for any other purpose than that described in this protocol. The Investigator must ensure that the IMP is used only in accordance with the protocol.

7.7 Procedures for monitoring subject complianceSubjects are expected to receive all doses of study drug as detailed in the schedule of assessments (Section 5.2). Any subject who deviates from the dosing schedule or misses any scheduled treatment should be reported to the Medical Monitor for determination of possible schedule adjustments and continued eligibility. These instances will be handled on a case-by-case basis.

At each visit after IMP is dispensed, subjects must return all unused IMP and empty IMP containers. Drug accountability must be done in the subject’s presence in order to obtain explanations regarding discrepancies in compliance with the dosing regimen. Drug accountability must be recorded on the Drug Accountability form.

ble forble for

nusenuse

COPY All ulr direcr direc

accoacco

This do

cumen

tcase ase

AA

cann

ot ntsnts

uled trled tedule dule

bb

be exex

s (s (SSus

edProcrocxpxpecec

to prp

cesu

pportprodurodu

his prots prorotocotoc

any gnee.gneemark

etinged coned con

of hisof hi

autho

rizati

onountabunta

r retainr retain

appli

catio

ncallcally ay d contaiconta

ed PFSsd PFStlyly aftafyybi

and a

ny ateate

the stthe sex

tensio

ns

mation mation studstudyy

he stue stue foe fo

or va

riatio

ns th

ereof.


Confidential of 119

If a subject is found to be persistently noncompliant (missing 2 or more consecutive scheduled IMP doses or missing 3 or more doses), the Sponsor in conjunction with the Investigator will make a decision as to whether the subject should be withdrawn from the study.

7.8 Concomitant medication(s)/treatment(s)The subject must not participate in any other clinical study or receive any unauthorized medication during the study period.

Should any treatment other than the investigational product be used, including over-the-counter products, an accurate record must be kept in the clinic chart (source documentation) and the CRF. This record should include the name of the drug, the dose, the date(s) of administration, and the indication for use.

7.8.1 Permitted concomitant treatments (medications and therapies)Subjects should keep concomitant medications for CD (eg, aminosalicylates) stable through the study period.

Topical hydrocortisone for skin disorders or not more than 800μg per day inhaled beclomethasone, or equivalent, for asthma are permitted.

Subjects who use antidiarrheals on an as-needed basis should continue their use as required and at the usual dose.

Shortterm antibiotic use for the treatment of acute infections is permitted during the study.

Oral contraceptive use should continue at a stable medication and dose, if already used at C87035 entry. If a subject becomes sexually active during the study, acceptable methods of birth control (eg, oral contraceptives) should be employed.

If a subject experiences a concomitant illness requiring pain relief (eg, headache) during the course of the study, non-narcotic opiate analgesia (eg, ibuprofen) is recommended.

Subjects should not receive any live or attenuated vaccination during the study, or within 3 months after last dose of study drug. If a subject is scheduled for vaccination during the study, the Investigator must contact UCB or its representative to discuss the type of vaccination planned.

Treatment of the injection site with an anesthetic cream (containing lidocaine and prilocaine; eg, EMLA®) prior to dosing is permissible. Its use will be recorded as concomitant medication on the CRF.

Tuberculosis prophylactic treatment should be captured in the concomitant medication page of the CRF.

Other concomitant medications and doses for conditions other than CD may be adjusted as clinically appropriate during the study period. Any changes in concomitant medications must be recorded in the CRF.

REDACTED acute acute

at a staat a staexuallexuallshsh

COPY d.d.

sis shosis s

This do

cumen

t OtheOtheclc

cann

ot n

rculosculoshe CRhe C

be pp

on ton tus

ede injee injeprior rior

to d. su

pport

annyf studyf stud

must cmust

any opop

y livy limark

eting

lyy aayyhould bould b

ant illnnt illnpiatepiat

autho

rizati

on ou

e infecinfec

able mble mactiact

appli

catio

n μg per dg per

uld cold co

andylateslate an

yd thed ths))

exten

sions

e dosedose

heh

or va

riatio

ns th

ereof.


Confidential of 119

7.8.2 Prohibited concomitant treatments (medications and therapies)Use of corticosteroids or corticotrophins for indications other than CD is not permitted. However, topical hydrocortisone for skin disorders or not more than 800μg per day inhaled beclomethasone, or equivalent, for asthma is permitted.

Concomitant use of the following immunosuppressants is not permitted:

• Azathioprine, 6-mercaptopurine, or methotrexate

• Mycophenolate or thalidomide

• Cyclosporine or tacrolimus

Use of any experimental unregistered therapy or biological therapy (within or outside a clinical study) or participation in any clinical study using nonbiological therapies is not permitted.

7.8.3 Rescue therapySubjects who require the following defined rescue therapy to treat an exacerbation of CD at any time during the study will be treated as treatment failures from and including the time of receiving rescue therapy. For the purpose of this study, the defined rescue therapy which would classify the subject as treatment failure is as follows:

• Anti-TNF therapy (other than CZP) or any biologic therapy for CD (eg, natalizumab)

• Immunosuppressants (eg, azathioprine/6-mercaptopurin, or methotrexate)

• Surgery related to exacerbation of CD (seton insertion per se is not to be considered surgery)

• Inpatient hospitalization for exacerbation of CD

• Increase of corticosteroid dose above Week 0 of C87035 levels as defined below:

− For subjects not taking corticosteroids at Week 0 of C87035◦ Any dose ≥10mg/day prednisone (or equivalent) is considered rescue therapy

− For subjects taking corticosteroids at Week 0 of C87035◦ Any increase ≥50% of the Week 0 dose is considered rescue therapy

◦ OR

◦ Any dose >40mg/day prednisone (or equivalent) is considered rescue therapy

7.9 Enrollment and numbering of subjectsTo enroll a subject, the Investigator must contact the IVRS. Subjects will retain the unique subject number allocated in C87035. This unique subject number will be required in all communications between the Investigator (or designee) and the IVRS regarding a particular subject. The IVRS will allocate container numbers to the subjects based on the unique subject

REDACTEDy biolobiol

e/6-/6-meme

f CD (f CD (

COPYyy, the, ths follos follo

This do

cumen

t 7.97.9TT

cann

ot ◦ AAbe

OROR used

y incincy r

totaktak supp

orting cng c

10mg/d0mg

ini

anyse ase a

cor

marketi

ng (setset

cerbatierbat

aboab

autho

rizati

on ows:ws:

ogic thogic th

ercaptercapt

etonton

appli

catio

n at an ext an efrom afrom

definedefin

and a

nyapieapi ex

tensio

ns

outsidutsideses

or va

riatio

ns th

ereof.


Confidential of 119

number during the course of the study. Subject numbers and container numbers will be tracked via the IVRS and also will be required to be entered into the CRF.

The IVRS will allocate containers of study medication as appropriate to the visit schedule.

8 STUDY PROCEDURES BY VISITDuring the study, the acceptable window between the study visits is +/-7 days relative to entry (Week 0).

8.1 Entry Week 0 Week 0 of CR0012 is equivalent to Week 62 of C87035 with the exceptions noted below. Subjects who were terminated from C87035 when the study was stopped by UCB completed all assessments required for Week 62/Visit 23 at the time of termination.

Before any study-related procedures are performed, an IRB/IEC approved informed consent will be properly executed and documented. The written informed consent of the child’s parent(s)/legally acceptable representative(s) must be obtained. In addition, where requested by local laws or by the IRB/IEC and according to the child’s age/competence, the Assent form should be obtained from the child. The subjects and their parent(s)/legally acceptable representative(s) will be given adequate time to consider any information concerning the study given to them by the Investigator or designee. As part of the informed consent procedure, subjects and their parent(s)/legally acceptable representative(s) will be given the opportunity to ask the Investigator any questions regarding potential risks and benefits of participation in the study.

Assessments to be performed include:

• Written informed consent

• Inclusion/ exclusion criteria

• Demography

• TB test

• TB questionnaire

The following ongoing information must be continued to be followed from C87035 to CR0012:

• Adverse events

• Concomitant medications

8.2 Week 2 Visit• Vital signs

• Adverse events


REDACTEDons reons reCOPY er ar As paAs pa

eptabeptab

This do

cumen

t 8.28.2

cann

ot rses

oncomncobe

e eve ev

usedngoingoi to ng

supp

ort an

y mark

eting

autho

rizati

onble reple regardinardin

appli

catio

nompeompparent(arent

y informinforrt of tht of t

and nt ot o

dition,itionan

ynformnforof thof th

exten

sions

elow. low.

compcomp

or va

riatio

ns th

ereof.


Confidential of 119

• Concurrent medical procedures

• Study drug administration (including training and self-injection under supervision, as appropriate)

• Dispensing of drug to subject/caregiver/appropriate designee as determined by the Investigator, if appropriate for home dosing

8.3 Phone call (home administration) or visit (clinic administration) (every 4 weeks and in between regular clinic visits beginning at Week 6)

After Week 2, subjects and/or parents/caregivers have the option of home administration of CZP upon appropriate training during a previous clinic visit(s) or can continue to have CZP administered every 4 weeks at the clinic. For subjects performing home administration, a phone call to the subject and/or the parents/caregiver will be performed by the Investigator (or designee) every 4 weeks between regular clinic visits. Subjects will have the option to either switch to home dosing or switch back to site administration at anytime during the study.

Assessments performed during the phone call or at the clinic visit include:

• Adverse events



• Study drug administration (check for compliance)

8.4 Regular clinic visits 8.4.1 Assessments every 12 weeks beginning at Week 14• Assessment of childbearing potential (female subjects only)

• Urine pregnancy test (female subjects of childbearing potential only)

• Physical examination


• Tanner stage

• Weight and height

• Vital signs

• Adverse events



• PCDAI

REDACTED

for comor co

COPY

This do

cumen

t •• AAca

nnotight aght a

VitalVital

bestagagus

ednaireaire

gege

to ati su

pport

ngg

(fema(fema

ionon

any

g poteg potemark

eting

its ts

ery 1ery

autho

rizati

on

mplianplian

appli

catio

n an

visit invisit in

andhavhav

nnytytimian

y the Ihe Inve thve

exten

sions

rationation

o havehaveistratstrat

or c c va

riatio

ns th

ereof.


Confidential of 119

• ESR/hematocrit/albumin for PCDAI

• CRP

• Hematology, clinical chemistry, and urinalysis

• Certolizumab pegol plasma concentration

• Anti-CZP antibody plasma concentration

• Autoantibody concentrations (ANA and anti-dsDNA)



8.4.2 Assessments at Weeks 14, 26, 38, 50 and then every 12 months thereafter:

• IMPACT III

• WPAI:CD (for children, for working individuals with CD, and for caregivers)

• Bone markers (osteocalcin, bone specific alkaline phosphatase, n-telopeptides)

8.5 Completion/Early Termination Visit• Assessment of childbearing potential (female subjects only)




• Tanner stage


• Vital signs

• Adverse events



• PCDAI


• CRP


• IMPACT III

• WPAI:CD (for children, for working individuals with CD, and for caregivers)

REDACTEDatioatiofemalfemal

ects ofects of

COPY ithth

ne phne ph

on

This do

cumen

tEE••

cann

ot urrur

CDACDA

ESES

be

rentrentus

ed ss

ant mnt m

to su

pport

any m

arketi

ng f c au

thoriz

ation

hosposp

n VisVisle subje subj

childchild

appli

catio

n

D,, and fand

sphatpha

and vere an

y ry 1ry

exten

sions

as as

byby ththyy

or va

riatio

ns th

ereof.


Confidential of 119





8.6 Reinduction visitsLoss of response must be confirmed at a clinic visit where assessments and labs are performed to determine PCDAI score. Scores cannot be confirmed until lab results are received by central lab a few days after the clinic visit. Once loss of response is confirmed, sites must contact the subject to return for the first Reinduction Visit.

Reinduction Week 0 assessments:

• PCDAI (using the ESR, hematocrit, and albumin results of the same visit)

• ESR, hematocrit, and albumin

• IMPACT-III

• WPAI:CD for children and/or WPAI:CD for working individuals

• WPAI:CD for caregivers of children with CD







• WPAI:CD for children and/or WPAI:CD for working individuals

• WPAI:CD for caregivers of children with CD

• Study drug administration will be performed at the clinic for all Reinduction injections (Weeks 0, 2, and 4). Subject resumes original schedule of clinic visits after reinduction. The clinic should contact the Study Monitor to determine the most appropriate way to resume the original schedule of clinic visits.

8.7 Unscheduled Visit• Vital signs

• Adverse events

REDACTED D

rit, andit, and

COPYrking king

This do

cumen

trere88

anno

tdyy dr dryyWeeksWeeks

The The

be

ruruus

ed

for cafor catohildhild su

pporthemhem

nd albud alb

dren

any : :

matma

marketi

ng d alal au

thoriz

ation

albulbu

appli

catio

n

ndividndivi

ande visvis an

y sit)it

exten

sions

e nfirmenfirme

or va

riatio

ns th

ereof.


Confidential of 119



Other safety and PK assessments (eg, CZP plasma sample) may be performed at the discretion of the Investigator as related to the nature of the visit.

8.8 Safety Follow-Up VisitThe SFU Visit is to be completed by all subjects 12 weeks after the final dose of study medication. For subjects who continue directly onto commercial CZP, a SFU Visit should be completed prior to the first dose of commercial drug administration.




• Vital signs

• Adverse events







9 SAFETY ASSESSMENTS9.1 Adverse eventsAdverse event information (duration, intensity, relationship to study drug, action taken, outcome, and seriousness will be recorded) will be obtained by observation and direct questioning of the subject and his/her parent(s)/legally acceptable representative(s), eg, “have you had any (other) medical problems since your last visit?” or “have you felt different in any way since your last visit?”

Ongoing AEs from C87035 will continue to be followed in CR0012. Adverse events will be assessed taken throughout the course of the study will be collected at every visit, phone contacts, and Unscheduled Visits.

9.1.1 Definition of adverse eventAn adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and

REDACTED nalnalysysisis

rationration

ntratntrat

COPY

This do

cumen

tsecontaconta

99

cann

ot yy

oing Aing Aessedssed

be (o(

youryourus

edouou

the suhe suotheothe

tousneusnesu

pport

eveneve

ation tion

any SSSESSEmark

eting

tiontion

NA andNA an

autho

rizati

on

s

appli

catio

n and

any e

xtens

ionsuld buld or bebe

varia

tions

there

of.


Confidential of 119

unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

In order to ensure complete safety data collection, all AEs occurring during the study (ie, after signing the Informed Consent form), including any pretreatment and posttreatment periods required by the protocol, must be reported in the CRF even if no investigational product was taken but specific study procedures were conducted. This includes all AEs not present prior to the initial visit and all AEs which recurred or worsened after the initial visit.

Signs or symptoms of the condition/disease for which the investigational product is being studied should be recorded as AEs only if their nature changes considerably or their frequency or intensity increases in a clinically significant manner as compared to the clinical profile known to the Investigator from the subject’s history or the Baseline Period (Week 0 of C87035).

9.1.2 Procedures for reporting and recording adverse eventsBesides the Investigator’s observations, the subject will be given the opportunity to report AEs spontaneously. A general prompt will also be given at each study visit to detect AEs, for example:

“Did you notice anything unusual about your health (since your last visit)?”

In addition, the Investigator should review any self-assessment procedures employed in the study.

9.1.3 Description of adverse eventsWhen recording an AE, the Investigator should use the overall diagnosis or syndrome using standard medical terminology, rather than recording individual symptoms or signs. The CRF and source documents should be consistent. Any discrepancies between the subject’s own words on his/her own records (eg, diary) and the corresponding medical terminology should be clarified in the source documentation.

Details for completion of the Adverse Event CRF (including judgment of relationship to study medication) are described in the CRF completion guidelines.

9.1.4 Follow-up on adverse eventsAn AE should be followed until it has resolved, has a stable sequelae, the Investigator determines that it is no longer clinically significant, or the subject is lost to follow-up.

If an AE is still ongoing at the end of the study for a subject, follow-up should be provided until resolution/stable level of sequelae, the Investigator no longer deems that it is clinically significant, or until the subject is lost to follow-up. If no follow-up is provided, the Investigator must provide a justification. The follow-up will usually be continued for12 weeks after the subject has discontinued their IMP.

9.1.5 Rule for repetition of an adverse eventAn increase in the intensity of an AE should lead to the repetition of the AE being reported with:

REDACTEDsselfelf

se evese eveator sator s

COPY yyour ou

ff a

This do

cumen

tignigniInveInve11

cann

otE is sE is sl resolreso

nificific

bethatthat us

ed l

be fobe fot itt it

to owow supp

ort

the Adthe Adescribescrib

u

any , d, d

mentamentamark

etingshouldhoul

han rechan rensistennsiste

diarydiar

autho

rizati

on he

assessmssess

entsentsd

appli

catio

nhe ope oph studystudy

ealthalth

ande eve ev

pp

any

en

exten

sions

ing ng

o the cthe criod (Wod (

or va

riatio

ns th

ereof.


Confidential of 119

• The outcome date of the first AE that is not related to the natural course of the disease being the same as the start date of the repeated AE, and the outcome of “worsening”,

• The AE verbatim term being the same for the first and repeated AE, so that the repeated AE can be easily identified as the worsening of the first one.

9.1.6 PregnancyShould a subject become pregnant after the first intake of any IMP, UCB’s Global Clinical Safety and Pharmacovigilance (GCSP) department should be informed immediately. The subject should be withdrawn from the study as soon as pregnancy is known and the following should be completed:

• The subject should return for an early discontinuation visit.

• The subject should immediately stop the intake of the investigational medicinal product or be down-titrated as instructed at the early discontinuation visit.

• An SFU Visit should be scheduled 12 weeks after the subject has discontinued their IMP.

The Investigator must inform the subject of information currently known about potential risks and about available treatment alternatives.

In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, UCB will ask the Investigator or designee to contact the subject and his partner to request consent via the Partner Pregnancy Consent form. If the partner agrees to provide additional information, the Pregnancy Report and Outcome form will be forwarded to the subject’s partner for completion.

The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be followed-up using the Pregnancy Report and Outcome form in which the Investigator has to report on the health of the mother and of the child. The health of the child must be followed for 30 days after birth for any significant medical issues.

In certain circumstances, UCB may request that follow-up is continued for a period longer than 30 days.

A pregnancy becomes a serious adverse event (SAE) in the following circumstances: miscarriage, abortion, or anomaly/birth defect of the child. Those SAEs must be additionally reported using the Investigator SAE Report form.

9.1.7 Overdose of investigational medicinal productExcessive dosing (beyond that prescribed in the protocol and including overdose) should be recorded in the CRF. Any SAE or nonserious AE associated with excessive dosing must be followed as any other serious or nonserious AE. These events may be symptomatic, in that the excessive dosing results in clinical signs and symptoms, or the excessive intake may itself be a symptom.

rollerolleo contao conta

nt formt ford Outcd Outc

COPYon cuon c

eded

This do

cumen

tExceExcerecrec

cann

otd usinusin

7

bee, abe, abngng

used

becomecom

to nc su

pport

e momor birth birth

es, Ues, U

anyancyancy

motheoth

marketi

ng co

on the Pn the of the pf the

R

autho

rizati

on

in a cn a cact thect the

m. If tm. If tome fme

appli

catio

n

rentlently y

and has dias di

any mem

n visin visex

tensio

ns ow

mediedi

orwingingva

riatio

ns th

ereof.


Confidential of 119

9.1.8 Safety signal detectionSelected data from this study will be reviewed periodically to detect as early as possible any safety concern(s) related to the IMP so that Investigators, clinical study subjects, regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible.

The Study Physician or medically qualified designee/equivalent will conduct an ongoing review of SAEs and perform ongoing SAE reconciliations in collaboration with the GCSP representative.

As appropriate for the stage of development and accumulated experience with the IMP, medically qualified personnel at UCB may identify additional safety measures (examples: AEs, vital signs, laboratory or electrocardiogram [ECG] results) for which data will be periodically reviewed during the course of the study.

Refer to Section 13.8 for details on the DSMB used in this study.

9.2 Serious adverse events9.2.1 Definition of serious adverse eventOnce it is determined that a subject experienced an AE, the seriousness of the AE must be determined. An SAE must meet 1 or more of the following criteria:

• Death

• Life-threatening

(Life-threatening does not include a reaction that might have caused death had it occurredin a more severe form.)

• Significant or persistent disability/incapacity

• Congenital anomaly/birth defect (including that occurring in a fetus)

• Important medical event that, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the other outcomes listed in the definition of serious

• (Important medical events may include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias that do not result in inpatient hospitalization, infections that require treatment with parenteral antibiotics, or the development of drug dependency or drug abuse.)

• Initial inpatient hospitalization or prolongation of hospitalization

(A patient admitted to a hospital, even if released on the same day, meets the criteria for the initial inpatient hospitalization. An emergency room visit that results in admission to the hospital would also qualify for the initial inpatient hospitalization criteria. However, emergency room visits that do not result in admission to the hospital would not qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the definition of serious [eg, life-threatening adverse experience, important medical event]).

REDACTED

eactionaction

/in/in

COPYwingwin

This do

cumen

t(A(tca

nnotal inl in

(AA

be lopp

npnpus

edn en e

ospitalspitalpmepme

toemeemesu

pport

d mmted in ed in

l evenl eve

anyt, bat, ba

maymay rymark

eting

ncapacicapaci

t (inclu(incl

ase

autho

rizati

on

n that n that

appli

catio

n iousneiousn

criteriariteri

and a

ny ex

tensio

ns

ples: ples: ll be l be

or va

riatio

ns th

ereof.


Confidential of 119

Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned surgery or elective surgery for a pre-existing condition that has not worsened or manifested in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a subject has a condition recorded on his/her medical history and later has a preplanned surgery for this condition, it is not appropriate to record the surgery or hospitalization as an SAE since there is no AE upon which to assess the serious criterion. Please note that, if the pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, this would then qualify as an AE and, if necessary, the seriousness of the event would need to be determined.)

9.2.2 Procedures for reporting serious adverse eventsIf an SAE is reported, UCB must be informed within 24 hours of receipt of this information by the site (see contact numbers for SAE reporting listed in the SAE Reporting section at the front of the protocol). The Investigator must forward to UCB (or its representative) a duly completed Investigator SAE Report form provided by UCB, even if the data are incomplete, or if it is obvious that more data will be needed in order to draw any conclusions. Information recorded on this form will be entered into the global safety database.

An Investigator SAE Report form will be provided to the Investigator. The Investigator SAE Report form must be completed in English.

Additional information (eg, autopsy or laboratory reports) received by the Investigator must be provided within 24 hours. All documents in the local language must be accompanied by a translation in English, or the relevant information included in the same document must be summarized in the Investigator SAE Report form.

The Investigator is specifically requested to collect and report to UCB (or its representative) any SAEs (even if the Investigator is certain that they are in no way associated with the investigational product), up to 12 weeks from the end of the study for each subject, and to also inform participating subjects of the need to inform the Investigator of any SAE within this period. Serious adverse events that the Investigator thinks may be associated with the investigational product must be reported to UCB regardless of the time between the event and the end of the study.

Upon receipt of the SAE form, UCB will perform an assessment of expectedness of the reported SAE .The assessment of the expectedness of the SAE is based on the Investigator’s Brochure.

9.2.3 Follow-up of serious adverse eventsAn SAE should be followed until it has resolved, has a stable sequelae, the Investigator determines that it is no longer clinically significant, or the subject is lost to follow-up.

Information on SAEs obtained after clinical database lock will be captured through the GCSP database without limitation of time.

9.3 Adverse events of interestAn AE of special interest is any AE which is listed in the European Risk Management Plan, or meets another commitment requiring nonstandard expedited reporting, even if the AE does

the the mationmation

port foport fo

sted tsted t

COPY repreporoll

This do

cumen

tInnforfordada

cann

ot AE shoE shoerminrmin

beFus

ed he ase a

F

to SAasseasse

supp

ortst be be

AE foAE fo

anyents thents t

e ree re

marketi

ng to coo co

ertain thrtain theeks froeks fr

of the of theh

autho

rizati

onrts) rerts) rocal lacal la

n incluincluorm.m.

olloll

appli

catio

n se.se.

stigatostigat

ec

and datadat

oncluoncluan

yntativntatita arta a

exten

sions

nformnformg sectsect

or va

riatio

ns th

ereof.


Confidential of 119

not fulfill the expedited reporting criteria of “serious”, “unexpected”, and “associated with the use of the drug.” Adverse events of special interest include:

• Serious infections including opportunistic infections

• Malignancies including lymphoma

• Congestive heart failure

• Demylinating-like disorders

• Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leucopenia

• Serious bleeding events

• Lupus and lupus-like illness

• Serious skin reactions (eg, Stevens Johnson Syndrome, toxic epidermal necrosis, and erythema multiforme)

9.4 Immediate reporting of adverse eventsThe following AEs must be reported immediately:

• SAE: AE that the Investigator classifies as serious by the above definitions regardless of causality

• Suspected transmission of an infectious agent via a medicinal product

• AE of interest (see Section 9.3)

9.5 Laboratory measurementsHematology assessments will include the following parameters: red blood cell (RBC) count, hemoglobin, hematocrit, platelets, white blood cell (WBC) count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils.

Clinical chemistry assessments will include the following parameters: Sodium, potassium, total calcium, glucose, creatinine, urea, total protein, albumin, alkaline phosphatase, gamma glutamyl aminotransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin.

For urinalysis, urine protein and blood will be measured by the dipstick method. If positive, microscopic assessments will be done for WBC, RBC, and casts and microbiological culture will be undertaken.

Hematology, clinical chemistry, and urinalysis parameters will be assessed at entry Week 0, every 12 weeks starting at Week 14, and at the Completion/Early Termination (ET) and SFU Visits.

Instructions on blood sample collection, processing, storage, and shipping will be provided in the laboratory manual for this study.

REDACTED agent agent

COPY ous byus b

This do

cumen

tHememeveeveVV

cann

otopicpice undund

matomato

besis, uis, c ac a

usedn

se (ALe (AL

urur

tosfersfer supp

ort baba

smentsment, creatcrea

anyts, wts, w

asophasopmark

eting

remeneme

ude thede thwhi

autho

rizati

on y thy

via a via a

appli

catio

n

he abhe ab

and a

nynecrnecrexte

nsion

s or v

ariati

ons t

hereo

f.


Confidential of 119

For subjects undergoing reinduction, the parameters ESR, hematocrit, and albumin will be measured at Reinduction Weeks 0, 2, and 4.

9.6 Other safety measurements9.6.1 DemographicsDemographics (date of birth, sex, and race) will be recorded at entry Week 0.

9.6.2 Assessment of childbearing potentialFor female subjects, childbearing potential will be assessed every 12 weeks starting at Week 14, and at the Completion /Early Termination Visits.

9.6.3 Pregnancy testFor female subjects of childbearing potential, urine pregnancy tests will be performed every 12 weeks starting at Week 14, and at the Completion/ET and SFU Visits.

9.6.4 Physical examinationGeneral appearance, ears, nose, throat, eyes, hair and skin, respiratory, cardiovascular, gastrointestinal, musculoskeletal, hepatic, neurological, and mental status will be assessed. Abnormalities will be recorded as an AE. Physical examination assessments will be performed every 12 weeks starting at Week 14, and at the Completion /ET and SFU Visits.

9.6.5 Tuberculin testAll sites may use either the purified protein derivatives (PPD) skin test or QuantiFERON®-TB GOLD test. Use of QFT-GOLD is acceptable provided the site has experience in organizing the QFT-GOLD testing; either the central laboratory or a local laboratory may be used. The test will be performed at entry Week 0.

Subjects who experience close contact with an individual with active TB during the conduct of the study must be referred to a physician specializing in TB to perform additional evaluations to exclude latent/active TB before subject may resume study treatment. Subjects who prematurely discontinue treatment for latent TB or who are noncompliant with prophylactic therapy must immediately discontinue further administration of study drug but need to complete the ET/SFU Visits.

9.6.5.1 Mantoux tuberculin skin test (PPD test)A Mantoux tuberculin skin test (PPD test) will be performed following the instructions below. Multiple puncture tests like the Tine and Heaf tests are not acceptable methods of testing because the amount of tuberculin injected intradermally cannot be precisely controlled.

The intradermal injection of a measured amount of tuberculin is the standard method of detecting infection with Mycobacterium tuberculosis. One-tenth milliliter of PPD (5 TU PPD-S or 2TU of PPD-RT 23, as recommended by the World Health Organization) is injected into the inner surface of the forearm. Other areas may be used, but the forearm is preferred. The use of a skin area free of lesions and away from veins is recommended. The injection is made using a one-quarter- to one-half-inch (1cm), 27-gauge needle and a tuberculin syringe. The tuberculin should be injected by a qualified health care worker just

REDACTED derivaderiva

QFT-QFT-GGOLD teOLD te be be

COPY mimat theat the

This do

cumen

tThe ihe idetdet(

cann

otbecaubecauolledolled

ii

beltipleltipl used

antntbercubercu

to ntoutousu

pport

ue tree trst immt imm

ET/SFUT/SFU

any

pptiveive T

reatrea

marketi

ng ests

perforperfor

act withct witphhysysici

autho

rizati

on

ativesativesGOLDGOLD

tinging

appli

catio

ntorytory, c,ental stantal s

ion asson asCompComp

and a

ny ex

tensio

ns

formform

or va

riatio

ns th

ereof.


Confidential of 119

beneath the surface of the skin, with the needle bevel upward. A discrete, pale elevation of the skin (a wheal) 6 to 10mm in diameter should be produced when the injection is done correctly. If it is recognized that the first test was improperly administered, another test dose can be given at once, selecting a site several centimeters away from the original injection. A note in the record should indicate the site chosen for the second test. Study subject should be instructed not to scratch the site and to avoid covering the area with a bandage.

Tests should be read by a trained health care worker between 48 and 72 hours after injection. Reading should be performed in good light, with the forearm slightly flexed at the elbow. The basis of reading is the presence or absence of induration, which may be determined byinspection (from a side view against the light as well as by direct light) and by palpation. The diameter of induration should be measured transversely to the long axis of the forearm and recorded in millimeters even those classified as negative. Erythema should not be measured. Subjects should never be allowed to read their own tuberculin skin tests. If a subject fails to return within 72 hours to have the PPD skin test read, an ELISA-based assay, such as QFT-GOLD, must be performed.

An induration of ≥5mm in response to the intradermal tuberculin skin test is considered to be a positive result and evidence for either latent or active TB.

In most countries, the most conservative definition of positivity for the tuberculin skin test is reserved for immunocompromised subjects, and this definition is to be applied here. The purpose of using this conservative definition of positivity is to maximize the likelihood of detecting latent TB.

9.6.6 Evaluation of signs and symptoms of TBSigns and symptoms of TB will be evaluated for all subjects using the questionnaire "evaluation of signs and symptoms of tuberculosis" provided in Section 17.1. This questionnaire should be used as a source document. The questionnaire will assist with the identification of subjects who may require prophylactic therapy for TB. A subject who answers “Yes” to the question

” is required to begin prophylactic treatment for latent TB. A “Yes” response to 1 or more of the other questions within the questionnaire should trigger further careful assessment of risk to determine if prophylactic or curative treatment for TB is required.

All subjects considered at high risk for TB infection will receive prophylactic TB treatment (eg, isonicotinic acid hydrazide [isoniazid; INH] therapy for 9 months [with vitamin B6]).

Subjects who do not initiate prophylactic treatment for latent TB per Sponsor requirement, prematurely discontinue prophylactic treatment for latent TB or are noncompliant with antituberculosis therapy, in the Investigator's opinion, must discontinue further use of study medication and be immediately withdrawn from study participation. Once withdrawn from study treatment, subjects should return for the ET Visit and complete all early withdrawal assessments, and complete a final SFU Visit 12 weeks after the last dose of study medication.

If active TB is suspected or confirmed, the subject must be withdrawn immediately from the study and discontinue study medication. The subject must return for the ET Visit and complete all early withdrawal assessments, and complete a final SFU Visit 12 weeks after the

REDACTED pospo

nd synd syvaluatvaluat

tt

COPYf posiposis dis defie

ositivsit

This do

cumen

t ntitutitmedmedstst

cann

ots whs whmaturelaturetubeube

betinicni us

ed

onsidernsideric aic a

toativeativesup

poror latenr late

re shore shoe t

ort an

yyy

any

anmark

eting

ted foed fubercubercu

urce dource drequirequm

autho

rizati

onfinitnit

ivityvity isiyy

ymptomptoforfor

appli

catio

nkin tekin t

ivityvity fofyyitiontion

and a

nysubsu

ayay, su, suex

tensio

ns

ion. Tion. Tearm aarm a

be mee meubjebje

or heh va

riatio

ns

he e

thereo

f.


Confidential of 119

last dose of study medication. Confirmed active TB is an SAE and must be captured on an SAE Report Form and provided to the Sponsor in accordance with SAE reporting requirements. As with all SAEs, periodic follow-up reports should be completed as per protocol requirement until such time as the TB infection resolves.

Follow-up information of the suspected or confirmed TB should be provided to UCB at least after 3, 9, and 12 months of start date of anti-TB treatment, including hematological and biochemical safety parameters, x-ray evolution, and TB diagnosis procedures used to follow up and confirm recovery of TB.

9.6.7 Vital signsSystolic and diastolic blood pressure and pulse rate will be measured 15 minutes prior to dosing (with a ±5 minutes window) in a sitting position at entry Week 0, Visit 2, every 12 weeks starting at Week 14, and at the Completion/ET, Unscheduled, and SFU Visits.

9.6.8 Concomitant medicationsDetails of all concomitant medications taken throughout the course of the study will be collected at every visit, phone contacts, and Unscheduled Visits. Ongoing concomitant medications from C87035 will continue to be followed in CR0012.

9.6.9 Medications for CDDetails of medication taken for the treatment of CD will be recorded throughout the study at scheduled site visits and via phone calls by the Investigator (designee) at every 4 week intervals between regular visits. In addition, information on medication taken as maintenance treatment for CD will be recorded throughout the study.

9.6.10 AutoantibodiesAutoantibody (ANA and anti-dsDNA) titers will be determined every 12 weeks starting at Week 14, and at the Completion/ET and SFU Visits.


10 EFFICACY ASSESSMENTS10.1 Disease activity/PCDAIThe subjects’ disease activity will be assessed using the PCDAI. The PCDAI was developed by pediatric inflammatory bowel disease (IBD) experts and was validated at 12 North American institutions (Hyams et al, 1991). It is a modification of the Clinical Disease Activity Index (CDAI) which is the accepted instrument to measure CD disease activity in clinical studies with adults. The PCDAI consists of 4 domains (laboratory, height/weight, examination, and history) with several assessments that are converted into a PCDAI score which can range from 0 to 100 points with a higher score indicating more severe disease activity. In comparison to the CDAI, the PCDAI decreases the weighting given to subjective historical terms, adds height velocity, and adds ESR to the laboratory measures included (Hyams et al, 1991; Otley et al, 1999). The PCDAI is provided in Section 17.2.

REDACTEDC

e Invee Invn, infor, info

ghout ghout

COPY D wiD wi

This do

cumen

tnexamexamwhwh

cann

otan inn invityty IIyy nnical cal

bec infc infnstnst

used

sesediseasdiseaflafl

toeaseassupp

ort his stis s

CAACYCYe

anyollectollec

tudt

marketi

ng

A) titers) titerT and T and

autho

rizati

onill be ill be estigatestigat

rmatiormatiot the stthe st

appli

catio

nof

OngoinOngoi012.012.

and

f the the an

y SFF exten

sions

rior toior to

2, ever everFU VU

or va

riatio

ns th

ereof.


Confidential of 119

The Investigator will calculate the subjects’ PCDAI scores every 12 weeks starting at Week 14, and at the Completion/ET Visit. Calculation of PCDAI scores is also necessary to determine whether a subject loses response (Section 5.1). For subjects undergoing reinduction, PCDAI scores will be calculated at Reinduction Weeks 0, 2, and 4.

For the calculation of the PCDAI score at a particular visit (to assess efficacy of CZP treatment), values for hematocrit, ESR, and albumin are used from the same clinic visit. Thus, the PCDAI score calculation cannot be completed until the laboratory values have been received at the site.

Since portions of the PCDAI calculations are based upon a 1-week (7-day) history recall of symptoms, subjects and/or caregivers will be contacted prior to the visit with a reminder that this information needs to be provided at the visit.

10.2 Erythrocyte sedimentation rateThe ESR will be assessed every 12 weeks starting at Week 14, and at the Completion/ET Visit. Results of these measurements form part of the PCDAI assessments described in Section 10.1.

For subjects undergoing reinduction, ESR will be assessed at Reinduction Weeks 0, 2, and 4.


10.3 C-reactive proteinLevels of CRP will be assessed every 12 weeks starting at Week 14, and at the Completion/ET Visit.


10.4 Tanner stageAssessments of subjects’ developmental stages will be performed to determine the subjects’ Tanner stages (Marshall and Tanner, 1969; Marshall and Tanner, 1970). These assessments will be performed every 12 weeks starting at Week 14, and at the Completion/ET Visit.

10.4.1 Bone markersMarkers of bone and collagen turnover, reflecting the childhood growth curve, will be measured at Weeks 14, 26, 38, 50 and then every 12 months thereafter, and at the Completion/ET Visit. These markers will include: osteocalcin, bone specific alkaline phosphatase, and n-telopeptides. Tests will be performed by a central laboratory facility.


10.5 HeightHeight will be recorded every 12 weeks starting at Week 14, and at the Completion/ET Visit. Height will be recorded after the shoes have been removed. Height should preferably be

REDACTED

weeksweek

onon

COPYstoragstora

This do

cumen

tnstrunstruthe the

cann

otion/on/phatashatas

rucruc

bet WeW/E/E

used

nnne anne anee

toe me msu

pport

veloveloand Tand T

ryy 1212yy ww

any

lopmopm

marketi

ng

, proceproceau

thoriz

ation

s startstart

appli

catio

n ReinduReindu

ge, ande, an

and e CC

ments dents dan

y CompCom

exten

sionsll ofl of

inder tnder or ff

varia

tions

there

of.


Confidential of 119

measured with a wall-mounted stedometer. Results of these measurements form part of the PCDAI assessments described in Section 10.1.

10.6 WeightWeight will be recorded after removal of shoes and heavy clothing. Weight will be measured every 12 weeks starting at Week 14, and at the Completion/ET Visit.

Results of the weight measurement will be used to determine the subject’s CZP dose as specified in Table 7-1. In addition, results of these measurements form part of the PCDAI assessments described in Section 10.1.

10.7 IMPACT-IIIThe IMPACT questionnaire is a disease-specific health-related quality of life (HRQOL) questionnaire for use in children with IBD that was originally developed and validated by a Canadian team (Griffiths et al, 1999; Otley et al, 2002). The IMPACT-III, a modified version of the original questionnaire, contains 35 questions assessing the following 6 domains: bowel symptoms, systemic symptoms, emotional functioning, social functioning, body image, and treatment/interventions. For each question, there are 5 Likert response options. Total IMPACT-III scores range from 35 to 185 with higher scores indicating better HRQOL. This questionnaire will be used to assess HRQOL of all subjects; however, it has only been validated for children aged ≥10 years in North America. The IMPACT-III questionnaire is provided in Section 17.3. The IMPACT-III questionnaire will be administered at Weeks 14, 26, 38, 50 and then every 12 months thereafter, and at the Completion /ET Visit.

For subjects undergoing reinduction, the IMPACT-III questionnaire will be administered at Reinduction Week 0.

The IMPACT-III questionnaire is a copyright of the Pediatric Inflammatory Bowel Disease Working Group on Quality of Life (copyright 2002). The IMPACT-III has been provided under licences, by the Pediatric Inflammatory Bowel Disease Working Group and must not be copied, distributed, or used in any way without prior written permission by the Pediatric Inflammatory Bowel Disease Working Group.

10.8 Days missed from school/work (WPAI:CD for children and for working individuals with CD)

The Work Productivity and Activity Impairment Questionnaire for children with CD (WPAI:CD) is used to

If a subject has left school and is working, the WPAI:CD for working individuals is used instead of the WPAI:CD for children. If a subject is both attending school and working, both the WPAI:CD for children and the WPAI:CD for working individuals are used.

The WPAI:CD for children questionnaire contains 6 questions:

, all 6 questions are completed, and

REDACTED stiostioerer, and, and

IMPAIMPA

COPYbjectbjecericarica

onnonn

This do

cumen

tworkork

ThThm

cann

otg indg indnding ding kinkin

te

isbe

useductivictiv

s useuseu

to kinkinsu

pport

se We W

missemissng ing

any in anin any

WorWo

marketi

ng

pyriyright ghtcopopyriyr

flammlamm

autho

rizati

on ThTh

naire waire wd at thd at th

ACT-CT-II

appli

catio

n iononponse oonse

ndicatinndicat; howehow

he IMhe IM

andwing wing

ninging

any vava

a moa mod66

exten

sions

HRQORQOalidalid

or va

riatio

ns th

ereof.


Confidential of 119

, the subject completes only question number 6 to . The 6 items are regrouped into 4 dimensions and the

scores are expressed as percentages, with higher numbers indicating greater impairment and less productivity (Reilly et al, 2008).

The WPAI:CD for working individuals questionnaire contains 6 questions:

The WPAI:CD for children questionnaire is administered to all subjects or the parent(s)/legally acceptable representative(s) and the WPAI:CD for working individuals questionnaire is only administered to subjects who work, under supervision of the Investigator or designee at Weeks 14, 26, 38, 50 and then every 12 months thereafter, and at the Completion /ET Visit.

For subjects undergoing reinduction, the WPAI:CD questionnaires will be administered at Reinduction Weeks 0 and 4.

The WPAI:CD questionnaire for children with CD (Section 17.4 ) and the WPAI:CD for working individuals are provided (Section 17.5).

10.9 Effect on the caregiver's work (WPAI:CD for caregivers)The WPAI:CD questionnaire for caregivers of children with CD is used to

he questionnaire contains 6 questions:

all 6 questions are completed, and if

, the caregiver completes only question number 6 to reflect . The 6 items are regrouped into 4 dimensions and the scores are expressed as percentages, with higher numbers indicating greater impairment and less productivity.

The questionnaire is administered under supervision of the Investigator or designee to the caregiver at Weeks 14, 26, 38, 50 and then every 12 months thereafter, and at the Completion/ET Visit.

For subjects undergoing reinduction, the WPAI:CD questionnaire will be administered at Reinduction Weeks 0 and 4.

The WPAI:CD questionnaire for caregivers of children with CD is provided in Section 17.6.

10.10 Concurrent medical proceduresAny concurrent medical procedures will be recorded throughout the course of the study at every visit, phone contacts, and Unscheduled Visits.

CTED wowoof chiof ch

DACT

REDARE

COPY tit

ork ork

This do

cumen

tReinein

ThT

cann

otetion/tion/

subjesubjed

bett WeWeus

edvityity

aire iaire

to ssedseyy

sup

ed asd a

tpo

rt

supp

ony

an

ya

gtin

g

rketin

markm

oriza

tion (WP(WP

ildrenldren

uthor

aut

appli

catio

n willwil

7.47.4 ) a)

and

ll bel b

any hereher ex

tensio

ns

ividuaviduathe the

or va

riatio

ns th

ereof.


Confidential of 119

11 PHARMACOKINETICS AND IMMUNOLOGICAL ASSESSMENTS

Blood samples will be collected to determine plasma concentrations of CZP and anti-CZP antibodies every 12 weeks starting at Week 14, and at the Completion/ET and SFU Visits. All of these blood draws will be performed prior to study drug administration (except for the Completion/ET and SFU Visits when there is no dosing) and all of them coincide with the blood collection times for the assessment of hematology and clinical chemistry parameters, so that no additional blood sampling is required at these visits.

Time and date of each blood draw will be documented on the CRF.


12 STUDY MANAGEMENT AND ADMINISTRATION 12.1 Adherence to protocolThe Investigator should not deviate from the protocol. In medical emergencies, the Investigator may use his/her medical judgment and may remove a study participant from immediate hazard before notifying UCB (or its representative) and the IRB/IEC in writing regarding the type of emergency and the course of action taken.

12.2 MonitoringUCB (or designee) will monitor the study to meet the Sponsor’s monitoring Standard Operating Procedures (SOPs), ICH-GCP guidelines, and applicable regulatory requirements, and to ensure that study initiation, conduct, and closure are adequate. Monitoring of the study may be delegated by UCB to a contract research organization (CRO) or a contract monitor.

The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be available during the monitoring visits to answer questions sufficiently and to provide any missing information. The Investigator(s)/institution(s) will permit direct access to source data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory inspection(s).

The Investigator will allow UCB (or designee) to periodically review all CRFs and corresponding source documents (eg, hospital and laboratory records for each study participant). Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress of the study, verify the accuracy and completeness of CRFs, ensure that all protocol requirements, applicable authorities regulations and Investigator’s obligations are being fulfilled, and resolve any inconsistencies in the study records.

12.2.1 Definition of source data All source documents must be accurate, clear, unambiguous, permanent, and capable of being audited. They should be made using some permanent form of recording (ink, typing, printing, optical disc). They should not be obscured by correction fluid or have temporary attachments (such as removable self-stick notes). Photocopies of CRFs are not considered acceptable source documents. Source documents are original records in which raw data are first

REDACTED to meeo mee

P guidP guidnductnductctct

COPYenentattaaction ctio

This do

cumen

t2.22.2AlAl

cann

otocol rcol g fulfifulfi

2 12 1

bee proe prouse

dourceurceMoMonitonito

toll alll ale d

supp

ortrelatedelate

llowllo

any visivis

stigatostigatd

marketi

ngt, andan

researresear

re expee expsits tits

autho

rizati

on ta

et the et the delineselinesndnd

appli

catio

nemergemerve a stuve a st

ve) ande) anaken.aken

and a

nyIONIONex

tensio

ns

proviprovi

or va

riatio

ns th

ereof.


Confidential of 119

recorded. These may include hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, pharmacy records, care records, ECG or other printouts, completed scales, or Quality of Life Questionnaires, for example. Source documents should be kept in a secure, limited access area.

The following data will be recorded directly in the CRF and will not appear in a source document as defined above: IMPACT-III and WPAI:CD.

Source documents that are computer generated and stored electronically must be printed for review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated by the Investigator and become a permanent part of the subject’s source documents. The Investigator will authorize the monitor to compare the content of the printout and the data stored in the computer to ensure all data are consistent.

Electronic data records such as holter monitor records or electroencephalogram records must be saved and stored as instructed by UCB (or designee).

12.2.2 Source data verificationSource data verification ensures accuracy and credibility of the data obtained. During monitoring visits reported data are reviewed with regard to being accurate, complete, and verifiable from source documents (eg, subject files, recordings from automated instruments, tracings [ECG], x-ray films, laboratory notes). All data reported on the CRF should be supported by source documents, unless otherwise specified in Section 13.2.1.

12.3 Data handling12.3.1 Case report form completionThe Investigator is responsible for prompt reporting of accurate, complete, and legible data in the CRFs and in all required reports.

Any change or correction to the CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry. Use of correction fluid is not permitted.

Corrections made after the Investigator’s review and signature of the completed CRF will be resigned and dated by the Investigator.

The Investigator should maintain a list of personnel authorized to enter data into the CRF.

Detailed instructions will be provided in the CRF completion guidelines.

12.3.2 Database entry and reconciliationCase report forms/external electronic data will be entered/loaded in a validated electronic database using a clinical data management system (CDMS). Computerized data cleaning checks will be used in addition to manual review to check for discrepancies and to ensure consistency of the data. Case report form data are entered into the clinical database using independent, double-data entry, with the exception of comment fields, which are verified by a second person.

An electronic audit trail system will be maintained within the CDMS to track all data changes in the database once the data has been saved initially into the system or electronically loaded. Regular backups of the electronic data will be performed.

REDACTED e s

mpletmpletompomp

COPYcordcordata reata

specspec

This do

cumen

t heckecconsconsinin

cann

otport port base uase u

cksks

beff

usedctionstions

DaDa

toouldouldsu

pportInveInve

he Ie Invenv

ld md m

anyinal enal

sti

marketi

ngpt repopt repo

RF shoRF shen

autho

rizati

on epop

cified ified

tionon

appli

catio

nata obtta obng accng ac

ngs frogs frportedorte

and a

ny mm ex

tensio

ns nts. nts.

nd thed the

m recre

or va

riatio

ns th

ereof.


Confidential of 119

12.3.3 Subject Entry and Enrollment log/Subject Identification Code listThe subject’s entry and enrollment will be recorded in the Subject Entry and Enrollment Log.

The Investigator will keep a Subject Identification Code list. This list remains with the Investigator and is used for unambiguous identification of each subject.

The subject’s consent and enrollment in the study must be recorded in the subject’s medical record. These data should identify the study and document the dates of the subject’s participation.

12.4 Termination of the studyUpon completion of the study, the monitor will conduct the following activities in conjunction with the Investigator, as appropriate:

• Return of all study data to UCB or its representatives while maintaining original source documents

• Data clarification and/or resolution

• Accountability, reconciliation, and arrangements for used and unused investigational products

• Review of site study records for completeness

• Discussion/reminder on archiving responsibilities

• Discussion of IRB/IEC requirements for study termination

• Arrangements for unused CRFs, lab supplies, and any other study related supplies

UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a single site, multiple sites, or at all sites at any time for reasons including, but not limited to, safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or unsatisfactory enrollment with respect to quality or quantity.

If the study is prematurely terminated or suspended, UCB (or its representative) will inform the Investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension, in accordance with applicable regulatory requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the termination or suspension by the Sponsor or by the Investigator/institution, as specified by the applicable regulatory requirement(s). In addition, arrangements will be made for the return of all unused investigational products and other material in accordance with UCB procedures for the study.

12.5 Archiving and data retentionThe Investigator will maintain adequate records for the study including CRFs, medical records, laboratory results, Informed Consent documents, drug dispensing and disposition records, safety reports, information regarding participants who discontinued, and other pertinent data.

REDACTEDbilitibilit

or studr stud

ab suppb sup

COPY

iesi

This do

cumen

t12.512.5TT

cann

otbyy

returnreturnB procB proc

be na

y they these

de r

iremeremeationation

toreasreassupp

ort th h

ely termy terutionsution

anyate orate o

respresmark

eting

p

y suspesuspl sites l sitesor i

autho

rizati

on

s

dydy termtermy

lies, ies,

appli

catio

n nd unusd unu

and a

nyorigorigexten

sions

gini

or va

riatio

ns th

ereof.


Confidential of 119

All essential documents are to be retained by the Investigator until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period, however, if required by the applicable regulatory requirement(s) or by an agreement with UCB (ICH-GCP Guideline, Section 4.9.5). The Investigator will contact UCB for authorization prior to the destruction of any study records or in the event of accidental loss or destruction of any study records. The Investigator will also notify UCB should he/she relocate or move the study-related files to a location other than that specified in the Sponsor’s study master file.

12.6 Audit and inspectionThe Investigator will permit study-related audits mandated by UCB and inspections by domestic or foreign regulatory authorities, after reasonable notice.

The main purposes of an audit or inspection are to confirm that the rights and well-being of the subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing study procedures) are appropriate for the study, and that all data relevant for the evaluation of the IMP have been processed and reported in compliance with the planned arrangements, the protocol, investigational site, and IRB/IEC SOPs, ICH/GCP, and applicable regulatory requirements.

The Investigator will provide direct access to all study documents, source records, and source data. If an inspection by a regulatory authority is announced, the Investigator will immediately inform UCB (or designee).

12.7 Good Clinical PracticeNoncompliance with the protocol, ICH/GCP, or local regulatory requirements by the Investigator, institution, institution staff, or designees of the Sponsor will lead to prompt action by UCB to secure compliance. Continued noncompliance may result in the termination of the site’s involvement in the study.

13 STATISTICSA description of statistical methods is presented below and will be described in more detail in the Statistical Analysis Plan (SAP).

13.1 Definition of analysis setsThe All Subject Population will include those subjects who are enrolled in the study. All available data entered into the database will be listed for this population.

The Safety Population will include all subjects enrolled who receive at least 1 injection of study treatment in this study. This population will be used to summarize the safety, PK, and immunological variables.

The Intention-to-Treat (ITT) Population will include all subjects irrespective of any protocol deviations who receive at least 1 injection of study treatment in this study and who have at least 1 efficacy measurement after the first injection of this study. This population will be used to summarize the efficacy variables.

REDACTEDall stuall strityity is is yy

acticactic

COPYRB/IERB/I

d

This do

cumen

t he estudstudimim

cann

otSubjSubjable dable da

SaSa

be

bjebjeus

ednalylys

DeDe

to tistitistisissis

supp

ort hehe

STICSTICtical ica

anyanceanc

e studstudmark

eting

eeH/GCPH/GC

staff, staffce Cce

autho

rizati

on

dydy dodoyyannouannou

appli

catio

n sigsigthat all hat al

mplianmpliaCC SOPSO

andhts ants an

gningnin

any

nd

exten

sions

ctionstions

or a a varia

tions

there

of.


Confidential of 119

13.2 General statistical considerationsSummary statistics will consist of sample size, frequencies, and corresponding percentages for categorical variables. For continuous variables, descriptive statistics (number of available observations, mean, median, standard deviation, minimum, and maximum) will be tabulated. Data summarized by visit will use nominal visits with the exception of data collected at withdrawal visits which will be summarized at the next scheduled nominal visit dependent on when the withdrawal visit occurs taking into account the allowable visit windows.

Summaries will be by treatment received at the end of C87035. Any other subgroups of interest such as subjects who have been reinduced in C87035 or reinduced during CR0012 will be detailed in the SAP.

For data such as Crohn’s disease history which are only collected at the Screening Visit of C87035, these will be defined as the Baseline values. For data which are collected at Week 0 of C87035 and prior to receiving any study treatment, the last nonmissing value prior to receiving any treatment will be defined as the Baseline values.

All analyses will be performed using the SAS software package.

All AEs will be coded and classified by primary System Organ Class (SOC) and Preferred Term (PT) according to the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA®).

All medications will be coded using World Health Organization Drug (WHODrg).

13.3 Planned safety analysesAll safety summaries will be based on the Safety Population as a whole, by treatment group, weight, and age stratum.

Treatment emergent adverse events will be summarized descriptively by primary SOC, high level term, and PT. Additional tables will summarize AEs by severity and relationship to study drug, and separate tables will be generated for AEs leading to withdrawal from the study, SAEs, and deaths. Other AEs of special interest including, but not limited to, infections will also be summarized.

The specific set of AEs reported as injection reactions will also be summarized along with their classification as either injection site reactions or systemic hypersensitivity reactions (the latter being further classified as acute or delayed).

Actual laboratory values and changes from Baseline in laboratory values will be summarized. Shift tables to show the change from Baseline in the absolute values and details of treatment emergent markedly abnormal values (based on Common Terminology Criteria for Adverse Events criteria) will be presented by variable.

Actual vital signs values and change from Baseline in vital signs values will be summarized.

Autoantibody levels will be assessed via the presence or absence of ANA and anti-dsDNA, and data will be summarized.

Extent of exposure to treatment will be presented descriptively.

REDACTEDalth alth

sessesthe Sthe S

COPY Me Me

OO

This do

cumen

t vene

ActActca

nnotbles tes t

gent mgent mnts cnts c

beoratooratotot

used

n asather cher c

toE

as eias esu

pport

her her mmarimmar

s repos rep

anywill bwill

r AEr A

marketi

ng af

will be will beles wiles w

bb

autho

rizati

on

Organirgani

fetfetyy

appli

catio

n n Classn Clas

ical Dical D

and

g any ectec

value valueex

tensio

ns 0012 012

ing Ving Victedted

or va

riatio

ns th

ereof.


Confidential of 119

13.4 Planned efficacy analysesAs the primary objective of the study is to evaluate safety there are no primary or secondary efficacy variables. Rather, efficacy variables will be measured to evaluate efficacy of longterm open label treatment with CZP.

All efficacy summaries, where applicable, will be presented by visit, treatment group, weight (20 to <40kg [44 to <88lbs] and ≥40kg [≥88lbs]) and age stratum (6 to 11 years and 12 to 17 years).

The proportion of subjects in clinical remission and the proportion of subjects in clinical response will be summarized using the number and percentage of subjects along with associated 95% confidence intervals (CI).

A subject who does not have all required data to derive a response status (response or remission) will be classified as a nonresponder/nonremitter at that particular time point. A subject who withdraws from the study or is reinduced, will be classified as a nonresponder/nonremitter from and including the time of withdrawal or reinduction.

If a subject receives rescue therapy, the subject will be considered as a treatment failure (nonresponder/nonremitter) from the timepoint of administration of first rescue therapy onwards.

Actual PCDAI scores and changes from Baseline in PCDAI scores will be summarized by presenting the mean, standard deviation (SD), 95% CI for the mean, median, minimum, and maximum values.

Levels of CRP and ESR and changes from Baseline in CRP levels and ESR (expressed as a ratio with the value measured at Baseline as denominator) will be summarized by presenting the geometric mean, coefficient of variation, 95% CI for the geometric mean, median, minimum, and maximum values.

IMPACT-III scores and changes from Baseline will be summarized by presenting the mean, SD, 95% CI for the mean, median, minimum, and maximum values.

The change from Baseline in growth score using the Tanner stage (assessing puberty), will be summarized using shift tables. Bone marker values and changes from Baseline in bone marker values will be summarized.

The proportion of days missed from school/work will be summarized by presenting the mean, SD, 95% CI for the mean, median, minimum, and maximum values.

Actual WPAI:CD scores and changes from Baseline in WPAI:CD scores will be summarized by presenting the mean, SD, 95% CI for the mean, median, minimum, and maximum values.The summaries will be presented separately for the WPAI:CD for children, WPAI:CD for working individuals with CD, and WPAI:CD for caregivers. Direct costs parameters will be summarized by period of onset using descriptive statistics.

REDACTED95%95%

om Baom Beline aeline ariaria

COPY in PCin PC

CC

This do

cumen

the eworkworksusu

cann

otWPAWPAesentiesenti

sumsum

be fo

AIAIus

ed

of daof daor thr th

tobe sube s supp

ort

e in grin gft tablet tablesumsum

anyfrofr

dian, mian, mmark

eting

as des deation, 9tion, 9

om Bom

autho

rizati

onCDAICDAICI CI for for

aselinselindenen

appli

catio

n d aas a ts a on of fon of

II s

and as as

or reior reian

yr timr tima a

exten

sions

onse onse o

or va

riatio

ns th

ereof.


Confidential of 119

13.5 Pharmacokinetics and immunological analysesPlasma concentrations of CZP at each visit will be summarized and plotted by anti-CZP antibody status (all subjects, antibody-positive, and antibody negative) for each age stratum, the overall population, and for the treatment groups. In addition, plasma concentrations will be summarized and plotted by weight stratum (<40kg; ≥40kg) for the treatment groups.

Individual anti-CZP antibody concentrations will be listed and the incidence of anti-CZP antibody positive subjects will be summarized by study visit and overall incidence by age stratum and by treatment group. Anti-CZP antibody positive status is defined as a subject having a value >2.4units/mL anti-CZP antibody at any time during the study.

Additionally, the PK data collected in CR0012 may be used for population PK modeling to supplement or validate the pediatric model derived from the data obtained in C87035. If performed, the analysis and results of this modeling will be provided in a separate report.

13.6 Handling of protocol deviationsNo Per Protocol population is defined in this study and thus no consideration with regards to deviations affecting such a population need to be considered. Nevertheless, for each interim analysis and final analysis, after all the data have been verified/coded/entered into the database, a review will be performed after last subject last visit. The purpose of this review will be to primarily check the quality of the data. The review will also help decide how to deal with problems in the subject’s data (for example: missing values, withdrawals, drop outs, protocol deviations). In addition, the review will be used to identify the use of rescue therapy. The preanalysis reviewers should ensure that the results of this review are communicated to the study team before locking the database.

After the preanalysis review, resolution of all issues and documentation of all decisions, the database will be locked.

13.7 Handling of dropouts or missing dataFor responder type variables, should a subject withdraw prior to completion of the study, then the subject will be classified as a nonresponder or nonremitter from and including the time of withdrawal.

A subject who does not have all the required data to derive a response status will be classified as a nonresponder or nonremitter at that particular time point.

If a subject receives rescue therapy or discontinues study treatment, then the subject will be classified as a treatment failure (nonresponder or nonremitter) from and including the time of the event, regardless of their score (PCDAI).

If a subject loses response and is reinduced, the subject will be classified as a nonresponder or nonremitter from and including the time of the reinduction.

In addition, for any other efficacy variables, no data will be used from and including the time of receiving rescue therapy in the summaries and analyses where relevant.

Unless part of an accepted imputation technique, any missing data during the study will remain missing.

REDACTED ampampwill bewill b

hat theat thbase.base.

on oon o

COPYt lastt lasThe revThe re

mple:ple

This do

cumen

t f a sa or noor no

II

cann

ot d asas

ent, reent, r

subjsub

bereceeces as a

usedder orr or

ceiveiv

tonotnot sup

port

, sed as aed as

t hh

any

houldhouldmark

eting

of all iof all i

opoupou

autho

rizati

onviewiew

: missmisse usede used

e resue resu

appli

catio

n sidedeverthelerthe

d/codedd/codevisit. Tisit. T

ew ww w

and

eraterat

any araar ex

tensio

ns

delingdeling870357035

rateate

or va

riatio

ns th

ereof.


Confidential of 119

If an AE has severity and/or relationship missing then the event will be assumed to be severe and/or highly probably related to the treatment.

For the WPAI:CD, handling of dropouts or missing data will be detailed in the SAP.

13.8 Planned interim analysis and data monitoringA DSMB will review safety data. The DSMB members will be independent of the Sponsor and Investigators. The DSMB members will be informed by GCSP (or designee) of all SAEs at the time of expedited reporting and will review periodically all emerging safety data (SAEs, AEs, safety laboratory data). Based on the safety data, the DSMB can recommend modifying/stopping the study.

No interim analyses are planned. Should a regulatory authority request an interim analysis, this will be performed according to the request.

13.9 Determination of sample sizeThis is an open-label study for subjects who completed C87035 and as such no formal sample size has been determined.

14 ETHICS AND REGULATORY REQUIREMENTS14.1 Informed consentSubject’s informed consent must be obtained and documented in accordance with local regulations, ICH-GCP requirements, and the ethical principles that have their origin in the principles of the Declaration of Helsinki.

Prior to obtaining informed consent, information should be given in a language and at a level of complexity understandable to the subject and his/her parent(s)/legally acceptable representative(s) in both oral and written form by the Investigator (or designee). Each subject and his/her parent(s)/legally acceptable representative(s) will have the opportunity to discuss the study and its alternatives with the Investigator.

Prior to participation in the study, the written Informed Consent form should be signed and personally dated by the subject, or his/her legal representative, and by the person who conducted the informed consent discussion (Investigator [or designee]). If applicable, a child Assent form may be used. The subject or his/her legal representative must receive a copy of the signed and dated Informed Consent/child Assent form. As part of the consent process, each subject must consent to direct access to his/her medical records for study-related monitoring, auditing, IRB/IEC review, and regulatory inspection.

If the Informed Consent/child Assent form is amended during the study, the Investigator (or the Sponsor, if applicable) must follow all applicable regulatory requirements pertaining to the approval of the amended Informed Consent form by the IRB/IEC and use of the amended form.

All studies conducted at centers in the United States must include the use of a Health Insurance Portability and Accountability Act (ie, HIPAA) Authorization form.

The subject and his/her parent(s)/legally acceptable representative(s) may withdraw their consent to participate in the study at any time. A subject is considered as enrolled in the study

REDACTED d dd dethicaethica

nformnformsubjsubj

COPY

docudoc

This do

cumen

tthe ahe aforfor

cann

ot g

InformnformSponSpon

be, aud, audus

ed dated ated

must cmust c

toe usee usI

supp

ortstudtud

ubject,ubjecd consd consedd

anyh thh th

dydy

marketi

ngmat

eect anct anten foren fo

table reable rhe Ihe

autho

rizati

on

umentumenal prinl prin

tion ion

appli

catio

n UIREMUIRE

and s suchsuch

any e

xtens

ions nd

m analm anal

or va

riatio

ns th

ereof.


Confidential of 119

when his/her parent(s)/legally acceptable representative(s) has signed the Informed Consent form. A CRF must not be started, nor may any study specific procedure be performed for a given subject, without having obtained his/her written consent to participate in the study.

14.2 Subject identification cardsUpon signing the Informed Consent and Assent form (as applicable), the subject or legal representative will be provided with a subject identification card in the language of the subject. The Investigator will fill in the name of the study and medical emergency contact information. The Investigator will instruct the subject to keep the card with them at all times.

14.3 Institutional Review Boards and Independent Ethics Committees

The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.

The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with the requirements of the current ICH-GCP version or applicable country-specific regulations will be responsible for the initial and continuing review and approval of the clinical study. Prior to initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed Consent form, Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other subject-related documents to be used for the study to the IRB/IEC for its review and approval.

Before initiating a study, the Investigator will have written and dated full approval from the responsible IRB/IEC for the protocol.

The Investigator will also promptly report to the IRB/IEC all changes in the study, all unanticipated problems involving risks to human subjects or others, and any protocol deviations, to eliminate immediate hazards to subjects.

The Investigator will not make any changes in the study or study conduct without IRB/IEC approval, except where necessary to eliminate apparent immediate hazards to the subjects. For minor changes to a previously approved protocol during the period covered by the original approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as allowed.

As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator will be responsible for submitting periodic progress reports to the IRB/IEC (based on the Committee’s requirements), at intervals appropriate to the degree of subject risk involved but no less than once per year. The Investigator should provide a final report to the IRB/IEC following study completion.

UCB (or its representative) will communicate safety information to the appropriate regulatory authorities and all active Investigators in accordance with applicable regulatory requirements. The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified by the applicable regulatory requirements in each concerned country. Where applicable, Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC notification.

REDACTED ll otll ond appnd app

r will hr will

COPYestigastigrochurrochu

otheoth

This do

cumen

t RB/B/

UCUC

cann

oton thon thlved bved b

B/IE/IE

ber wilr wius

ed ed.ed

IRB/IRB/

to mama

dsu

pportke

ecessarcessaprevioprevi

mayay bby

any

ananymark

eting

port to tort to

sks to hks tohazahaz

autho

rizati

onure, Ie,

er subr subprovalroval

have whave w

appli

catio

n IRBRBable couble co

eview aviewtor/UCBor/UCInvInv

and

B/IEB/I

anyve thve the

xtens

ions

ocal cal h

or es.es. varia

tions

there

of.


Confidential of 119

14.4 Subject privacyUCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this study, all data forwarded to UCB (or designee) will be identified only by the subject number assigned at Screening in C87035.

The Investigator agrees that representatives of UCB, its designee, representatives of the relevant IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the subject’s primary medical records that directly concerns this study (including, but not limited to, laboratory test result reports, ECG reports, admission/discharge summaries for hospital admissions occurring during a subject’s study participation, and autopsy reports for deaths occurring during the study).

14.5 Protocol amendmentsProtocol changes may affect the legal and ethical status of the study and may also affect the statistical evaluations of sample size and the likelihood of the study fulfilling its primary objective.

Significant changes to the protocol will only be made as an amendment to the protocol and must be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being implemented.

15 FINANCE, INSURANCE, AND PUBLICATIONInsurance coverage will be handled according to local requirements.

Finance, insurance, and publication rights are addressed in the Investigator and/or CRO agreements as applicable.

16 REFERENCESGriffiths AM, Nicholas D, Smith C, Munk M, Stephens D, Durno C, et al. Development of a quality-of-life index for pediatric inflammatory bowel disease: dealing with differences related to age and IBD type. J Pediatr Gastroenterol Nutr. 1999;28(4):S46-S52.

Hanauer SH, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s Disease: the ACCENT I randomised trial. Lancet. 2002;359(9317):1541-49.

Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, et al. Development and validation of a pediatric Crohn’s disease activity index. J Pediatr Gastroenterol Nutr. 1991;12(4):439-47.

Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, et al. Induction and maintenance infliximab therapy for the treatment of moderate to severe Crohn’s disease inchildren. Gastroenterology. 2007;132(3):863-73.

Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44(235):291-303.

Marshall WA, Tanner JM. Variations in pattern of pubertal changes in boys. Arch Dis Child. 1970;45(239):13-23.

REDACTED g to log to lo

ts are as are

COPY AND AND

This do

cumen

t mainainchildchild

cann

otnterotero

ms J, Cms J, Cntennten

bent ant a

rol Nrolus

ed

rryy GDGDyyandand

to4141-44sup

port

J PJ

G, LLichtichab for b for4949

anyc infc in

PediaPediamark

eting

C, Mun, Munflanfl

autho

rizati

onPUPUocal recal re

addresddres

appli

catio

n ndmentdmenuthoritiuthori

BB

and llilinan

y yy alsalyyng itng

exten

sionseportport or ries ries va

riatio

ns th

ereof.


Confidential of 119

Otley A, Loonen H, Parekh N, Sherman PM, Griffiths AM. Assessing activity of pediatric Crohn’s disease: which index to use? Gastroenterology. 1999;116(3):527-31.

Otley A, Smith C, Nicholas D, Munk M, Avolio J, Sherman PM, et al. The IMPACT questionnaire: a valid measure of health-related quality of life in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2002;35(4):557-63.

Reilly MC, Gerlier L, Brabant Y, Brown, M. Validity, reliability and responsiveness of the Work Productivity and Activity Impairment questionnaire in Crohn’s disease. Clin Ther. 2008; 30(2):393-404.

Rutgeerts P, D'Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, et al. Efficacy and safety of retreatment with anti-tumour necrosis factor antibody (infliximab) to maintain remission in Crohn’s Disease. Gastroenterology. 1999;117(4):761-9.

Sandborn WJ, Feagan BG, Hanauer SB, Present DH, Sutherland LR, Kamm MA, et al. An engineered human antibody to TNF (CDP571) for active Crohn’s disease: a randomized double-blind placebo-controlled trial. Gastroenterology. 2001;120(6):1330-8.

Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short term study of chimeric monoclonal antibody cA2 to tumour necrosis factor alpha for Crohn’s Disease. Crohn’s Disease cA2 Study Group. N Engl J Med. 1997;37(15):1029-35.

REDACTED COPYMedMe

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tion BraakBraak

ecrosis ecrosis1997;31997

and

e: a: 1330330

anym MAm MA

a rana raex

tensio

ns

fficacyfficacymaintmaint

AA

or va

riatio

ns th

ereof.

REDACTED COPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tion a

nd an

y exte

nsion

s or v

ariati

ons t

hereo

f.


Confidential of 119

17.2 Pediatric Crohn’s Disease Activity IndexInstructions on scoring are provided in the PCDAI’s user guide following the questionnaire. Scoring items are marked with an asterisk (*).

HISTORY (Recall; 1 week)*

Abdominal pain*:

None (0)

Mild – Brief, does not interfere with activities (5)

Mod / severe - daily, longer lasting, affects activities, nocturnal (10)

Stools (per day)*:

Formed stools or up to 1 liquid stool, no blood (0)

Up to 2 semi-formed with small blood, or 2 to 5 liquid with or without small blood (5)

Any gross bleeding, or ≥ 6 liquid, or nocturnal diarrhea (10)

Patient Functioning – General Well-Being*:

No limitation of activities, well (0)

Occasional difficulty in maintaining appropriate activities, below par (5)

Frequent limitation of activity, very poor (10)

REDACTED odd

or 2 toor 2 t

COPY

This do

cumen

t can

notent limnt li be

d used

ac

ifficufficu

toctivitivi sup

port nere

tie

any

ral Wral

marketi

ng

nocturnoctu

autho

rizati

on

o 5 liqo 5 liq

appli

catio

n and

any

any ex

tensio

ns

(0(te

or va

riatio

ns th

ereof.


Confidential of 119

LABORATORY

Hematocrit (%) ≤10 yrs: ≥33 (0)

28-32 (2.5)

<28 (5)

Males 11-14yrs: ≥35 (0)

30-34 (2.5)

<30 (5)

Males 15-19yrs: ≥37 (0)

32-36 (2.5)

<32 (5)

Females 11-19yrs : ≥34 (0)

29-33 (2.5)

<29 (5)

ESR (mm/h) <20 (0)

20-50 (2.5)

>50 (5)

ALBUMIN (g/dL) ≥3.5 (0)

3.1-3.4 (5)

≤3.0 (10)

REDACTED COPY

This do

cumen

t can

not b

eN (gN (gused

(g/dg/d

to su

pport

any m

arketi

ng au

thoriz

ation

appli

catio

n

<32<32

and a

ny

aex

tensio

ns (0)0)

(2.(2.io

xt

or va

riatio

ns th

ereof.


Confidential of 119

EXAMINATION

Weight*:

Weight gain or voluntary weight stable/loss (0)

Involuntary weight stable, weight loss 1-9% (5)

Weight loss ≥10% (10)

Height* - Score using (a) criteria when possible

a) Height velocity ≥-1SD (0)

Height velocity < -1SD, >-2SD (5)

Height velocity ≤ -2SD (10)

OR

b) < 1 channel decrease (0)

≥1 to < 2 channel decrease (5)

≥ 2 channel decrease (10)

Abdomen

No tenderness, no mass (0)

Tenderness, or mass without tenderness (5)

Tenderness, involuntary guarding, definite mass (10)

REDACTED COPY

This do

cumen

tTenTenca

nnot dernesernes

d

benessness used

to su

pport

any m

arketi

ng au

thoriz

ation

appli

catio

n and

any e

xtens

ions 5))

(10(10n

te

or va

riatio

ns th

ereof.


Confidential of 119

Perirectal disease

None, asymptomatic tags (0)

Inflamed tags or 1-2 indolent fistula(e) or fissure(s), scant drainage, no tenderness

(5)

Active fistula, drainage, tenderness, or abscess (10)

Extra-intestinal Manifestations

Fever ≥ 38.5ºC for 3 days over past week, oral ulcers, definite arthritis, uveitis, erythema nodosum, P. gangrenosum

None (0)

One (5)

≥ Two (10)

TOTAL SCOREREDACTED C

OPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tionhritisitisan

d iss

any e

xtens

ions 0)0)

onor

varia

tions

there

of.


Confidential of 119

PCDAI USER’S GUIDE

This guide is intended to help nurse coordinators and physicians complete the PCDAI in order to assess disease activity in children with CD participating in clinical trials.

HISTORY

All calculations are based upon a 1-week (7-day) history recall of symptoms. The history recall should be solicited from the patient and/or caregiver.

1. Abdominal pain

The descriptions in the PCDAI of “mild” and “moderate/severe” should be used to guide in scoring the pain. Note that duration, effect on activities, and nocturnal occurrence separate moderate/severe from mild. If pain varies in severity during the week, patient should be scored according to the most severe pain. However, mild pain should be present on at least two days to score 5 points rather than 0 points.

2. Stools

The intent is to score the stool pattern during the preceding week.

To facilitate scoring, first categorize the patient as having blood in the stool or not.

If there is no blood in the stool, score as follows:

• Formed stools or up to 1 loose stool daily = 0

• Two to five liquid or very loose stools on 1 or more days = 5

• Six or more liquid or very loose stools on 1 or more days or any nocturnal diarrhea = 10

If blood is present in the stool on any day during the past week, score as follows:

• Small amounts of blood in stool (on toilet paper or small spots in stool, etc.) = 5

• Any gross bleeding (large amounts on stool or colors the water in the toilet, etc.) = 10

3. Patient functioning, general well-beingIf there is variation during the week, patient should be scored according to the most significant limitation of activity, even if only one day of the week, as long as likely due to Crohn’s disease and not to an intercurrent illness.

REDACTED s:s:

ilyly = 0= 0y

ools onools o

tooto

COPY dini

havingavin

This do

cumen

t can

not b

em

seaseseasus

edion don dmitatioitati

to ningin su

pportrge amge a

ng, gg,

anytool tool

m

marketi

ng n

ols on ls on

nyy day dayyy

(o(

autho

rizati

on g b

0

1 or1 or

appli

catio

n

week.eek.

bloodloo

and preprean

ynt shnt shresenese

exten

sions

to guito guince sence sh

or va

riatio

ns th

ereof.


Confidential of 119

PHYSICAL EXAMINATION

4. Weight

The intent is to assess the ability to normally maintain or gain weight.

Voluntary weight stable/loss means patient maintaining or losing weight on purpose.

Involuntary weight stable means patient wants to gain weight but cannot.

To calculate percentage weight loss use formula:

Historic weight – Current weightX 100 = % weight loss

Historic weight

Take historic weight as maximal weight attained within preceding 4 to 6 months, excluding any value that reflects excess weight due to corticosteroid use.

5. Height

The intent is to assess the normalcy vs impairment of the patient’s recent linear growth.

Note that post-pubertal patients will score 0 points. For patients still growing, there are 2 options for scoring. Method (a) is preferred. Method (b) to be used if data required for (a) are unavailable.

Method (a):Height velocity (cm/year), the most sensitive parameter, should be used if reliable height measurements are available from the preceding 6 to 12 months.

Convert height increment during preceding 6 to 12 months into velocity (cm/year) as follows:

Present height – Height 6 – 12 months previouslyX 12 = Height velocity (cm/year)

Interval (months) between heights

Using height velocity chart, determine centile for height velocity (see below for a copy).

Height velocity should ideally be plotted according to bone age rather than chronologic age. However, if maturity is appropriate for age (not delayed or advanced) it is reasonable to plot and score height velocity according to chronologic age.

REDACTEDints.intsd. Metd. Met

COPY of the of the

FF

This do

cumen

t d cann

ovelocelocever, iver, i

scorscor

be t ve

citcitus

ed

veloceloc

to mo su

pport6 6 –– 11

onths)nthspp

anyg preg pr

2

marketi

ng

nsitive nsitive preceprec

eceec

autho

rizati

on pp

For pator pathod (hod (

appli

catio

n to

patienatien

and

o 6 m6 man

y exte

nsion

s or v

ariati

ons t

hereo

f.


Confidential of 119

In follow-up visits of short-term clinical trials less than 4 months duration, score height velocity the same as the initial score unless there has been an actual height gain.

Method (b):If reliable height measurements from 6 to 12 months previously are lacking (often the case with newly diagnosed patients), use any earlier heights to assess previous height centile and compare with current height centile. Score according to degree of decrease in height centile.

Guidelines to calculate and incorporate the results of the Height velocity (cm/year) into the PCDAI

REDACTED COPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tion a

nd an

y exte

nsion

s or v

ariati

ons

oo

thereo

f.


Confidential of 119

Height Velocity Reference Values for Calculating the PCDAI (Males)Age (years) Height Velocity in cm per year (Males)

Minus 2SD Minus 1SD Mean

2.5 5.7 7 8.3

3 5.4 6.6 7.8

3.5 5.1 6.3 7.4

4 4.9 6 7.1

4.5 4.7 5.8 6.8

5 4.6 5.6 6.6

5.5 4.5 5.4 6.4

6 4.3 5.3 6.2

6.5 4.2 5.1 6

7 4.2 5 5.9

7.5 4.1 4.9 5.8

8 3.9 4.8 5.6

8.5 3.8 4.6 5.4

9 3.8 4.5 5.3

9.5 3.7 4.5 5.2

10 3.7 4.4 5.1

10.5 3.7 4.4 5.1

11 3.7 4.4 5.2

11.5 3.8 4.6 5.3

12 4 4.9 5.7

12.5 4.8 5.8 6.7

13 6.2 7.4 8.6

13.5 7.1 8.3 9.5

14 6.1 7.2 8.4

14.5 4.1 5.3 6.5

15 2.4 3.6 4.7

15.5 1.2 2.3 3.3

16 0.4 1.3 2.2

16.5 0.1 0.7 1.5

17 0.1 0.4 0.9

17.5 0.1 0.1 0.5

REDACTED DCT

ACDAAAA

RE

COPY 4.6Y

O

This do

cumen

t 6.5.5

1717enumumumu

cann

ot noca

be

beus

ed d

seussssto

supp

ort

6.26.rtpp

s

any

88 ny

amark

eting

gggngke

t

ma

autho

rizati

on

4.54.5nati

oriut

appli

catio

n nnnnnat

pla

and nd

any .22

66any ex

tensio

ns

enenenenex

or va

riatio

ns th

ereof.


Confidential of 119

Height Velocity Chart (males)

AAAAAAAAAAAAAAAAAAAAAACCCCCCCCCCCCCCCCCCCCCCCCCTTTTTTTTTTTTTTTTTTTTTTTTTEEEEEEEEEEEEEEEEEEEEEEEEDDDDDDDDDDDDDDDDDDDDDDD

RRRRRRRRRRRRRRRRRRRRRRREEEEEEEEEEEEEEEEEEEEEEEDDDDDDDDDDDDDDDDDDDDDAAAAAAAAAAAAAAAAAAAAAAAAACCCCCCCCCCCCCCCCCCCCCCC

RRRRRR

CCCCCCCCCCCCCCCCCCCCCCCCCCCOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOPPPPPPPPPPPPPPPPPPPPPPPPPPYYYYYYYYYYYYYYYYYYYYYY

CCCCCCCCCCCCCCCCCCCCC

This do

cumenmeennnnnnnnnnnnnnnnnnnnnnn

ttttttttttttttttttt me

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnooooooooooooootttttttttttttttttt

ccccccccccccccaaaaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnnnnnnnnnnnnn

eeeeeeeeebbbbbbbbbbbbbbbbeeeeeeeeeeeeee uuuuuuuuuuuuuuuuuuuuuuuuuusssssssssssssssssssssss

eeeeeeeeeeeeedddddddddddddddddddd

uuuuuuuu

ttttttttttttooooooooooooooooottttttttttttttttttttttooooooooooooooooo

ooooooooooooooooooooooooooooooooooooooooooooorrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrtttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttttt

sssssssssssssssssssssssssuuuuuuuuuuuuuuuuuuuuuuuuuppppppppppppppppppppppppppppppppppppppppppppppppppp

ooooooooooooooooooooooorrrrrrrrrrrrraaaaaaaaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnnnnnnn

yyyyyyyyyyyyyyyyyyyyyyyyyyy

tttttttttttttttiiiiiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnnnnnnnnnnggggggggggggggggg

mmmmmmmmmmmmmmmmmmmmmmmmmmaaaaaaaaaaaaaaaaaaaaaaaaarrrrrrrrrrrrrrrrrrrrrrrrkkkkkkkkkkkkkkkkkkkkeeeeeeeeeeeeeeeeeetttttttttttttttttttttttttiiiiiiiiiiiiiiiiiiiiiiii

nnnnnnnnnnnnnnnnnnnnnnn

mmmmmmmmmmmmmmmmmmmmmmm

iiiiiiiiiiiiiiiiiiiiiiioooooooooooooooooooooonnnnnnnnnnnnnnnnnnnnn

ttttttttttthhhhhhhhhhhhhhhhhhhhoooooooooooooooooooooooooorrrrrrrrrrrrrrrrrrrrrrrrriiiiiiiiiiiiiiiiiiiiiiizzzzzzzzzzzzzzzzzzz

aaaaaaaaaaaaaaaaatttttttttttttttttttttttttttiiiiiiiiiiiiiiiiiiiiiiiiiiiiioooooooooooooooooooooooooo

aaaaaaaaaaaaaaaaaaaaaaauuuuuuuuuuuuuuuuuuuuuuuutttttttttttttttttttttthhhhhhhhhhhhhhhhhhhoooooooooooooooo

lllllllllllllllliiiiiiiiiiiiiiiiiiiiicccccccccccccccccccccccccaaaaaaaaaaaaaaaaaaaaaaaaaattttttttttttttttttttiiiiiiiiiiiiiiiiiiiooooooooooooooooooooooooooo

nnnnnnnnnnnnnnnnnnnnnnnnnnnn

aaaaaaaaaaaaaaaaaaaaaaaapppppppppppppppppppppppppppppppppppppppppppppppplllllllllllllllllllliiiiiiiiiiiiiiiiii

ccccccccccccccccc

aaaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnnnnddddddddddddddddddddddddddddd

aaaaaaaaaaaaa

nnnnnnnnnnnnnnyyyyyyyyyyyyyyyyyyyyyyyyyyyyy

aaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnnnnnyyyyyyyyyyyyyyyyyyyyyyyy

s

nnnnnnnnnnnnnnnnnnnnnnnnsssssssssssssssssssssssssssiiiiiiiiiiiiiiiiiiiiiiiiiiooooooooooooooooooooooooooonnnnnnnnnnnnnnnnnnnnnnnnnn

s

eeeeeeeeeeeeeeeeeeeeeeeeexxxxxxxxxxxxxxxxxxxxxttttttttttttttttttttttttteeeeeeeeeeeeeeeeeeeeeeeennnnnnnnnnnnnnnnnnnnnnnnn

ssssssssssssssssss

or va

riatio

ns th

ereof.


Confidential of 119

Height Velocity Reference Values for Calculating the PCDAI(Females)

Age (years) Height Velocity in cm per year (Females)

Minus 2SD Minus 1SD Mean

2.5 5.9 7.3 8.6

3 5.5 6.9 8.1

3.5 5.2 6.4 7.6

4 4.9 6.1 7.2

4.5 4.7 5.8 6.8

5 4.6 5.6 6.6

5.5 4.5 5.5 6.4

6 4.4 5.3 6.2

6.5 4.3 5.2 6.1

7 4.3 5.2 6

7.5 4.3 5.1 5.9

8 4.2 5 5.8

8.5 4.2 4.9 5.7

9 4.2 5 5.8

9.5 4.3 5 5.8

10 4.4 5.3 6.2

10.5 4.7 5.7 6.8

11 5.7 6.6 7.7

11.5 6.1 7.2 8.3

12 5.2 6.3 7.3

12.5 3.6 4.8 5.9

13 2.4 3.3 4.3

13.5 1.3 2.2 2.9

14 0.4 1.1 1.8

14.5 0 0.5 1

REDACTED 55

4.94 9EDCT

EDR

COPY PY

CO

This do

cumen

t can

not otno

c

be

bbeus

ed d

usto33t

supp

o.22 po

rt po

66su

any y

amark

eting

tin

g

rkmmmmm

autho

rizati

on n

za55 ho

au

appli

catio

n 6.16.1 nca

pppppap

and ndndndnd

any e

xtens

ions o

r vari

ation

s the

reof.


Confidential of 119

Height Velocity Chart (females)

CCCCCCCCCCCCCCCCCCCCCCCCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD

RRRRRRRRRRRRRRRRRRRRRRRRRREEEEEEEEEEEEEEEEEEEEEEEEEEEEEEDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACCCCCCCCCCCCCCCCCCCCCCCCCCCCTTTTTTTTTTTTTTTTTT

RRRRRRRRRRRRRRRR

CCCCCCCCCCCCCCCCCCCCCOOOOOOOOOOOOOOOOOOOOOOOOOPPPPPPPPPPPPPPPPPYYYYYYYYYYYYYYYY

CCCCCCCCCCCCCCCCCCCCCCCCCCCCCOOOOOOOOOOOOOOO

This do

cumen

ten

t en

nnnnnnnnnnnooooooooooooooooooooooooooooooootttttttttttttttttttttttttttttt

ccccccccccccccccccccccccaaaaaaaaaaaaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

bbbbbbbbbbbbbbbbbbbbbbbbbbeeeeeeeeeeeeeeeeeeeeeeeee uuuuuuuuuuusssssssssssssssssssssssss

eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeedddddddddddddddddddddddddddddd

uuuuuuuuuusssoooooottttttttttttttttttttttttooooooooooooooooooooooooo

rrrrrrrrrrrrrrrrrrrrrrrrrrttttttttttttttttttttttttttttttttttttttttttttttttttttt

ssssssssssssssssssssuuuuuuuuuuuuuuuuuuuuuuuuupppppppppppppppppppppppppppppppppppppppppppppppppppppp

oooooooooooooooooooooooooooorrrrrrrrrrrrrrrrrrrrrrrtttttttttttttttttttttttt

sssssssss

aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy

nnnnnnnnnnnnnnnnggggggggggggggggggggg

mmmmmmmmmmmmmmmmmmmmmmmmmmmmmaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaarrrrrrrrrrrrrrrrrrrrrrrrrrrrrkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkeeeeeeeeeeeeeeeeeeeeeeeeeeetttttttttttttttttttiiiiiiiiiiiiiiiiiii

nnnnnnnnnnnnnnnnnnnnnnnnggggggggggggggggggg

mmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmaaaaaaaaaaaaaaaaa

ooooooooooooooonnnnnnnnnnnnnnnnnnnnn

hhhhhhhhhhhhhhhooooooooooooooooooooorrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrriiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiizzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz

aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaattttttttttttttttttttttttttttttiiiiiiiiiiiiiiiiooooooooooooooooooooooooooonnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

aaaaaaaaaaaaaaaaaaaaaaaaaaaauuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuttttttttttttttttttttttttttttttttttttttthhhhhhhhhhhhhhhhhhhhhhhhhhooooooooooooooooooooo

iiiiiiiiiiicccccccccccccccccccccccccccccccccccaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaatttttttttttttttttttttttttttttiiiiiiiiiiiiiiiiiiiiiiiiiioooooooooooooooooooooooooooo

nnnnnnnnnnnnnnnnnnnnnnnnn

aaaaaaaaaaaaaappppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppplllllllllllllllllllllllllllllliiiiiiiiiiiiiiiiiiiiiiiiiiii

cccccccccccccccccccccaaaaaaaa

aaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnnnnnnnnnnddddddddddddddddddddddddddddddddddddddd

aaaaaaaaaaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnn

yyyyyyyyyyyyyyyyyyyyyyaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

yyyyyyyyyyyyyyyyyyyyyyyyyyy

sisssssssssssssssiiiiiiiiiiiiiiiiiiiiooooooooooooooooooooooooooooooooooooonnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnssssssssssssssssssssss

eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeexxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxtttttttttttttttttttttttttttttttttttteeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeennnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

ssssssssssssssssssssiiiiiiiiiiior roor

varia

tions

there

of.


Confidential of 119

Calculating height velocity:

1. Use the present height and height measurement during proceeding 6-12 months.

2. Calculate the height velocity as follows;

Present height – Height (6 – 12 months previously) x 12 = Height velocity (cm/year)

Interval (months) between heights

Ideally, bone age rather than chronologic age should be used. However, if maturity is appropriate for age (not delayed or advanced) it is reasonable to use chronologic age.

Scoring for the PCDAI:

Velocity less than “Minus 2 SD” scores 10 points

Velocity between “Minus 2 SD” and “Minus 1 SD” scores 5 points

Velocity greater than “Minus 1 SD” scores zero points.

Example:

If the subject is a male who is 10 years old:

1. Use the present height and height measurement during proceeding 6-12 months.

2. Calculate the height velocity as per equation provided.

3. For example in this 10-years-old male the height velocity comes up to 4 cm/year.

4. Next step refer to the table for height velocity values reference for males (provided).

5. You will notice that the 4 cm height velocity falls between the range of minus2SD and minus1SD.

6. The score for the PCDAI will be (5 points) as per above scoring guideline.

7. Go to the PCDAI and enter the #5 and complete the scoring of the PCDAI.

References:

REDACTED

rs ors o

COPY SDS

zero zero

This do

cumen

t can

notThe The

7.7. GG

beminminus

ed refe

ill notll nonu

tofer tfer su

pportht velovelo

n this 10this 1

anynd hend h

oc

marketi

ng

old: ld:

i

autho

rizati

on pop ap

plica

tion

scores cores

ointsoints

and a

ny ex

tensio

ns

ty is y is ic agec age

or va

riatio

ns th

ereof.


Confidential of 119

1. J.M. Tanner, Davies PSW. Clinical Longitudinal Standards for height and height velocity for North American children. J Pediatr 1985;107:317-29.

2. Jeffery Hyams, George D. Ferry, etal, development and validation of a pediatric Crohn’s disease activity index. J of Pediatric Gastroenterology and Nutrition 1991:12:439-47.

REDACTED COPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tion a

nd an

y exte

nsion

s or v

ariati

ons t

hereo

f.

REDACTED COPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tion a

nd an

y exte

nsion

s or v

ariati

ons t

hereo

f.


Confidential of 119

17.7 Protocol amendment #1Rationale for the amendment

The telephone numbers for reporting SAEs during business hours or outside business hours have been indicated. The inclusion and exclusion criteria were simplified to include any subject who completed C87035. Pregnancy due to oral contraceptive failure is not considered an SAE; the change was made to comply with Sponsor SAE reporting procedures. An additional example of an important medical event relevant to subjects with CD (infections that require treatment with parenteral antibiotics) was provided. An inconsistency in Visit 2 vital signs compared to the Schedule of Study Assessments was corrected in Section 9.6.7.

Specific changes

Change # 1 –Serious adverse reporting telephone numbers (page 5)


Fax Europe and Rest of the World (except Japan): +32 2 386 24 21USA: +1 800 880 6949Canada: +1 877 582 8842

Phone Europe and Rest of the World (except Japan): +32 2 386 24 68USA & Canada: +1 678 799 4007

Has been changed to:


Fax Europe and Rest of the World (except Japan): +32 2 386 24 21USA: +1 800 880 6949Canada: +1 877 582 8842

Phone During business hours: Outside business hours:

Europe and Rest of the World (except Japan): +32 2 386 24 68USA & Canada:

+1 770 970 2709

Europe and Rest of the World (except Japan): +32 2 386 24 68USA & Canada:

+1 678 799 4007

Change #2 - Inclusion criterion (Section 6.1) To be eligible to participate in this study, all of the following criteria must be met:


REDACTED

AC

))RE

COPY pt Jappt JapP

Y

This do

cumen

tChanChanToT

cann

ot

ca

be U

beus

ed uroprop

(excepexcepUSUS

to pepeosu

pport

88 877 5877

businbusinpps

anyof thf t

0 6940 694ma

the Wthemarketi

ng

, safetysafetyg

ma

autho

rizati

onpan):an)

ho

appli

catio

n386 286 2

+ap

and

aan

y y y unbunbyex

tensio

ns .6.7.6.7. or 2 2 va

riatio

ns th

ereof.


Confidential of 119


3. Subject satisfied the Inclusion criteria at time of entry into C87035 and completed the study (Week 62 Visit).



To be eligible to participate in this study, all of the following criteria must be met:



3. Subject completed the C87035 study (Week 62 Visit).


Change #3 - Exclusion criterion (Section 6.2)

Subjects are not permitted to enroll in the study if the following criterion is met:

1. Any exclusion criterion that would have prevented the subject from participation in C87035.


Subjects are not permitted to enroll in the study if the following criterion is met:

1. Subject did not complete the C87035 study (Week 62 Visit).

Change #4 – Pregnancy (Section 9.1.6; last paragraph)

A pregnancy becomes a serious adverse event (SAE) in the following circumstances: miscarriage, abortion, or anomaly/birth defect of the child. Pregnancy is considered as an SAE in case of contraceptive failure (eg, birth control pill taken each day without having been forgotten or use of permanent contraceptive devices). Those SAEs must be additionally reported using the Investigator SAE Report form.


A pregnancy becomes a serious adverse event (SAE) in the following circumstances: miscarriage, abortion, or anomaly/birth defect of the child. Pregnancy is considered as an SAE in case of contraceptive failure (eg, birth control pill taken each day without

REDACTEDomitomi8.1)..1).

on 6.2on 6.2

n the n the

COPY 62 Vis2 V

itanitan

This do

cumen

tbeen beenreprep

cann

otancyncy

rriageriageE in cE in c

f

be P

yy bbyyus

ed

PregPreg

to su

pportto enrto en

ompletmple

any m

arketi

ngstudystud

d have d have

autho

rizati

on sit)

nt mednt me

2) )

appli

catio

nd relrelaccordaccor

t). ).

and

lliaia

anynt formnt forex

tensio

ns

approvpprove parpar

or va

riatio

ns th

ereof.


Confidential of 119

having been forgotten or use of permanent contraceptive devices). Those SAEs must be additionally reported using the Investigator SAE Report form.

Change #5 – Definition of serious adverse event (Section 9.2.1; bullet 3)


• (Important medical events may include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.)



• (Important medical events may include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias that do not result in inpatient hospitalization, infections that require treatment with parenteral antibiotics, or the development of drug dependency or drug abuse.)

Change #6 – Vital signs (Section 9.6.7)

Systolic and diastolic blood pressure and pulse rate will be measured 15 minutes prior to dosing (with a ±5 minutes window) in a sitting position at entry Week 0, every 12 weeks starting at Week 14, and at the Completion/ET, Unscheduled, and SFU Visits.


Systolic and diastolic blood pressure and pulse rate will be measured 15 minutes prior to dosing (with a ±5 minutes window) in a sitting position at entry Week 0, Visit 2, every 12 weeks starting at Week 14, and at the Completion/ET, Unscheduled, and SFU Visits.

REDACTED

nd pulnd puln a sin a si

COPY reaeabuse.abuse

This do

cumen

t can

not b

e use

d to s

uppo

rwindwindek 14, ak 14

anyessureessur

dowdo

marketi

ngittingittingetion/Eetion/E

autho

rizati

on

se rate rat

appli

catio

nrequirequas that s that

ent wient w)

and

ii

any mam

to preto prex

tensio

ns

may jay

or va

riatio

ns th

ereof.


Confidential of 119

17.8 Protocol Amendment 2Rationale for the amendment

the decision was made to stop C87035 after determining it was inadequate to address the efficacy of CZP for labeling in pediatric subjects. CR0012 was amended to allow subjects ongoing in C87035 to enter CR0012 without having completed C87035, and for treatment in CR0012 to be continued until a subject reached the age of 18 years or CZP is approved for use in the US by pediatric subjects with CD.

Additional updates were made to reflect the current UCB contacts, regulatory status of CZP, subject exposure, and to comply with the updated UCB definition of AEs of interest.

The format and style of the document was changed to comply with UCB’s new document-authoring software; these changes are not specifically noted.

Specific changes:

1. Cover page

Old text:

PROTOCOL CR0012


COMPLETED C87035

PHASE 2B

IND Number: 11197

Sponsor:

SCHWARZ BIOSCIENCES, INC.

A Member of the UCB Group of Companies


Raleigh, NC 27617

UNITED STATES

REDACTED LL C LL

CENTENTZUMZUMAA

COPY

CRC

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

MAAACTACTIVIV

MPLMPL

autho

rizati

on

R00R00

TERTERABAB

appli

catio

n and

any e

xtens

ions of CZPof CZP

st.t.

w

or va

riatio

ns

ts

thereo

f.


Confidential of 119




New text:

PROTOCOL CR0012


COMPLETED C87035 OR WERE TERMINATED FROM C87035 WHEN THE STUDY WAS STOPPED BY UCB

PHASE 2B

IND Number: 11197

Sponsor:


A Member of the UCB Group of Companies8010 Arco Corporate Drive

Raleigh, NC 27617

UNITED STATES




Amendment 2 08 May 2012 Substantial

REDACTEDmber: mber:

SponSpon

COPY

This do

cumen

t nnntenca

nnotProPro

AmeAmen

be

otoote us

ed

mendmened to

supp

ort an

y80180mark

eting

BIOSCBIOS

r of theof thma

autho

rizati

on

1111971197

nsor:sor:

appli

catio

n PEan

d TEEED ED

anyASAS

ED EDex

tensio

ns

S THTHENN AA

SESE

or va

riatio

ns th

ereof.


Confidential of 119

2. Page 2, Sponsor declaration

Old text:

New text:

Clinical Project Manager_____________________________Date/Signature

Clinical Trial Biostatistician PhD _____________________________

Date/Signature

Study Physician, MD _____________________________

Date/Signature

Clinical Program Director , DVM _____________________________

Date/Signature

REDACTETED OOOOOOOOOOOOOOOPPPPPPPPPPPPPPP

CCCCCCCCCCCCCCCOOOOOOOOOOOOOOOOPY

This do

cumen

t ClCl

cann

onot b

eysicsicbe

used

iciacia

to su

pport

sticianticia

any m

arketi

ng au

thoriz

nnnnnnnnnnnnnn

rizati

oooooooonnnnnnnnnnnnnnn

ation

aaapppaappli

cati

annnnnnnnnnnnnndddddddd

and

ny

nyany ex

ttteeennennnnnnssn

sns

nsion

tens

or va

riatio

ns

v

thereo

f.


Confidential of 119

3. Page 3, Study contact information

Old text:

SponsorSCHWARZ BIOSCIENCES, INC.

A Member of the UCB Group of Companies


Raleigh, NC 27617

UNITED STATES

Principal/Coordinating Investigator



Phone:

Fax:

Clinical Project ManagerName: , MS


Phone:

Fax:

Clinical Study Biostatistician Name: , MS

Address: 208 Bath RoadSlough, Berkshire, SL1 3WE, UK

Phone:

Fax:

REDACTED ED

AC

COPY AACO

This do

cumen

t ntca

nnot ame:me:ot

AddAddanbeStudStu us

ed

dd

to tosu

ppo

upupupupuppo

rtRaleialeor

ppo

anyArcoArc

eigheigh

mao Cm

arketi

ng

, Mkemark

autho

rizati

on n

zaho

appli

catio

n nca

tan

d any

exten

sions

or va

riatio

ns th

ereof.


Confidential of 119

Clinical Monitoring Contract Research OrganizationName: Kendle International, Inc.

Address: 1200 Carew Tower441 Vine StreetCincinnati, Ohio 45202

Phone: +1 800 733 1572

Fax: +1 513 381 7684

New text:



Raleigh, NC 27617

UNITED STATES

Principal/Coordinating Investigator



Phone:

Fax:

Clinical Project ManagerName:


Phone:

Fax:

REDACTED

, MD, MDAC

CorpCorpREE

COPY

This do

cumen

tFFntca

nnot

PhonPhonno

c

be s: us

ed d

usto

MaMat

supp

ort rt

Manaan

tny

yan

yy marketi

ng

porate porateNC 276C 27

g

arma

autho

rizati

on

thoa

appli

catio

n and

any e

xtens

ions ss or o

varia

tions

there

of.


Confidential of 119

Clinical Study Biostatistician Name: , PhD


Phone:

Fax:

Medical MonitorName: , MD

Address: 5610 Point West DriveOakwood, GA 30566

Phone:

Fax:

Clinical Monitoring Contract Research OrganizationName: PRA International

Address: Glen Lake 64130 Parklake AvenueRaleigh, NC 27612

Phone: 919-786-8200

Fax: 919-786-8201

4. Section 1, Summary (paragraphs 1 through 6)

Old text:

This is a Phase 2b, open-label, multicenter study to assess the safety of certolizumab pegol (CDP870, CZP) in children and adolescents with active Crohn’s disease (CD) who completed C87035.

C87035 was a Phase 2, open-label, multicenter study to assess the safety, efficacy, pharmacokinetics (PK), and immunogenicity of CZP in children and adolescents ages 6 to 17 with moderately to severely active Crohn’s disease. The study was performed as a post approval commitment following the Food and Drug Administration (FDA) approval of CZP for the treatment of adults with moderately to severely active CD.

Certolizumab pegol, the investigational medicinal product (IMP) is a humanized antibody fragment antigen binding (Fab′), with specificity for human tumor necrosis factor alpha

REDACTEDch Och O

nalnal TE

6akeake

DA

COPY PY

OrO

This do

cumen

twith ith appapp

cann

ot 35 wa5 warmacmac

be ZP us

ed2b, op2b, opP) inP) in

to su

pport

99rt

y (p(pararan

y 66

-786-786-nymark

eting

e AveAvenn

NC 2761C 276

8200820ar

autho

rizati

on

rganrganriz

uth

appli

catio

n

ca

app

and

anan

y exte

nsion

s

ene

or va

riatio

ns th

ereof.


Confidential of 119

(TNF), conjugated to polyethylene glycol (PEG). The drug intended for use in this study is the liquid formulation of CZP in a prefilled syringe (PFS).

All subjects who complete the Week 62 assessments in C87035 (up to 100 subjects anticipated) are eligible to enter this open-label extension study. Following entry, subjects may continue on the CZP dose they were receiving at the end of C87035 (Low-Dose Group or High-Dose Group [weight adjusted in kg]) every 4 weeks (Q4W) for a 52-week open-label Treatment Period. The first clinic visit of this study should coincide with the Week 62 Visit of C87035. Home administration of CZP by the subject/caregiver/appropriate designee as determined by the Investigator will be permitted following appropriate training at clinic visits. A Safety Follow-Up (SFU) Visit will be conducted 12 weeks after the last dose of study medication.


A Data and Safety Monitoring Board (DSMB) will periodically review all emerging safety data. Interim analyses will be performed on an annual basis starting from 1 year after the first subject’s first visit in CR0012 has occurred.

New text:

This is a Phase 2b, open-label, multicenter study to assess the safety of certolizumab pegol (CDP870, CZP) in children and adolescents with active Crohn’s disease (CD) who completed C87035 or were terminated from C87035 when the study was stopped by UCB.

C87035 was a Phase 2, open-label, multicenter study to assess the safety, efficacy, pharmacokinetics (PK), and immunogenicity of CZP in children and adolescents ages 6 to 17 with moderately to severely active Crohn’s disease. The study was performed as a postapproval commitment following the Food and Drug Administration (FDA) approval of CZP for the treatment of adults with moderately to severely active CD.

the decision was made to stop C87035 after determining it was inadequate to address the efficacy of CZP for labeling in pediatric subjects. Subjects ongoing in the study were given the opportunity to enter CR0012 without having completed C87035.

Certolizumab pegol, the investigational medicinal product (IMP) is a humanized antibody fragment antigen binding (Fab′), with specificity for human tumor necrosis factor alpha (TNF), conjugated to polyethylene glycol (PEG). The drug intended for use in this study is the liquid formulation of CZP in a prefilled syringe (PFS).

All subjects who complete Week 62 of C87035 or were terminated from C87035 when the study was stopped by UCB (and completed all assessments required for Week 62/Visit 23 at the time of termination) are eligible to enter this open-label extension study.

Following entry, subjects may continue on the CZP dose they were receiving at the end of C87035 (Low-Dose Group or High-Dose Group [weight adjusted in kg]) every 4 weeks

REDACTED COPY

udyudy to toyyts withts wit

7035 w7035 w

multicmultic

This do

cumen

t can

not b

e use

d to su

pport

any m

arketi

ng au

thoriz

ation

appli

catio

n and

any e

xtens

ions o

r vari

ation

s the

reof.

e of of

le for for Pediatredi

7035 at035 ame).).

review eviewarting farting

o assessassesh activh activ

when twhen

center centegenicitenicit

CrohnCrohnwing thing t

ts with with the the

dress thress n the stthe s

d C870d C87

b pegolpegoantigenntige

conjugconjuiquid fquid

All subAll sustudstuW

po


Confidential of 119

(Q4W) for a 52-week open-label Treatment Period. The first clinic visit of this study should coincide with the last visit of C87035 (Week 62/Visit 23). Home administration of CZP by the subject/caregiver/appropriate designee as determined by the Investigator will be permitted following appropriate training at clinic visits. For subjects performing home administration, a phone call to the subject and/or the parents/caregiver will be performed by the Investigator (or designee) every 4 weeks between regular clinic visits.A Safety Follow-Up (SFU) Visit will be conducted 12 weeks after the last dose of study medication.


A Data and Safety Monitoring Board (DSMB) will periodically review all emerging safety data. Interim analyses will be performed on an annual basis starting from 1 year after the first subject’s first visit in CR0012 has occurred.

5. Section 2, Introduction (paragraph 6 and paragraph 8)

Old text:

Paragraph 6 -

Certolizumab pegol is an engineered, humanized antigen-binding fragment (Fab' fragment) conjugated to PEG with specificity for human TNF. Certolizumab pegol (CIMZIA®) has been approved in the US and Switzerland for reducing the signs and symptoms of CD and maintaining the clinical response in adult subjects with moderately to severely active disease who have had an inadequate response to conventional therapy.

Paragraph 8 -

The safety of CZP has been assessed in 2192 adult subjects with CD representing over 2456 patient years of exposure. Certolizumab pegol is well tolerated. The incidence of injection site reactions and hypersensitivity-type reactions was low. There were no reports of anaphylaxis or anaphylactoid-type reactions with CZP. All available data in CD show the safety of CZP is consistent with the known risks of anti-TNF therapies.

New text:Paragraph 6-

Certolizumab pegol is an engineered, humanized antigen-binding fragment (Fab' fragment) conjugated to PEG with specificity for human TNF. Certolizumab pegol (CIMZIA) has been approved in the US, Switzerland, Russia, Brazil, and Chile for reducing the signs and symptoms of CD and maintaining the clinical response in adult subjects with moderately to severely active disease who have had an inadequate response to conventional therapy.

Paragraph 8-

The safety of CZP has been assessed in 2518 adult subjects with CD representing over 2837 patient years of exposure. Certolizumab pegol is well tolerated. The incidence of

REDACTEDed aned aan TNan TN

d for refor rdult suult su

e to ce to

COPY

ntiti

This do

cumen

tprp

sysympmpyyysevsev

cann

otumamaugatedgated

roveove

be

ababus

ed to

sis supp

ortd hyhypepeyyctoidctoid

stent stent

any ssesse

. Cert Cerer

marketi

ngubj

conveconve

ed ined i

autho

rizati

on

tigen-gen-bbNF. CeF. Ce

educinducinbjectsects

appli

catio

n and

g frofrod anymergmer

om omaex

tensio

ns

CrohnCrohnonseconse

or va

riatio

ns th

ereof.


Confidential of 119

injection site reactions and hypersensitivity-type reactions was low. There were no reports of anaphylaxis or anaphylactoid-type reactions with CZP. All available data in CD show the safety of CZP is consistent with the known risks of anti-TNF therapies.

6. Section 3, Study objectives

Old text:

The primary objective of this open-label, multicenter study is to assess the longterm safety and tolerability of CZP in children and adolescents with moderately to severely active CD who completed C87035. The secondary objectives of this study are to assess the longterm efficacy, PK, and immunogenicity of CZP treatment on this population.

New text:

The primary objective of this open-label, multicenter study is to assess the longterm safety and tolerability of CZP in children and adolescents with moderately to severely active CD who completed C87035 or were terminated from C87035 when the study was stopped by UCB. The secondary objectives of this study are to assess the longterm efficacy, PK, and immunogenicity of CZP treatment on this population.

7. Section 5.1, Study description (paragraphs 1 through 6)

Old text:

This is a Phase 2, open-label, multicenter study in children and adolescents with moderately to severely active CD who completed C87035 to assess the longterm safety and tolerability of CZP.

All subjects who complete the Week 62 assessments in C87035 are eligible to enter this open-label study. Subjects may continue on CZP at the dose they were receiving at the end of C87035 (Low-Dose Group or High-Dose Group [weight adjusted in kg; see Section 7.2 and Table 7-1]) every 4 weeks for a 52-week open-label Treatment Period. The first clinic visit should coincide with the Week 62 visit of C87035. First study drug administration occurs 2 weeks later (Week 2) and subsequent clinic visits for safety and efficacy assessments are scheduled at 12-week intervals. After Week 2, subjects or parents/caregivers/appropriate designee as determined by the Investigator have the option of home administration of CZP upon appropriate training during a previous clinic visit(s) or continuing to have CZP administered every 4 weeks at the clinic. For subjects performing home administration, a phone call to the subject and/or the parents/caregiver will be performed by the Investigator (or designee) every 4 weeks between regular clinic visits in order to capture potential AEs and changes in concomitant medications, and to check compliance with home dosing. An SFU Visit will be conducted 12 weeks after the last dose of study medication for subjects.



Interim analyses will be performed on an annual basis starting from 1 year after the first subject’s first visit in CR0012 has occurred.

REDACTED in cin 35 to a5 to a

62 ass62 assnuenue

COPY ouou

chchi

This do

cumen

tPleasleasto Sto S

cann

otngesgesVisit Visit

sese

bee) eve) eii

used

eryry 44yyhe suhe su

toaininaini4

supp

ort subub

ervals. rvalsd byby ththyyingng

any62 vi62 v

bseqbsemark

eting

sessese on CZon CZ

Dose Gose G-weekweekvisi

autho

rizati

on

ildrendrenassess sess

ssmsm

appli

catio

n erm

6))

andstudytud

m efm efan

ygg

erely erelyy wy

exten

sions

m

gtermterm

or va

riatio

ns th

ereof.


Confidential of 119

Subjects who become ≥18 years during CR0012 may continue in the study at the Investigator’s discretion.

New text:This is a Phase 2, open-label, multicenter study in children and adolescents with moderatelyto severely active CD who completed C87035, or were terminated from C87035 when the study was stopped by UCB, to assess the longterm safety and tolerability of CZP.

All subjects who complete Week 62 of C87035 or were terminated from C87035 when the study was stopped by UCB (and completed all assessments required for Week 62/Visit 23 at the time of termination) are eligible for entry.

All subjects who complete the Week 62 assessments in C87035 are eligible to enter this open-label study. Subjects may continue on CZP at the dose they were receiving at the end of C87035 (Low-Dose Group or High-Dose Group [weight adjusted in kg; see Section 7.2 and Table 7-1]) every 4 weeks until the subject reaches the age of 18 years or CZP is approved for use in the US by pediatric subjects with CD. The first clinic visit should coincide with the last visit of C87035 (Week 62/Visit 23). First study drug administration occurs 2 weeks later (Week 2) and subsequent clinic visits for safety and efficacy assessments are scheduled at 12-week intervals. After Week 2, subjects or parents/caregivers/appropriate designee as determined by the Investigator have the option of home administration of CZP upon appropriate training during a previous clinic visit(s) or continuing to have CZP administered every 4 weeks at the clinic. For subjects performing home administration, a phone call to the subject and/or the parents/caregiver will be performed by the Investigator (or designee) every 4 weeks between regular clinic visits in order to capture potential AEs and changes in concomitant medications, and to check compliance with home dosing. An SFU Visit will be conducted 12 weeks after the last dose of study medication for subjects.



Interim analyses will be performed on an annual basis starting from 1 year after the first subject’s first visit in CR0012 has occurred.

Subjects who become ≥18 years during CR0012 may continue in the study at the Investigator’s discretion.

8. Section 5.1.1, Study duration per subject

Old text:

The maximum study duration of CZP treatment may be up to 52 weeks. An SFU visit will be conducted 12 weeks following the last dose of study drug.


weekweekbject abject a

ee) evee) evanges anges

FU VFU V

COPYWeW

ed byed by tyning ningk

This do

cumen

tOld tld t

ThTh

cann

ot atotot

ectionctio

tete

be ho bo beor’sor’sbus

edirst vrst vedbecbecu

towill bwill toiisu

pporty reviereviey

can recan r

beb

anyepresepremark

eting

inVisit wVisit w

AssesAsse

autho

rizati

ondurindurins at theat the

and/ornd/orvery 4ry 4

n concon

appli

catio

nudyudy dyyafetfety ay

2, subj2, subthe Invhe In

ng

and

yeaeat cliniclindd

anyee See S

ars oars ex

tensio

ns

enterenterening at ng at SeS

or va

riatio

ns th

ereof.


Confidential of 119

New text:

The maximum study duration of CZP treatment may be until the subject reaches the age of 18 years or CZP is approved for use in the US by pediatric subjects with CD. An SFU visit will be conducted 12 weeks following the last dose of study drug.


9. Section 5.1.2, Planned number of subjects and sites

Old text:

It is anticipated that the approximately 30 to 40 centers which participated in C87035 will participate in this study. Those subjects who completed Week 62 of C87035 may be enrolled in this study (up to 100 subjects anticipated).


• Last subject first visit: Jan 2013

• Last subject last visit: Mar 2014 (including the SFU Visit)

New text:It is anticipated that the approximately 30 to 40 centers which participated in C87035 will participate in this study. Those subjects who completed Week 62 of C87035 or were terminated from C87035 when the study was stopped by UCB (and completed all assessments required for Week 62/Visit 23 at the time of termination) may be enrolled in this study.


• Last subject first visit: Jun 2012

• Last subject last visit: to be determined (including the SFU Visit)

REDACTEDs stos sto3 at th at th

COPYrs whrs wpleted pletedoppop

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

terminerm

autho

rizati

ond WeWe

ped bped bhe time tim

appli

catio

n

ich parch paeekeek

and a

ny ex

tensio

ns will will

e enroenro

or va

riatio

ns th

ereof.

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

100

of 1

19

10.S

ectio

n 5.

2, S

ched

ule

of s

tudy

ass

essm

ents

(Tab

le 5

-1)

Old

text

:

Tab

le5-

1.Sc

hedu

le o

f stu

dyas

sess

men

ts

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic

adm

inis

trat

ionb

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

26,

10,

18,

22,

30

, 34,

42,

46

14, 2

6, 3

8, 5

052

62

Writ

ten

info

rmed

con

sent

X

Ass

essm

ent o

f inc

lusi

on/ e

xclu

sion

cr

iteria

X

Dem

ogra

phy

X

Life

styl

eC

8703

5

Cro

hn’s

dis

ease

his

tory

C87

035

Med

ical

and

surg

ical

his

tory

C87

035

Ass

essm

ent o

f chi

ldbe

arin

g po

tent

ial

C87

035

XX

Preg

nanc

y te

ste

C87

035

XX

X

Phys

ical

exa

min

atio

nC

8703

5X

XX

TB te

stX

TB q

uest

ionn

aire

XX

XX

Tann

er st

age

C87

035

XX

REDACTED

42, 4

42, ED

AC

RER

COPY PY

22, 2, 4646

PYPYPYYPY

This do

cumen

t can

not

noca

be

beus

ed d

seto CC tto

supp

ort rt

703503

5

o

C87

087

up

any

anmark

eting

ng

kekrkeke rkem

autho

rizati

on

1414 tioza

tho

appli

catio

n

itsitsbb

ap

and ddd

andan

y exte

nsion

s

ex

or va

riatio

ns

onthe

reof.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

101

of 1

19

Tab

le5-

1.Sc

hedu

le o

f stu

dyas

sess

men

ts

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic

adm

inis

trat

ionb

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

26,

10,

18,

22,

30

, 34,

42,

46

14, 2

6, 3

8, 5

052

62

Hei

ght

C87

035

XX

Wei

ght

C87

035

XX

Vita

l sig

nsf

C87

035

XX

XX

X

Adv

erse

eve

ntsa

C87

035

XX

XX

XX

Con

com

itant

med

icat

ions

aC

8703

5X

XX

XX

X

Con

curr

ent m

edic

al p

roce

dure

sC

8703

5X

XX

XX

X

PCD

AI

C87

035

XX

ESR

/hem

atoc

rit/a

lbum

in fo

r PC

DA

IC

8703

5X

X

CR

PC

8703

5X

X

Hem

atol

ogy/

chem

istry

/urin

alys

isC

8703

5X

XX

IMPA

CT

III

C87

035

XX

WPA

I:CD

gC

8703

5X

X

Cer

toliz

umab

peg

ol p

lasm

a co

ncen

tratio

nhC

8703

5X

XX

Ant

i-CZP

ant

ibod

y pl

asm

a co

ncen

tratio

niC

8703

5X

XX

Aut

oant

ibod

ies (

AN

A a

nd a

nti-d

sDN

A)

C87

035

XX

X

Bon

e m

arke

rs (o

steo

calc

in, b

one

spec

ific

C87

035

XX

XX EDCT

EEEDRER

COPY YYYYPYCO

This do

cumen

t can

not

ti-ds

Dds

D

n, b

on, b

on

noca

be

ntra

tira

t

DN

DNbe

used

ionon

hh

dd

ion

ionse

to CC ttosu

pport

5

rt

703503

5po

C87

087su

any

anmark

eting

ing

rke rkrkrkrkm

autho

rizati

on n

tio att

XX

hor

XXau

appli

catio

n

5050

XX

at

Xp

and ndnndndnd andan

yy y er

min

rmin

exten

sions

letio

n/et

ion/

ioooooor or

varia

tions

on

thereo

f.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

102

of 1

19

Tab

le5-

1.Sc

hedu

le o

f stu

dyas

sess

men

ts

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic

adm

inis

trat

ionb

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

26,

10,

18,

22,

30

, 34,

42,

46

14, 2

6, 3

8, 5

052

62

alka

line

phos

phat

ase,

n-te

lope

ptid

es)

Stud

y dr

ug a

dmin

istra

tionj

XX

X

Rei

nduc

tionk

Loss

of r

espo

nse

mus

t be

conf

irmed

at a

clin

ic v

isit

whe

re a

sses

smen

ts a

nd la

bs a

re p

erfo

rmed

to

dete

rmin

e PC

DA

I sco

re. S

core

s can

not b

e co

nfirm

ed u

ntil

lab

resu

lts a

re re

ceiv

ed b

y ce

ntra

l lab

a

few

day

s afte

r the

clin

ic v

isit.

Onc

e lo

ss o

f res

pons

e is

con

firm

ed, s

ites m

ust c

onta

ct th

e su

bjec

t to

retu

rn fo

r the

firs

t Rei

nduc

tion

Vis

it.R

eind

uctio

n W

eek

0 (f

irst r

eind

uctio

n do

se) i

s fol

low

ed b

y R

eind

uctio

n W

eek

2 (s

econ

d do

se, 2

w

eeks

afte

r firs

t dos

e), a

nd R

eind

uctio

n W

eek

4 (th

ird d

ose,

2 w

eeks

afte

r sec

ond

dose

). Su

bjec

ts

shou

ld re

turn

to th

e cl

inic

for e

ach

Rei

nduc

tion.

Sub

ject

resu

mes

the

orig

inal

sche

dule

of c

linic

vi

sits

afte

r rei

nduc

tion.

The

clin

ic sh

ould

con

tact

the

Stud

y M

onito

r to

dete

rmin

e th

e m

ost

appr

opria

te w

ay to

resu

me

the

orig

inal

sche

dule

of c

linic

vis

its.

Rei

nduc

tion

Wee

k 0

asse

ssm

ents

: PC

DA

I: ES

R, h

emat

ocrit

, and

alb

umin

; IM

PAC

T-II

I; W

PAI:C

DR

eind

uctio

n W

eek

2 as

sess

men

ts: P

CD

AI:

ESR

, hem

atoc

rit, a

nd a

lbum

inR

eind

uctio

n W

eek

4 as

sess

men

ts: P

CD

AI:

ESR

, hem

atoc

rit, a

nd a

lbum

in; W

PAI:C

DA

NA

=ant

inuc

lear

ant

ibod

y; C

RP=

C-r

eact

ive

prot

ein;

CZP

=cer

toliz

umab

peg

ol; d

sDN

A=d

oubl

e-st

rand

ed d

eoxy

ribon

ucle

ic a

cid

(ant

ibod

y);

ESR

=ery

thro

cyte

sedi

men

tatio

n ra

te; E

T=Ea

rly T

erm

inat

ion;

PC

DA

I=Pe

diat

ric C

rohn

’s D

isea

se A

ctiv

ity In

dex;

SFU

=Saf

ety

Follo

w-U

p; T

B=t

uber

culo

sis;

W

PAI:C

D=W

ork

Prod

uctiv

ity a

nd A

ctiv

ity Im

pairm

ent Q

uest

ionn

aire

for C

D

a.W

eek

0 of

CR

0012

is e

quiv

alen

t to

Wee

k 62

(sta

tus e

valu

atio

n) o

f C87

035

with

the

follo

win

g ex

cept

ions

: writ

ten

info

rmed

con

sent

, ass

essm

ent o

f in

clus

ion/

excl

usio

n cr

iteria

, dem

ogra

phy,

TB

test

ing,

and

TB

que

stio

nnai

re. O

ngoi

ng A

Es a

nd c

onco

mita

nt m

edic

atio

ns fr

om C

8703

5 w

ill c

ontin

ue to

be

follo

wed

in C

R00

12. O

ther

ass

essm

ents

will

be

take

n fr

om th

e C

8703

5 da

taba

se b

y U

CB

.

b.A

fter W

eek

2, su

bjec

ts o

r par

ents

/car

egiv

ers h

ave

the

optio

n of

hom

e ad

min

istra

tion

of C

ZP u

pon

appr

opria

te tr

aini

ng d

urin

g a

prev

ious

clin

ic v

isit(

s)

REDACTED

s can

ns c

ant.

Onc

et.

Onc

ect

ion

Vtio

n V

first

refir

st r

se),

anse

), an

cli

cl

COP

d at

a

d at

ano

OPY YYYYPYOP

This do

cumen

t

bjec

tje

c

cann

ot

a, d

ea,

de

2. O

the

. Oth

e

cts

cts

be

lent

ten

t temem

used=E

aEativ

ity I

vity

I

o

to

e prp

arly

ar

ly

sup

prot

ein

roteup

port

nduc

tidu

ctR

eind

uR

eind

sup

any

n W

n W

DD

marketi

ng

nd R

eid

Re

nic

fic

for eor

efff

on. T

hen.

Th

to re

sum

o re

suW

eeW

e

autho

rizati

on

clin

iccl

inic

ot b

e co

be c

oe

loss

olo

ss o

Vis

it.V

isit.

indu

ctnd

uct

einin

naappli

catio

n

5050 at

Xpla

and ndnndndnd andan

yy y er

min

rmin

exten

sions

letio

n/et

ion/

ioooooor or

varia

tions

on

thereo

f.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

103

of 1

19

Tab

le5-

1.Sc

hedu

le o

f stu

dyas

sess

men

ts

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic

adm

inis

trat

ionb

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

26,

10,

18,

22,

30

, 34,

42,

46

14, 2

6, 3

8, 5

052

62

or c

an c

ontin

ue to

hav

e C

ZP a

dmin

iste

red

ever

y 4

wee

ks a

t the

clin

ic. F

or su

bjec

ts p

erfo

rmin

g ho

me

adm

inis

tratio

n, a

pho

ne c

all t

o th

e su

bjec

t and

/or

the

pare

nts/

care

give

r will

be

perf

orm

ed b

y th

e In

vest

igat

or (o

r des

igne

e) e

very

4 w

eeks

bet

wee

n re

gula

r clin

ic v

isits

in o

rder

to c

aptu

re p

oten

tial A

Es

and

chan

ges i

n co

ncom

itant

med

icat

ions

, and

to c

heck

com

plia

nce

with

hom

e do

sing

. Sub

ject

s will

hav

e th

e op

tion

to e

ither

switc

h to

hom

e do

sing

or

switc

h ba

ck to

site

adm

inis

tratio

n at

any

time

durin

g th

e st

udy.

c.V

ital s

igns

, con

com

itant

med

icat

ion,

and

AEs

mus

t be

asse

ssed

at e

very

Uns

ched

uled

Vis

it. O

ther

safe

ty a

nd P

K a

sses

smen

ts (e

g,C

ZP p

lasm

a sa

mpl

e)

may

be

perf

orm

ed a

t the

dis

cret

ion

of th

e In

vest

igat

or a

s rel

ated

to th

e na

ture

of t

he v

isit.

d.Th

e SF

U V

isit

shou

ld b

e pe

rfor

med

12

wee

ks a

fter t

he fi

nal d

ose

of st

udy

med

icat

ion.

For

subj

ects

con

tinui

ng d

irect

ly o

nto

com

mer

cial

CZP

, a S

FU

Vis

it sh

ould

be

com

plet

ed p

rior t

o th

e fir

st d

ose

of c

omm

erci

al d

rug

adm

inis

tratio

n.

e.Fo

r all

fem

ales

pos

t men

ses,

a ur

ine

preg

nanc

y te

st w

ill b

e co

nduc

ted

at a

ll re

gula

rly sc

hedu

led

clin

ic v

isits

exc

ept W

eek

2.

f.V

ital s

igns

will

be

colle

cted

15

min

utes

prio

r to

dosi

ng w

ith a

±5

min

ute

win

dow

.

g.D

ays m

isse

d fr

om sc

hool

will

be

asse

ssed

usi

ng th

e W

PAI:C

D fo

r chi

ldre

n. T

he ti

me

mis

sed

from

wor

k w

ill b

e as

sess

ed u

sing

the

WPA

I:CD

for

wor

king

indi

vidu

als w

ith C

D. T

he e

ffec

t of t

he c

hild

’s C

D o

n th

e ca

regi

ver’

s pro

duct

ivity

will

be

asse

ssed

usi

ng th

e W

PAI:C

D fo

r car

egiv

ers o

f ch

ildre

nw

ith C

D.

h.Pl

asm

a sa

mpl

es w

ill b

e co

llect

ed to

det

erm

ine

the

conc

entra

tion

of C

ZP e

very

12

wee

ks st

artin

g at

Wee

k 14

, and

at t

he C

ompl

etio

n/Ea

rly T

erm

inat

ion

and

SFU

Vis

its. S

ampl

es w

ill b

e co

llect

ed b

efor

e do

sing

(exc

ept f

or th

e C

ompl

etio

n/ET

and

SFU

Vis

its w

hen

ther

e is

no

dosi

ng).

i.A

nti-C

ZP a

ntib

ody

conc

entra

tions

in p

lasm

a w

ill b

e co

llect

ed e

very

12

wee

ks st

artin

g at

Wee

k 14

, and

at t

he C

ompl

etio

n/ET

and

SFU

Vis

its (a

nti-C

ZP

antib

ody

mea

sure

men

ts w

ill b

e m

ade

usin

g th

e sa

mpl

es ta

ken

for P

K m

easu

rem

ents

att

hese

tim

e po

ints

, so

addi

tiona

l blo

od d

raw

s will

not

be

requ

ired)

.

j.If

hom

e ad

min

istra

tion

is p

erfo

rmed

, suf

ficie

nt st

udy

drug

will

be

disp

ense

d at

the

sche

dule

d ev

ery

12-w

eek

clin

ic v

isit

to la

st u

ntil

the

next

sche

dule

d

REDACTED

ever

y U

very

Uto

the

to th

e

dose

dose

COPYpp4

wee

4 w

eem

e do

sim

e do

si

This do

cumen

t

ratioati

cann

ot

ntra

ttra

ts w

ill b

will

b

ion

ion

i

be

e

tion

tio

used

o de

ter

dete

colle

colle

to su

pport

g th

e W

g th

e W

fthe

chi

the

ch

any

ng w

ithng

wi

marketi

ng

of st

uof

stu

al d

rug

aal

dru

g

be c

ondu

e co

nd

autho

rizati

on

ing.

Sng

. S

Uns

che

nsch

ena

ture

natu

re

appli

cat

rmin

g ho

min

g h

ks b

etw

s bet

wSu

bS

ation

5050 atan

d ndnndndnd andan

yy y er

min

rmin

exten

sions

letio

n/et

ion/

ioooooor or

varia

tions

on

thereo

f.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

104

of 1

19

Tab

le5-

1.Sc

hedu

le o

f stu

dyas

sess

men

ts

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic

adm

inis

trat

ionb

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

26,

10,

18,

22,

30

, 34,

42,

46

14, 2

6, 3

8, 5

052

62

clin

ic v

isit.

k.If

a su

bjec

t has

not

bee

n pr

evio

usly

rein

duce

d in

C87

035,

the

subj

ect i

s elig

ible

for 1

rein

duct

ion

due

to lo

ss o

f res

pons

e in

CR

0012

.

REDACTED COPY

le fo

r 1le

for

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on

1 r

appli

cat

rein

duei

ndu

ation

5050 atan

d ndnndndnd andan

yy y er

min

rmin

exten

sions

letio

n/et

ion/

ioooooor or

varia

tions

on

thereo

f.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

105

of 1

19

New

text

:

Tab

le 5

-1.

Sche

dule

of s

tudy

ass

essm

ents

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic a

dmin

istr

atio

nb

Reg

ular

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

2E

very

4 w

eeks

beg

inni

ng

at W

eek

6 an

d in

be

twee

n re

gula

r cl

inic

vi

sits

Eve

ry 1

2 w

eeks

be

ginn

ing

at W

eek

14+1

2 w

eeks

af

ter

last

do

se o

f st

udy

drug

Writ

ten

info

rmed

con

sent

X

Ass

essm

ent o

f inc

lusi

on/

excl

usio

n cr

iteria

X

Dem

ogra

phy

X

Life

styl

eC

8703

5

Cro

hn’s

dis

ease

his

tory

C87

035

Med

ical

and

surg

ical

his

tory

C87

035

Ass

essm

ent o

f chi

ldbe

arin

g po

tent

ial

C87

035

XX

Preg

nanc

y te

ste

C87

035

XX

X

Phys

ical

exa

min

atio

nC

8703

5X

XX

TB te

stX

TB q

uest

ionn

aire

XX

XX

Tann

er st

age

C87

035

XX

Hei

ght

C87

035

XX

Wei

ght

C87

035

XX

Vita

l sig

nsf

C87

035

XX

XX

X

EDCT

EDR

COPY OPC

This do

cumen

t can

not CC nnnno

cann

be

C87

C87be

8707 be

used

d

5

dddd

035

035us

to tsu

pport

tttpo

rtpopoop

su

any y

amark

eting

ng

ke

autho

rizati

on

zaori hoooo

au

appli

catio

n

ek 1

4k

14

plic

ap

anddddd

andan

yEar

Ea

Ter

mT

erm

exten

sions

on

s

mpl

eti

plet

ite

or va

riatio

ns

onthe

reof.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

106

of 1

19

Tab

le 5

-1.

Sche

dule

of s

tudy

ass

essm

ents

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic a

dmin

istr

atio

nb

Reg

ular

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

2E

very

4 w

eeks

beg

inni

ng

at W

eek

6 an

d in

be

twee

n re

gula

r cl

inic

vi

sits

Eve

ry 1

2 w

eeks

be

ginn

ing

at W

eek

14+1

2 w

eeks

af

ter

last

do

se o

f st

udy

drug

Adv

erse

eve

ntsa

C87

035

XX

XX

XX

Con

com

itant

med

icat

ions

aC

8703

5X

XX

XX

X

Con

curr

ent m

edic

al p

roce

dure

sC

8703

5X

XX

XX

X

PCD

AI

C87

035

XX

ESR

/hem

atoc

rit/a

lbum

in fo

r PC

DA

IC

8703

5X

X

CR

PC

8703

5X

X

Hem

atol

ogy/

chem

istry

/urin

alys

isC

8703

5X

XX

IMPA

CT

III

C87

035

Xl

X

WPA

I:CD

gC

8703

5X

lX

Cer

toliz

umab

peg

ol p

lasm

a co

ncen

tratio

nhC

8703

5X

XX

Ant

i-CZP

ant

ibod

y pl

asm

a co

ncen

tratio

niC

8703

5X

XX

Aut

oant

ibod

ies (

AN

A a

nd a

nti-

dsD

NA

)C

8703

5X

XX

Bon

e m

arke

rs (o

steo

calc

in,

bone

spec

ific

alka

line

phos

phat

ase,

n-te

lope

ptid

es)

C87

035

Xl

X

REDACTED ED

DAR

COPY PY

CCCCC

This do

cumen

t can

notCC

annn

be eus

ed d

0355

ddddto tsu

pport

tpo

rt

upp

any y

amark

eting

ng

ar m

autho

rizati

on

ioniza ori

ut

appli

catio

n tio

XX

lic

XXap

and

andan

y ny ex

tensio

ns

tion/

on

/ ar

ly

rly

min

atin

a

ioooooor or

varia

tions

on

thereo

f.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

107

of 1

19

Tab

le 5

-1.

Sche

dule

of s

tudy

ass

essm

ents

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic a

dmin

istr

atio

nb

Reg

ular

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

2E

very

4 w

eeks

beg

inni

ng

at W

eek

6 an

d in

be

twee

n re

gula

r cl

inic

vi

sits

Eve

ry 1

2 w

eeks

be

ginn

ing

at W

eek

14+1

2 w

eeks

af

ter

last

do

se o

f st

udy

drug

Stud

y dr

ug a

dmin

istra

tionj

XX

X

Rei

nduc

tionk

Loss

of r

espo

nse

mus

t be

conf

irmed

at a

clin

ic v

isit

whe

re a

sses

smen

ts a

nd la

bs a

re p

erfo

rmed

to d

eter

min

e PC

DA

I sco

re.

Scor

es c

anno

t be

conf

irmed

unt

il la

b re

sults

are

rece

ived

by

cent

ral l

ab a

few

day

s afte

r the

clin

ic v

isit.

Onc

e lo

ss o

f re

spon

se is

con

firm

ed, s

ites m

ust c

onta

ct th

e su

bjec

t to

retu

rn fo

r the

firs

t Rei

nduc

tion

Vis

it.R

eind

uctio

n W

eek

0 (f

irst r

eind

uctio

n do

se) i

s fol

low

ed b

y R

eind

uctio

n W

eek

2 (s

econ

d do

se, 2

wee

ks a

fter f

irst d

ose)

, and

R

eind

uctio

n W

eek

4 (th

ird d

ose,

2 w

eeks

afte

r sec

ond

dose

). Su

bjec

ts sh

ould

retu

rn to

the

clin

ic fo

r eac

h R

eind

uctio

n.

Subj

ect r

esum

es th

e or

igin

al sc

hedu

le o

f clin

ic v

isits

afte

r rei

nduc

tion.

The

clin

ic sh

ould

con

tact

the

Stud

y M

onito

r to

dete

rmin

e th

e m

ost a

ppro

pria

te w

ay to

resu

me

the

orig

inal

sche

dule

of c

linic

vis

its.

Rei

nduc

tion

Wee

k 0

asse

ssm

ents

: PC

DA

I: ES

R, h

emat

ocrit

, and

alb

umin

; IM

PAC

T-II

I; W

PAI:C

DR

eind

uctio

n W

eek

2 as

sess

men

ts: P

CD

AI:

ESR

, hem

atoc

rit, a

nd a

lbum

inR

eind

uctio

n W

eek

4 as

sess

men

ts: P

CD

AI:

ESR

, hem

atoc

rit, a

nd a

lbum

in; W

PAI:C

D

AN

A=a

ntin

ucle

ar a

ntib

ody;

CR

P=C

-rea

ctiv

e pr

otei

n; C

ZP=c

erto

lizum

ab p

egol

; dsD

NA

=dou

ble-

stra

nded

deo

xyrib

onuc

leic

aci

d (a

ntib

ody)

; ES

R=e

ryth

rocy

te se

dim

enta

tion

rate

; ET=

Early

Ter

min

atio

n; P

CD

AI=

Pedi

atric

Cro

hn’s

Dis

ease

Act

ivity

Inde

x; S

FU=S

afet

y Fo

llow

-Up;

TB

=tub

ercu

losi

s;

WPA

I:CD

=Wor

k Pr

oduc

tivity

and

Act

ivity

Impa

irmen

t Que

stio

nnai

re fo

r CD

a Wee

k 0

of C

R00

12 is

equ

ival

ent t

o th

e la

st v

isit

(Wee

k62

; sta

tus e

valu

atio

n) o

f C87

035

with

the

follo

win

g ex

cept

ions

: writ

ten

info

rmed

con

sent

, as

sess

men

t of i

nclu

sion

/exc

lusi

on c

riter

ia, d

emog

raph

y, T

B te

stin

g, a

nd T

B q

uest

ionn

aire

. Ong

oing

AEs

and

con

com

itant

med

icat

ions

from

C87

035

will

co

ntin

ue to

be

follo

wed

in C

R00

12. O

ther

ass

essm

ents

will

be

take

n fr

om th

e C

8703

5 da

taba

se b

y U

CB

. Sub

ject

s who

wer

e te

rmin

ated

from

C87

035

whe

n th

e st

udy

was

stop

ped

by U

CB

com

plet

ed a

ll as

sess

men

ts r

equi

red

for

Wee

k 62

/Vis

it 23

at t

he ti

me

of te

rmin

atio

n.b A

fter W

eek

2, su

bjec

ts o

r par

ents

/car

egiv

ers h

ave

the

optio

n of

hom

e ad

min

istra

tion

of C

ZP u

pon

appr

opria

te tr

aini

ng d

urin

g a

prev

ious

clin

ic v

isit(

s) o

r ca

n co

ntin

ue to

hav

e C

ZP a

dmin

iste

red

ever

y 4

wee

ks a

t the

clin

ic. F

or su

bjec

ts p

erfo

rmin

g ho

me

adm

inis

tratio

n, a

pho

ne c

all t

o th

e su

bjec

t and

/or t

he

pare

nts/

care

give

r will

be

perf

orm

ed b

y th

e In

vest

igat

or (o

r des

igne

e) e

very

4 w

eeks

bet

wee

n re

gula

r clin

ic v

isits

in o

rder

toca

ptur

e po

tent

ial A

Es a

nd

chan

ges i

n co

ncom

itant

med

icat

ions

, and

to c

heck

com

plia

nce

with

hom

e do

sing

. Sub

ject

s will

hav

e th

e op

tion

to e

ither

switc

h to

hom

e do

sing

or s

witc

h ba

ck to

site

adm

inis

tratio

n at

any

time

durin

g th

e st

udy.

c Vita

l sig

ns, c

onco

mita

nt m

edic

atio

n, a

nd A

Es m

ust b

e as

sess

ed a

t eve

ry U

nsch

edul

ed V

isit.

Oth

er sa

fety

and

PK

ass

essm

ents

(eg,

CZP

pla

sma

sam

ple)

may

owed

owe

seco

nd

seco

nd

ic v

isits

c vi

sits

ume

thm

e th

PCD

AI

PCD

AI

s: P

CD

s: P

C

COPY

sses

sss

eby

cen

tby

cen

o re

turn

o re

turn

db

db

This do

cumen

t can

not

tioiot a

nytim

anyt

imt m

edi

med

i

be

ed b

ybyon

s, on

s,

used

give

rsve

rsed

eve

d ev

ey

thy

th

to

plet

epl

et hh

supp

ort

Wee

kee

k66

raph

y, T

aphy

,ss

men

tssm

ents

ted

ted

any

n; P

Que

stio

Que

sti

62

mark

erto

lizum

toliz

uPC

DPC

D

rketin

g : D

AI:

ESD

AI:

EPC

DA

I:PC

DA

rk

autho

rizati

onfor t

hor

thy

Rei

ndR

eind

dose

). S

ose)

. Ss a

fter r

afte

r re

orig

inor

igin

ESR

, ES

R,

appli

catio

n tio

ents

and

nt

s an

al la

b a

al la

b a

hef

he

lic

and

andan

y ny ex

tensio

ns

tion/

on

/ ar

ly

rly

min

atin

a

ioooooor or

varia

tions

on

thereo

f.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

108

of 1

19

Tab

le 5

-1.

Sche

dule

of s

tudy

ass

essm

ents

Tre

atm

ent P

erio

d

Vis

it or

pho

ne c

all

(+/-7

days

)E

ntry

aV

isit

Phon

e ca

ll (h

ome

adm

inis

trat

ion)

or v

isit

(clin

ic a

dmin

istr

atio

nb

Reg

ular

Clin

ic V

isits

bC

ompl

etio

n/

Ear

ly

Ter

min

atio

n

Uns

ched

uled

V

isitc

SFU

d

Wee

k0

2E

very

4 w

eeks

beg

inni

ng

at W

eek

6 an

d in

be

twee

n re

gula

r cl

inic

vi

sits

Eve

ry 1

2 w

eeks

be

ginn

ing

at W

eek

14+1

2 w

eeks

af

ter

last

do

se o

f st

udy

drug

be p

erfo

rmed

at t

he d

iscr

etio

n of

the

Inve

stig

ator

as r

elat

ed to

the

natu

re o

f the

vis

it.d Th

e SF

U V

isit

shou

ld b

e pe

rfor

med

12

wee

ks a

fter t

he fi

nal d

ose

of st

udy

med

icat

ion.

For

subj

ects

con

tinui

ng d

irect

ly o

nto

com

mer

cial

CZP

, a S

FU V

isit

shou

ld b

e co

mpl

eted

prio

r to

the

first

dos

e of

com

mer

cial

dru

g ad

min

istra

tion.

e For a

ll fe

mal

es p

ost m

ense

s, a

urin

e pr

egna

ncy

test

will

be

cond

ucte

d at

all

regu

larly

sche

dule

d cl

inic

vis

its e

xcep

t Wee

k 2.

f Vita

l sig

ns w

ill b

e co

llect

ed 1

5 m

inut

es p

rior t

o do

sing

with

a ±

5 m

inut

e w

indo

w.

g Day

s mis

sed

from

scho

ol w

ill b

e as

sess

ed u

sing

the

WPA

I:CD

for c

hild

ren.

The

tim

e m

isse

d fr

om w

ork

will

be

asse

ssed

usi

ng th

eW

PAI:C

D fo

r wor

king

in

divi

dual

s with

CD

. The

eff

ect o

f the

chi

ld’s

CD

on

the

care

give

r’s p

rodu

ctiv

ity w

ill b

e as

sess

ed u

sing

the

WPA

I:CD

for c

areg

iver

s of c

hild

ren

with

CD

.h Pl

asm

a sa

mpl

es w

ill b

e co

llect

ed to

det

erm

ine

the

conc

entra

tion

of C

ZP e

very

12

wee

ks st

artin

g at

Wee

k 14

, and

at t

he C

ompl

etio

n/Ea

rly T

erm

inat

ion

and

SFU

Vis

its. S

ampl

es w

ill b

e co

llect

ed b

efor

e do

sing

(exc

ept f

or th

e C

ompl

etio

n/ET

and

SFU

Vis

its w

hen

ther

e is

no

dosi

ng).

i Ant

i-CZP

ant

ibod

y co

ncen

tratio

ns in

pla

sma

will

be

colle

cted

eve

ry 1

2w

eeks

star

ting

at W

eek

14, a

nd a

t the

Com

plet

ion/

ET a

nd S

FU V

isits

(ant

i-CZP

an

tibod

y m

easu

rem

ents

will

be

mad

e us

ing

the

sam

ples

take

n fo

r PK

mea

sure

men

ts a

t the

se ti

me

poin

ts, s

o ad

ditio

nal b

lood

dra

ws w

ill n

ot b

e re

quire

d).

j If h

ome

adm

inis

tratio

n is

per

form

ed, s

uffic

ient

stud

y dr

ug w

ill b

e di

spen

sed

at th

e sc

hedu

led

ever

y 12

-wee

k cl

inic

vis

it to

last

unt

il th

e ne

xt sc

hedu

led

clin

ic

visi

t.k If

a su

bjec

t has

not

bee

n pr

evio

usly

rein

duce

d in

C87

035,

the

subj

ect i

s elig

ible

for 1

rein

duct

ion

due

to lo

ss o

f res

pons

e in

CR

0012

.l M

easu

red

at W

eeks

14,

26,

38,

50

and

then

eve

ry 1

2 m

onth

s the

reaf

ter.REDACTEDg

win

dow

win

dow

ldre

n. T

dren

. pr

odpr

oducuc

n of

CZ

n of

CZ

hehe

COPY

n. F

on.

F

ular

ly

ular

ly

This do

cumen

t can

not b

e use

d to s

uppo

rt

C87

035,

8703

y 12

m12

monon

any

will

w

il

marketi

ng

ZP e

vevC

ompl

eC

ompl

eve

ry 1

2er

y 12

for P

Kfo

r PK

bb

autho

rizati

on

sche

dsc

hed

The

timTh

e tim

ctiv

ity

tivity

ve

rve

r

appli

catio

subj

ects

bjec

t

tion

tioan

d an

dany ny

exten

sions

tion/

on

/ ar

ly

rly

min

atin

a

ioooooor or

varia

tions

on

thereo

f.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

109

of 1

19

11.S

ectio

n 5.

3, S

chem

atic

dia

gram

(fig

ure)

Old

text

:

New

text

:

EEEEEEEEDDDDDDDD

AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCTTTTTTTTTTTTTTTTTTTTTTTTTTTEEEEEEEEDDDDDDDD

REEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAARRRRR

OPYYYYYYY

CO

This do

cumen

t can

not b

e use

ded to

oooooooooooooooooooooooooooooooooorrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrttttttttttttttttttttttttttttttttttttt

suuuuuuppppppppppppppppppppp

ooooooooooooooooooooooooooooooooooos

nyyyyyyyy

aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaany

ng

arkettttttttiiiiiiii

nnnnnnnng

mar

nnnnnnnnnnza

tioooooooonnnnnnnnn

ttttttttttttttttttthhhhhhhhhhhhhhhooriz

a

auuuuuuuuttttttttttttthhhhhhhhh

on

licatio

n

appli

ca

dan

d anyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy

snnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnssssssssssssssssssssssssssssssssssssssssssssssssss

iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiioooooooooooooooooooooooons

eeeeeeeeeexxxxxxxxxxxxxxxxxxxxxxxxxxxxxtttttttttttttttttttttttttttttttttttttteeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeennnnnn

s

e

or va

riatio

ns

onthe

reof.

0808MM

UC

B08

May

201

2C

linic

al S

tudy

Pro

toco

lC

erto

lizum

ab p

egol

CR

0012

Con

fiden

tial

Page

110

of 1

19

CZP

=cer

toliz

umab

peg

ol; Q

4W=e

very

4 w

eeks

CCCCCCCCCCCOOOOOOOOOOPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eti eting

autho

rizati

oooooooooooooonnnnnnnnnnn ap

plica

tiioooooooonnn a

nd

y an

yexten

sions

or va

riatio

ns

onthe

reof.

0808MM


Confidential of 119

12. Section 5.4, Rational for study design and selection of dose

Old text:Following the Food and Drug Administration (FDA) approval of CZP for the treatment of CD in adults, C87035 was a postapproval commitment to investigate the administration of CZP administration in children and adolescents with moderately to severely active CD. This study will provide continued treatment of CZP to subjects who completed C87035 and who, in the Investigator’s opinion, would benefit from continued administration of CZP.

The primary objective of this open-label study is to assess the longterm safety and tolerability of CZP in children and adolescents with moderately to severely active CD who completed C87035. The secondary objectives of this study are to assess the longterm efficacy, PK, and immunogenicity of CZP treatment on this population. Subjects may continue on CZP at the dose they were receiving at the end of C87035.

New text:

Following the Food and Drug Administration (FDA) approval of CZP for the treatment of CD in adults, C87035 was a postapproval commitment to investigate the administration of CZP administration in children and adolescents with moderately to severely active CD. This study will provide continued treatment of CZP to subjects who completed C87035 or were terminated from C87035 when the study was stopped by UCB and who, in the Investigator’s opinion, would benefit from continued administration of CZP.

The primary objective of this open-label study is to assess the longterm safety and tolerability of CZP in children and adolescents with moderately to severely active CD who completed C87035 or were terminated from C87035 when the study was stopped by UCB. The secondary objectives of this study are to assess the longterm efficacy, PK, and immunogenicity of CZP treatment on this population. Subjects may continue on CZP at the dose they were receiving at the end of C87035.

13. Section 6.1, Inclusion criteria (item #3)

Old text:

3. Subject completed the C87035 study (Week 62 Visit).

New text:3. Subject completed the C87035 study (Week 62 Visit) or was terminated from

C87035 when the study was stopped by UCB and completed all assessments required for Week 62/Visit 23 at the time of termination.

REDACTEDs ss stotocontinucontinu

l study studywith mwith m

8787

COPYto

modemodsubjecsubjecop

This do

cumen

t can

not

jjC870C870reqreq

beect cect cus

ed mplp toletelete

supp

ortcritecrite

d

anyend oend m

arketi

ngmoderde

7035 w035 we to ass to as

on thion thf

auyy tho

rizati

oncts wts wpped bped b

ued adued ad

is to is toyyeraera

appli

catio

n f CZP CZP

estigatestigaratelatelyywhoh

and a

nye one onexten

sions

olerablerab

ompleomplecacyacy PPn CC

or , va

riatio

ns th

ereof.


Confidential of 119

14. Section 6.2, Exclusion criteria (item #1)

Old text:

1. Subject did not complete the C87035 study (Week 62 Visit).

New text:

1. Subject did not complete the C87035 study (Week 62 Visit) or was terminated from C87035 when the study was stopped by UCB but did not complete all assessments required for Week 62/Visit 23 at the time of termination.

15. Section 7.7, Procedures for monitoring and subject compliance (final paragraph)

Old text:If a subject is found to be persistently noncompliant (missing 2 or more consecutive scheduled IMP doses or missing 3 or more doses over the 52-week Treatment Period), the Sponsor in conjunction with the Investigator will make a decision as to whether the subject should be withdrawn from the study.

New text:

If a subject is found to be persistently noncompliant (missing 2 or more consecutive scheduled IMP doses or missing 3 or more doses over the 52-week Treatment Period), the Sponsor in conjunction with the Investigator will make a decision as to whether the subject should be withdrawn from the study.

16. Section 8.1, Entry Week 0

New text added at the beginning:

Week 0 of CR0012 is equivalent to Week 62 of C87035 with the exceptions noted below. Subjects who were terminated from C87035 when the study was stopped by UCB completed all assessments required for Week 62/Visit 23 at the time of termination.

17. Section 8.2, Week 2 Visit (final bullet)

Old text:

• Dispensing of drug to subject/caregiver/appropriate designee as determined by the Investigator, if appropriate for home dosing (for Weeks 6 and 10)

New text:

• Dispensing of drug to subject/caregiver/appropriate designee as determined by the Investigator, if appropriate for home dosing (for Weeks 6 and 10)

REDACTED

WW

COPY missmiser theer theOPY

makemake

This do

cumen

t can

not ensns

vestigaestigabe

singsing

used

f apf a tougg

apprapprsu

pport

it

g to sto s

any (fina(finamark

eting

Weekeek 626

m C87m C8red foed f

autho

rizati

one a dee a deap

plica

tion

g 2 or m2 or 5252--wwap

i

andwhewhean

yent Peent Petheeth

exten

sions

aph)ph)

cutiveutive

or va

riatio

ns th

ereof.


Confidential of 119

18. Section 8.3 (section heading text)

Old text:

Phone call (home administration) or visit (clinic administration) (Weeks 6, 10, 18, 22, 30, 34, 42, 46)

New text:

Phone call (home administration) or visit (clinic administration) (every 4 weeks and in between regular clinic visits beginning at Week 6)

19. Section 8.4 (section heading text and content)

Old text:

8.4 Weeks 14, 26, 38, 50 Visits

• Assessment of childbearing potential (female subjects only)




• Tanner stage


• Vital signs

• Adverse events



• PCDAI


• CRP


• IMPACT III

• WPAI:CD (for children, for working individuals with CD and for caregivers)






REDACTED COPY

This do

cumen

t• AA

••

cann

otAI:C:C

Certolerto

A

be

CDCDus

edclinlin

IIIII

to nicnicsu

pportmin forn fo

any m

arketi

ng

s

autho

rizati

on ap

plica

tion a

nd

ly)y)an

y exte

nsion

s or v

ariati

ons t

hereo

f.


Confidential of 119

• Dispensing of drug to subject/caregiver/appropriate designee as determined by the Investigator, if appropriate for home dosing:

− Week 14 (for Weeks 18 and 22)



New text:

8.4 Regular clinic visits

8.4.1 Assessments every 12 weeks beginning at Week 14

• Assessment of childbearing potential (female subjects only)




• Tanner stage


• Vital signs

• Adverse events



• PCDAI


• CRP


• IMPACT III

• WPAI:CD (for children, for working individuals with CD and for caregivers)






REDACTED COPY

This do

cumen

t• AA

•

cann

otolizulizu

Anti-nti-CC

be CD

umumus

ed

D (foD (fou

to su

pport

cal chal ch

any or PCDor PCmark

eting

autho

rizati

on ap

plica

tion a

nd an

y exte

nsion

s or v

ariati

ons t

hereo

f.


Confidential of 119





• 8.4.2 Assessments at Weeks 14, 26, 38, 50 and then every 12 months thereafter:

− IMPACT III

− WPAI:CD (for children, for working individuals with CD, and for caregivers)

− Bone markers (osteocalcin, bone specific alkaline phosphatase, n-telopeptides)

20. Section 8.5 (section heading text)

Old text:

Completion (Week 52)/Early Termination Visit

New text:

Completion/Early Termination Visit

21. Section 9.3 (section heading test and bullet list)

Old text:

Section heading-

Adverse events of special interest

Bullet list-

• Infections including serious opportunistic infections

• Malignancies including lymphoma and leukemia





• Lupus and lupus-like syndrome


New text:

Section heading-

Adverse events of interest

REDACTED t COPY list)ist)

This do

cumen

tee cann

otpus anus an

SerioSerio

bebleele

d

usedemia, mia,

eedieed

to e su

pport

ymy

ureure

disodiso

any

pp

mphomphomark

eting

portuportu

autho

rizati

on ap

plica

tion a

nd an

y exte

nsion

s giversivers

lopepopep

or va

riatio

ns th

ereof.


Confidential of 119

Bullet list-

• Serious infections including opportunistic infections

• Malignancies including lymphoma





• Lupus and lupus-like illness


22. Section 9.4, Immediate reporting of adverse events (last bullet)

Old text:

• AE of special interest (see Section 9.3)

New Text:

• AE of special interest (see Section 9.3)

23. Section 10.4.1, Bone markers

Old text:

Markers of bone and collagen turnover, reflecting the childhood growth curve, will be measured every 12 weeks starting at Week 14, and at the Completion/ET Visit. These markers will include: osteocalcin, bone specific alkaline phosphatase, and n-telopeptides. Tests will be performed by a central laboratory facility.


New text:Markers of bone and collagen turnover, reflecting the childhood growth curve, will be measured at Weeks 14, 26, 38, 50 and then every 12 months thereafter, and at the Completion/ET Visit. These markers will include: osteocalcin, bone specific alkaline phosphatase, and n-telopeptides. Tests will be performed by a central laboratory facility.


REDACTED COPY

This do

cumen

tInstrunstrutheth

cann

ot aa

letion/etion/sphatsphat

be bon

atat WWus

ed

ne ane a

to al su

pport

a cence

ample cmple for thfor th

anyin, bon, b

entrent

marketi

ng

ver, refer, reat Weat W

autho

rizati

on ap

plica

tion

et)) and

)an

y exte

nsion

s

crosisrosis

or va

riatio

ns th

ereof.


Confidential of 119

24. Section 10.7, IMPACT-III (first paragraph)

Old text:

The IMPACT questionnaire is a disease-specific health-related quality of life (HRQOL) questionnaire for use in children with IBD that was originally developed and validated by a Canadian team (Griffiths et al, 1999; Otley et al, 2002). The IMPACT-III, a modified version of the original questionnaire, contains 35 questions assessing the following 6 domains: bowel symptoms, systemic symptoms, emotional functioning, social functioning, body image, and treatment/interventions. For each question, there are 5 Likert response options. Total IMPACT-III scores range from 35 to 185 with higher scores indicating better HRQOL. This questionnaire will be used to assess HRQOL of all subjects; however, it has only been validated for children aged ≥10 years in North America. The IMPACT-III questionnaire is provided in Section 17.3. The IMPACT-III questionnaire will be administered every 12 weeks starting at Week 14, and at the Completion /ET Visit.

New text:

The IMPACT questionnaire is a disease-specific health-related quality of life (HRQOL) questionnaire for use in children with IBD that was originally developed and validated by a Canadian team (Griffiths et al, 1999; Otley et al, 2002). The IMPACT-III, a modified version of the original questionnaire, contains 35 questions assessing the following 6 domains: bowel symptoms, systemic symptoms, emotional functioning, social functioning, body image, and treatment/interventions. For each question, there are 5 Likert response options. Total IMPACT-III scores range from 35 to 185 with higher scores indicating better HRQOL. This questionnaire will be used to assess HRQOL of all subjects; however, it has only been validated for children aged ≥10 years in North America. The IMPACT-III questionnaire is provided in Section 17.3. The IMPACT-III questionnaire will be administered at Weeks 14, 26, 38, 50 and then every 12 months thereafter and at the Completion /ET Visit.

25. Section 10.8, Days missed from school/work (WPAI:CD for children and for working individuals with CD) (paragraph 4)

Old text:

The WPAI:CD for children questionnaire is administered to all subjects or the parent(s)/legally acceptable representative(s) and the WPAI:CD for working individuals questionnaire is only administered to subjects who work, under supervision of the Investigator or designee every 12 weeks starting at Week 14, and at the Completion /ET Visit.

New text:

The WPAI:CD for children questionnaire is administered to all subjects or the parent(s)/legally acceptable representative(s) and the WPAI:CD for working individuals questionnaire is only administered to subjects who work, under supervision of the Investigator or designee at Weeks 14, 26, 38, 50 and then every 12 months thereafter, and at the Completion /ET Visit.

REDACTEDre arre arwith higith hig

QOL oQOL oin Non No

CTCT

COPY TT

assessiassessning,ning

This do

cumen

t heeparenparenququ

cann

ot ext:xt:

WPWP

be us

edonlyonlyr desidesi

toceptcept supp

ort

ldren qdren qtabb

anyCD) CD)mark

eting

rthIII queIII qu

s therether

m schm sc

autho

rizati

on, soci, soci 5 Lik5 Lik

gher sher sof all sf all sh Amh A

appli

catio

nalityity oyyevelopvelop

IMPACMPAng theng th

al

and a

ny ex

tensio

ns. ThiThen n

onnaironnaireveryever

or iiva

riatio

ns th

ereof.


Confidential of 119

26. Section 10.9, Effect on the caregiver's work (WPAI:CD for caregivers) (paragraph 2)

Old text:The questionnaire is administered under supervision of the Investigator or designee to the caregiver every 12 weeks starting at Week 14, and at the Completion/ET Visit.

New text:The questionnaire is administered under supervision of the Investigator or designee to the caregiver at Weeks 14, 26, 38, 50 and then every 12 months thereafter, and at the Completion/ET Visit.

27. Section 13.8, Planned interim analysis and data monitoring

Old text:

A DSMB will review safety data. The DSMB members will be independent of the Sponsor and Investigators. The DSMB members will be informed by GCSP (or designee) of all SAEs at the time of expedited reporting and will review periodically all emerging safety data (SAEs, AEs, safety laboratory data). Based on the safety data, the DSMB can recommend modifying/stopping the study.

In order to assess the continuing longterm safety and efficacy of CZP, interim analyses will be performed on an annual basis starting from 1 year after the first subject’s first visit in CR0012 has occurred. The analyses will include all variables collected during the relevant period for all subjects included in the study at the time of the analysis. As no sample size calculation was performed, no formal statistical testing will be carried out and, thus, no adjustment to any significance level needs to be considered.

Should a regulatory authority request an additional interim analysis for a time other than as stated above, this will be performed according to the request.

New text:

A DSMB will review safety data. The DSMB members will be independent of the Sponsor and Investigators. The DSMB members will be informed by GCSP (or designee) of all SAEs at the time of expedited reporting and will review periodically all emerging safety data (SAEs, AEs, safety laboratory data). Based on the safety data, the DSMB can recommend modifying/stopping the study.

In order to assess the continuing longterm safety and efficacy of CZP, interim analyses will be performed on an annual basis starting from 1 year after the first subject’s first visit in CR0012 has occurred. The analyses will include all variables collected during the relevant period for all subjects included in the study at the time of the analysis. As no sample size calculation was performed, no formal statistical testing will be carried out and, thus, no adjustment to any significance level needs to be considered.No interim analyses are planned. Should a regulatory authority request an additional interim analysis for a time other than as stated above, this will be performed according to the request.

REDACTED1 yea1 yelude aude a

dyy at that thyystatististatist

needsneed

COPY nd effnd efearear

This do

cumen

televlevtsamsammea

cann

otperfperfot in Cin Canvanvac

beo asso assbeus

edety lay l

ppingpingto

iteditedlablab

supp

ortetyty datdatyyDSMBDSMd repd re

any m

arketi

ngds to bs to b

t an addan add accod acc

autho

rizati

onficacicac

afafter terfffall varil vari

he timhe timcal teal te

appli

catio

nor

emergemerthe DSthe D

cycy oy

anddenten

r desdesan

y nt ofnt o

exten

sions

or va

riatio

ns th

ereof.


Confidential of 119

18 DECLARATION AND SIGNATURE OF INVESTIGATORI confirm that I have carefully read and understood this protocol and agree to conduct this clinical study as outlined in this protocol, according to current Good Clinical Practice and local laws and requirements.

I will ensure that all subinvestigators and other staff members read and understand all aspects of this protocol.

I have received and read all study-related information provided to me.

The objectives and content of this protocol as well as the results deriving from it will be treated confidentially, and will not be made available to third parties without prior authorization by UCB.

All rights of publication of the results reside with UCB, unless other agreements were made in a separate contract.

Investigator:

__________________________________

Printed Name

__________________________________

Date/Signature

REDACTED ____ COPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on

________

Date/Date

appli

catio

n and

eememany

mentmenex

tensio

ns

will be ill be ior or

or va

riatio

ns th

ereof.

protocol cr0012 an open-label, multicenter study to … · ucb 08 may 2012 clinical study protocol...

Documents