Conditions: Crohn's Disease
Keywords: Certolizumab Pegol Cimzia® Crohn's Disease Children and Adolescents with Crohn's Disease
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the long-term safety and tolerability of certolizumab pegol (CZP) treatment in children and adolescents with moderately to severely active Crohn's disease. Secondarily, to assess the long-term efficacy, pharmacokinetics (PK), and immunogenicity of CZP treatment in children and adolescents with moderately to severely active Crohn's disease.

Detailed description:

Arms:
arm 1: 400 mg administered subcutaneously every 4 weeks for subjects ≥ 40 kg or 200 mg for subjects 20 to \< 40 kg arm 2: 200 mg administered subcutaneously every 4 weeks for subjects ≥ 40 kg or 100 mg for subjects 20 to \< 40 kg

Interventions: intervention 1: certolizumab pegol intervention 2: certolizumab pegol
Intervention descriptions: intervention 1: 400 mg administered subcutaneously every 4 weeks for subjects ≥ 40 kg or 200 mg for subjects 20 to \< 40 kg intervention 2: 200 mg administered subcutaneously every 4 weeks for subjects ≥ 40 kg or 100 mg for subjects 20 to \< 40 kg

Protocol document:
Prot_000.pdf: 
UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 1 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 
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and any extensions or variations thereof.


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 2 of 119
SPONSOR DECLARATION
I 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.
EDACTE
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 3 of 119
STUDY CONTACT INFORMATION
Sponsor
UCB BIOSCIENCES, INC.
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Sponsor Study Physician
Name:
, MD
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617, USA
Phone:
Fax:
Clinical Project Manager
Name:
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617, USA
Phone:
Fax:
Clinical Study Biostatistician 
Name:
, PhD
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617, USA
Phone:
Fax:
REDACTED 
rate Dr
ate Dr
27617
2761
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 4 of 119
Medical Monitor
Name:
, MD
Address:
5610 Point West Drive
Oakwood, GA 30566
Phone:
Fax:
Clinical Monitoring Contract Research Organization
Name:
PRA International
Address:
Glen Lake 6
4130 Parklake Avenue
Raleigh, NC 27612
Phone:
919-786-8200
Fax:
919-786-8201
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 5 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
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 6 of 119
TABLE OF CONTENTS
LIST OF ABBREVIATIONS..................................................................................................10
1
SUMMARY.....................................................................................................................12
2
INTRODUCTION ...........................................................................................................13
3
STUDY OBJECTIVES....................................................................................................14
4
STUDY VARIABLES.....................................................................................................14
4.1
Safety variables......................................................................................................14
4.2
Efficacy variables...................................................................................................15
4.3
Pharmacokinetic and immunological variables .....................................................16
5
STUDY DESIGN.............................................................................................................16
5.1
Study description ...................................................................................................16
5.1.1
Study duration per subject ...........................................................................17
5.1.2
Planned number of subjects and sites ..........................................................17
5.1.3
Anticipated regions and countries................................................................17
5.2
Schedule of study assessments...............................................................................18
5.3
Schematic diagram.................................................................................................22
5.4
Rationale for study design and selection of dose...................................................23
6
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................23
6.1
Inclusion criteria ....................................................................................................23
6.2
Exclusion criteria ...................................................................................................23
6.3
Withdrawal criteria ................................................................................................23
7
STUDY TREATMENTS.................................................................................................25
7.1
Description of investigational medicinal product(s)..............................................25
7.2
Treatments to be administered...............................................................................25
7.3
Packaging...............................................................................................................27
7.4
Labeling .................................................................................................................27
7.5
Handling and storage requirements .......................................................................27
7.6
Drug accountability................................................................................................28
7.7
Procedures for monitoring subject compliance......................................................28
7.8
Concomitant medication(s)/treatment(s) ...............................................................29
7.8.1
Permitted concomitant treatments (medications and therapies) ..................29
7.8.2
Prohibited concomitant treatments (medications and therapies) .................30
7.8.3
Rescue therapy.............................................................................................30
7.9
Enrollment and numbering of subjects ..................................................................30
8
STUDY PROCEDURES BY VISIT ...............................................................................31
8.1
Entry Week 0 .........................................................................................................31
8.2
Week 2 Visit ..........................................................................................................31
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08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 7 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................................................................................................32
8.4.1
Assessments every 12 weeks beginning at Week 14...................................32
8.4.2
Assessments at Weeks 14, 26, 38, 50 and then every 12 months 
thereafter:.....................................................................................................33
8.5
Completion/Early Termination Visit .....................................................................33
8.6
Reinduction visits...................................................................................................34
8.7
Unscheduled Visit..................................................................................................34
8.8
Safety Follow-Up Visit..........................................................................................35
9
SAFETY ASSESSMENTS..............................................................................................35
9.1
Adverse events.......................................................................................................35
9.1.1
Definition of adverse event..........................................................................35
9.1.2
Procedures for reporting and recording adverse events...............................36
9.1.3
Description of adverse events......................................................................36
9.1.4
Follow-up on adverse events .......................................................................36
9.1.5
Rule for repetition of an adverse event........................................................36
9.1.6
Pregnancy.....................................................................................................37
9.1.7
Overdose of investigational medicinal product ...........................................37
9.1.8
Safety signal detection.................................................................................38
9.2
Serious adverse events...........................................................................................38
9.2.1
Definition of serious adverse event .............................................................38
9.2.2
Procedures for reporting serious adverse events..........................................39
9.2.3
Follow-up of serious adverse events............................................................39
9.3
Adverse events of interest......................................................................................39
9.4
Immediate reporting of adverse events..................................................................40
9.5
Laboratory measurements......................................................................................40
9.6
Other safety measurements....................................................................................41
9.6.1
Demographics ..............................................................................................41
9.6.2
Assessment of childbearing potential ..........................................................41
9.6.3
Pregnancy test..............................................................................................41
9.6.4
Physical examination...................................................................................41
9.6.5
Tuberculin test .............................................................................................41
9.6.5.1
Mantoux tuberculin skin test (PPD test) ............................................41
9.6.6
Evaluation of signs and symptoms of TB....................................................42
9.6.7
Vital signs ....................................................................................................43
9.6.8
Concomitant medications ............................................................................43
9.6.9
Medications for CD .....................................................................................43
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08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 8 of 119
9.6.10
Autoantibodies.............................................................................................43
10
EFFICACY ASSESSMENTS .........................................................................................43
10.1
Disease activity/PCDAI.........................................................................................43
10.2
Erythrocyte sedimentation rate ..............................................................................44
10.3
C-reactive protein...................................................................................................44
10.4
Tanner stage...........................................................................................................44
10.4.1
Bone markers ...............................................................................................44
10.5
Height.....................................................................................................................44
10.6
Weight....................................................................................................................45
10.7
IMPACT-III...........................................................................................................45
10.8
Days missed from school/work (WPAI:CD for children and for working 
individuals with CD)..............................................................................................45
10.9
Effect on the caregiver's work (WPAI:CD for caregivers)....................................46
10.10 Concurrent medical procedures .............................................................................46
11
PHARMACOKINETICS AND IMMUNOLOGICAL ASSESSMENTS.......................47
12
STUDY MANAGEMENT AND ADMINISTRATION.................................................47
12.1
Adherence to protocol............................................................................................47
12.2
Monitoring .............................................................................................................47
12.2.1
Definition of source data..............................................................................47
12.2.2
Source data verification ...............................................................................48
12.3
Data handling.........................................................................................................48
12.3.1
Case report form completion .......................................................................48
12.3.2
Database entry and reconciliation................................................................48
12.3.3
Subject Entry and Enrollment log/Subject Identification Code list.............49
12.4
Termination of the study........................................................................................49
12.5
Archiving and data retention..................................................................................49
12.6
Audit and inspection ..............................................................................................50
12.7
Good Clinical Practice...........................................................................................50
13
STATISTICS ...................................................................................................................50
13.1
Definition of analysis sets......................................................................................50
13.2
General statistical considerations...........................................................................51
13.3
Planned safety analyses..........................................................................................51
13.4
Planned efficacy analyses ......................................................................................52
13.5
Pharmacokinetics and immunological analyses.....................................................53
13.6
Handling of protocol deviations.............................................................................53
13.7
Handling of dropouts or missing data....................................................................53
13.8
Planned interim analysis and data monitoring.......................................................54
13.9
Determination of sample size.................................................................................54
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08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 9 of 119
14
ETHICS AND REGULATORY REQUIREMENTS......................................................54
14.1
Informed consent ...................................................................................................54
14.2
Subject identification cards....................................................................................55
14.3
Institutional Review Boards and Independent Ethics Committees........................55
14.4
Subject privacy.......................................................................................................56
14.5
Protocol amendments.............................................................................................56
15
FINANCE, INSURANCE, AND PUBLICATION.........................................................56
16
REFERENCES ................................................................................................................56
17
APPENDICES .................................................................................................................58
17.1
Tuberculosis questionnaire ....................................................................................58
17.2
Pediatric Crohn’s Disease Activity Index..............................................................59
17.3
IMPACT III ...........................................................................................................72
17.4
Work Productivity and Activity Impairment Questionnaire for children with 
CD (WPAI:CD for children)..................................................................................80
17.5
Work Productivity and Activity Impairment Questionnaire for working 
individuals with CD (WPAI:CD for working individuals with CD).....................82
17.6
Work Productivity and Activity Impairment Questionnaire for caregivers of 
children with CD (WPAI:CD for caregivers of children with CD).......................84
17.7
Protocol amendment #1 .........................................................................................86
17.8
Protocol Amendment 2 ..........................................................................................89
18
DECLARATION AND SIGNATURE OF INVESTIGATOR .....................................119
LIST OF TABLES
Table 5-1. Schedule of study assessments .............................................................................18
Table 7-1. Doses of CZP in CR0012 .....................................................................................26
LIST OF FIGURES
Figure 5-1: Schematic Diagram...............................................................................................22
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 10 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
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08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 11 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
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08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 12 of 119
1
SUMMARY
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 
(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. 
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 13 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
INTRODUCTION
Tumor 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.
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 14 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 OBJECTIVES
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.
4
STUDY VARIABLES
4.1
Safety variables
•
AEs
•
Laboratory parameters (hematology, biochemistry, urinalysis)
•
Vital signs
•
Autoantibodies (ANA and anti-dsDNA antibody)
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 15 of 119
4.2
Efficacy variables
Main 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 
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 16 of 119
4.3
Pharmacokinetic and immunological variables
•
Plasma concentrations of CZP
•
Detection of anti-CZP antibodies
5
STUDY DESIGN
5.1
Study description
This 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.
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 17 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 subject
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.
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 sites
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.
•
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 countries
This study will be conducted in the US, Canada, Australia, and New Zealand.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 18 of 119
5.2
Schedule of study assessments
Table 5-1.
Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call (home 
administration)or visit 
(clinic administrationb
Regular Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
Every 4 weeks beginning 
at Week 6 and in between 
regular clinic visits
Every 12 weeks 
beginning at Week 14
+12 weeks 
after last 
dose of 
study drug
Written informed consent
X
Assessment of inclusion/ 
exclusion criteria
X
Demography
X
Life style
C87035
Crohn’s disease history
C87035
Medical and surgical history
C87035
Assessment of childbearing 
potential
C87035
X
X
Pregnancy teste
C87035
X
X
X
Physical examination
C87035
X
X
X
TB test
X
TB questionnaire
X
X
X
X
Tanner stage
C87035
X
X
Height
C87035
X
X
Weight
C87035
X
X
Vital signsf
C87035
X
X
X
X
X
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 19 of 119
Table 5-1.
Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call (home 
administration)or visit 
(clinic administrationb
Regular Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
Every 4 weeks beginning 
at Week 6 and in between 
regular clinic visits
Every 12 weeks 
beginning at Week 14
+12 weeks 
after last 
dose of 
study drug
Adverse eventsa
C87035
X
X
X
X
X
X
Concomitant medicationsa
C87035
X
X
X
X
X
X
Concurrent medical procedures
C87035
X
X
X
X
X
X
PCDAI
C87035
X
X
ESR/hematocrit/albumin for 
PCDAI
C87035
X
X
CRP
C87035
X
X
Hematology/chemistry/urinalys
is
C87035
X
X
X
IMPACT III
C87035
Xl
X
WPAI:CDg
C87035
Xl
X
Certolizumab pegol plasma 
concentrationh
C87035
X
X
X
Anti-CZP antibody plasma 
concentrationi
C87035
X
X
X
Autoantibodies (ANA and anti-
dsDNA)
C87035
X
X
X
Bone markers (osteocalcin, 
bone specific alkaline 
phosphatase, n-telopeptides)
C87035
Xl
X
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 20 of 119
Table 5-1.
Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call (home 
administration)or visit 
(clinic administrationb
Regular Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
Every 4 weeks beginning 
at Week 6 and in between 
regular clinic visits
Every 12 weeks 
beginning at Week 14
+12 weeks 
after last 
dose of 
study drug
Study drug administrationj
X
X
X
Reinductionk
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.
Reinduction Week 0 (first reinduction dose) is followed by Reinduction Week 2 (second dose, 2 weeks after first dose), and 
Reinduction Week 4 (third dose, 2 weeks after second dose). Subjects should return to the clinic for each Reinduction. 
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.
Reinduction Week 0 assessments: PCDAI: ESR, hematocrit, and albumin; IMPACT-III; WPAI:CD
Reinduction Week 2 assessments: PCDAI: ESR, hematocrit, and albumin
Reinduction Week 4 assessments: PCDAI: ESR, hematocrit, and albumin; WPAI:CD
ANA=antinuclear antibody; CRP=C-reactive protein; CZP=certolizumab pegol; dsDNA=double-stranded deoxyribonucleic acid (antibody); 
ESR=erythrocyte sedimentation rate; ET=Early Termination; PCDAI=Pediatric Crohn’s Disease Activity Index; SFU=Safety Follow-Up; TB=tuberculosis; 
WPAI:CD=Work Productivity and Activity Impairment Questionnaire for CD
aWeek 0 of CR0012 is equivalent to the last visit (Week 62; status evaluation) of C87035 with the following exceptions: written informed consent, 
assessment of inclusion/exclusion criteria, demography, TB testing, and TB questionnaire. Ongoing AEs and concomitant medications from C87035 will 
continue to be followed in CR0012. Other assessments will be taken from the C87035 database by UCB. 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.
bAfter Week 2, subjects 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 in order to capture potential AEs and 
changes in concomitant medications, and to check compliance with home dosing. Subjects will have the option to either switch to home dosing or switch 
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 21 of 119
Table 5-1.
Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call (home 
administration)or visit 
(clinic administrationb
Regular Clinic Visitsb
Completion/ 
Early 
Termination
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Visitc
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beginning at Week 14
+12 weeks 
after last 
dose of 
study drug
back to site administration at anytime during the study.
cVital signs, concomitant medication, and AEs must be assessed at every Unscheduled Visit. 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.
dThe SFU Visit should be performed 12 weeks after the final dose of study medication. For subjects continuing directly onto commercial CZP, a SFU Visit 
should be completed prior to the first dose of commercial drug administration.
eFor all females post menses, a urine pregnancy test will be conducted at all regularly scheduled clinic visits except Week 2.
fVital signs will be collected 15 minutes prior to dosing with a ±5 minute window.
gDays missed from school will be assessed using the WPAI:CD for children. The time missed from work will be assessed using the WPAI:CD for working 
individuals with CD. The effect of the child’s CD on the caregiver’s productivity will be assessed using the WPAI:CD for caregivers of children with CD.
hPlasma samples will be collected to determine the concentration of CZP every 12 weeks starting at Week 14, and at the Completion/Early Termination and 
SFU Visits. Samples will be collected before dosing (except for the Completion/ET and SFU Visits when there is no dosing).
iAnti-CZP antibody concentrations in plasma will be collected every 12 weeks starting at Week 14, and at the Completion/ET and SFU Visits (anti-CZP 
antibody measurements will be made using the samples taken for PK measurements at these time points, so additional blood draws will not be required).
jIf home administration is performed, sufficient study drug will be dispensed at the scheduled every 12-week clinic visit to last until the next scheduled clinic 
visit.
kIf a subject has not been previously reinduced in C87035, the subject is eligible for 1 reinduction due to loss of response in CR0012.
lMeasured at Weeks 14, 26, 38, 50 and then every 12 months thereafter.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 22 of 119
5.3
Schematic diagram
Figure 5-1:
Schematic Diagram
CZP=certolizumab pegol; Q4W=every 4 weeks
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 23 of 119
5.4
Rationale for study design and selection of dose
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.
6
SELECTION AND WITHDRAWAL OF SUBJECTS
6.1
Inclusion criteria
To 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 criteria
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) 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 criteria
Subjects (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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 24 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.
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 25 of 119
7
STUDY TREATMENTS
7.1
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 administered
Details 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 26 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 Group
Dose frequency
Q4W
Q4W
Subject weight
20 to <40kg (44 to <88lbs)
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≥40kg (≥88lbs)
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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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 27 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 self̻
administer 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
Packaging
Each site will receive uniquely numbered PFSs. The PFSs will be packaged in individual 
protective containers with a uniquely numbered carton.
7.4
Labeling
Clinical 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 requirements
The 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
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 28 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 accountability
A 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 compliance
Subjects 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 29 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 30 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 therapy
Subjects 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 subjects
To 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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 31 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 VISIT
During 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
•
Concomitant medications
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 32 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
•
Concomitant medications
•
Concurrent medical procedures
•
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
•
TB questionnaire
•
Tanner stage
•
Weight and height
•
Vital signs
•
Adverse events
•
Concomitant medications
•
Concurrent medical procedures
•
PCDAI
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 33 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)
•
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
8.4.2
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)
•
Urine pregnancy test (female subjects of childbearing potential only)
•
Physical examination
•
TB questionnaire
•
Tanner stage
•
Weight and height
•
Vital signs
•
Adverse events
•
Concomitant medications
•
Concurrent medical procedures
•
PCDAI
•
ESR/hematocrit/albumin for PCDAI
•
CRP
•
Hematology, clinical chemistry, and urinalysis
•
IMPACT III
•
WPAI:CD (for children, for working individuals with CD, and for caregivers)
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 34 of 119
•
Certolizumab pegol plasma concentration
•
Anti-CZP antibody plasma concentration
•
Autoantibody concentrations (ANA and anti-dsDNA)
•
Bone markers (osteocalcin, bone specific alkaline phosphatase, n-telopeptides)
8.6
Reinduction visits
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.
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
Reinduction Week 2 assessments: 
•
PCDAI (using the ESR, hematocrit, and albumin results of the same visit)
•
ESR, hematocrit, and albumin
Reinduction Week 4 assessments: 
•
PCDAI (using the ESR, hematocrit, and albumin results of the same visit)
•
ESR, hematocrit, and albumin
•
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
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 35 of 119
•
Concomitant medications
•
Concurrent medical procedures
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 Visit
The 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.
•
Urine pregnancy test (female subjects of childbearing potential only)
•
Physical examination
•
TB questionnaire
•
Vital signs
•
Adverse events
•
Concomitant medications
•
Concurrent medical procedures
•
Hematology, clinical chemistry, and urinalysis
•
Certolizumab pegol plasma concentration
•
Anti-CZP antibody plasma concentration
•
Autoantibody concentrations (ANA and anti-dsDNA)
9
SAFETY ASSESSMENTS
9.1
Adverse events
Adverse 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 event
An 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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 36 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 events
Besides 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 events
When 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 events
An 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 for
12 weeks after the subject has discontinued their IMP. 
9.1.5
Rule for repetition of an adverse event
An increase in the intensity of an AE should lead to the repetition of the AE being reported 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 37 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
Pregnancy
Should 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 product
Excessive 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 38 of 119
9.1.8
Safety signal detection
Selected 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 events
9.2.1
Definition of serious adverse event
Once 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 occurred
in 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]).
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 39 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 events
If 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 events
An 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 interest
An 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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 40 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 events
The 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 measurements
Hematology 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 41 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 measurements
9.6.1
Demographics
Demographics (date of birth, sex, and race) will be recorded at entry Week 0.
9.6.2
Assessment of childbearing potential
For 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 test
For 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 examination
General 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 test
All 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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 42 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 by
inspection (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 TB
Signs 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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 43 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 signs
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.
9.6.8
Concomitant medications
Details 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 CD
Details 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
Autoantibodies
Autoantibody (ANA and anti-dsDNA) titers will be determined every 12 weeks starting at 
Week 14, and at the Completion/ET and SFU Visits. 
Instructions on blood sample collection, processing, storage, and shipping will be provided in 
the laboratory manual for this study.
10
EFFICACY ASSESSMENTS
10.1
Disease activity/PCDAI
The 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 44 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 rate
The 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.
Instructions on blood sample collection, processing, storage, and shipping will be provided in 
the laboratory manual for this study.
10.3
C-reactive protein
Levels of CRP will be assessed every 12 weeks starting at Week 14, and at the 
Completion/ET Visit. 
Instructions on blood sample collection, processing, storage, and shipping will be provided in 
the laboratory manual for this study.
10.4
Tanner stage
Assessments 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 markers
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.
Instructions on blood sample collection, processing, storage, and shipping will be provided in 
the laboratory manual for this study.
10.5
Height
Height 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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 45 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
Weight
Weight 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-III
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. 
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: 
 
 
 
 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 46 of 119
, the subject completes only question number 6 to 
 
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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
 
 
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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 procedures
Any concurrent medical procedures will be recorded throughout the course of the study at 
every visit, phone contacts, and Unscheduled Visits. 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 47 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.
Instructions on blood sample collection, processing, storage, and shipping will be provided in 
the laboratory manual for this study.
12
STUDY MANAGEMENT AND ADMINISTRATION 
12.1
Adherence to protocol
The 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
Monitoring
UCB (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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 48 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 verification
Source 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 handling
12.3.1
Case report form completion
The 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 reconciliation
Case 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 49 of 119
12.3.3
Subject Entry and Enrollment log/Subject Identification Code list
The 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 study
Upon 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 retention
The 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 50 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 inspection
The 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 Practice
Noncompliance 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
STATISTICS
A 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 sets
The 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 51 of 119
13.2
General statistical considerations
Summary 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 analyses
All 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 52 of 119
13.4
Planned efficacy analyses
As 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 53 of 119
13.5
Pharmacokinetics and immunological analyses
Plasma 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 deviations
No 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 data
For 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 54 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 monitoring
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.
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 size
This is an open-label study for subjects who completed C87035 and as such no formal sample 
size has been determined.
14
ETHICS AND REGULATORY REQUIREMENTS
14.1
Informed consent
Subject’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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 55 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 cards
Upon 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 56 of 119
14.4
Subject privacy
UCB 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 amendments
Protocol 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 PUBLICATION
Insurance 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
REFERENCES
Griffiths 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 in
children. 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 57 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 59 of 119
17.2
Pediatric Crohn’s Disease Activity Index
Instructions 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)
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 60 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)
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 61 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)
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 62 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 SCORE
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This document cannot be used to support any marketing authorization application
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on or variations thereof.


UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 63 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-being
If 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 64 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 weight
X 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 previously
X 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. 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 65 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
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 66 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
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 67 of 119
Height Velocity Chart (males)
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 68 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
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1.1
1.8
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 69 of 119
Height Velocity Chart (females)
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 70 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:
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 71 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.
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 86 of 119
17.7
Protocol amendment #1
Rationale 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)
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
Europe and Rest of the World (except Japan): +32 2 386 24 68
USA & Canada: +1 678 799 4007
Has been changed to:
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
Change #2 - Inclusion criterion (Section 6.1) 
To 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.
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 87 of 119
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 satisfied the Inclusion criteria at time of entry into C87035 and completed the 
study (Week 62 Visit). 
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).
Has been changed to:
To 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). 
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).
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.
Has been changed to:
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.
Has been changed to:
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 
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08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 88 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 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, or the development of drug dependency or drug abuse.)
Has been changed to:
•
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.)
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.
Has been changed to:
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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 89 of 119
17.8
Protocol Amendment 2
Rationale 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
AN OPEN-LABEL, MULTICENTER STUDY TO ASSESS THE 
SAFETY OF CERTOLIZUMAB PEGOL IN CHILDREN AND 
ADOLESCENTS WITH ACTIVE CROHN’S DISEASE WHO 
COMPLETED C87035 
PHASE 2B
IND Number: 11197
Sponsor:
SCHWARZ BIOSCIENCES, INC.
A Member of the UCB Group of Companies
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
REDACTED 
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MA
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of CZP
of CZP
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ts
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 90 of 119
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
07 May 2010
N/A
Amendment 1
29 Jun 2010
Substantial
New text:
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.
A Member of the UCB Group of Companies
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
REDACTED
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 91 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
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 92 of 119
3. Page 3, Study contact information
Old text:
Sponsor
SCHWARZ BIOSCIENCES, INC.
A Member of the UCB Group of Companies
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Principal/Coordinating Investigator
Sponsor Study Physician
Name:
, MD
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617, USA
Phone:
Fax:
Clinical Project Manager
Name:
, MS
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617, USA
Phone:
Fax:
Clinical Study Biostatistician 
Name:
, MS
Address:
208 Bath Road
Slough, Berkshire, SL1 3WE, UK
Phone:
Fax:
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 93 of 119
Clinical Monitoring Contract Research Organization
Name:
Kendle International, Inc.
Address:
1200 Carew Tower
441 Vine Street
Cincinnati, Ohio 45202
Phone:
+1 800 733 1572
Fax:
+1 513 381 7684
New text:
UCB BIOSCIENCES, INC.
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Principal/Coordinating Investigator
Sponsor Study Physician
Name:
, MD
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617, USA
Phone:
Fax:
Clinical Project Manager
Name:
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617, USA
Phone:
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 94 of 119
Clinical Study Biostatistician 
Name:
, PhD
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617, USA
Phone:
Fax:
Medical Monitor
Name:
, MD
Address:
5610 Point West Drive
Oakwood, GA 30566
Phone:
Fax:
Clinical Monitoring Contract Research Organization
Name:
PRA International
Address:
Glen Lake 6
4130 Parklake Avenue
Raleigh, 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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 95 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.
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. 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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 96 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.
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. 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 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 97 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.
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.
Interim analyses will be performed on an annual basis starting from 1 year after the first 
subject’s first visit in CR0012 has occurred.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 98 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 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.
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.
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.
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.
The end of the study is defined as the date of the last SFU visit of the last subject in the study.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 99 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.
The end of the study is defined as the date of the last SFU visit of the last subject in the study.
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).
•
First subject first visit: Jul 2010
•
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.
•
First subject first visit: Jul 2010
•
Last subject first visit: Jun 2012
•
Last subject last visit: to be determined (including the SFU Visit)
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UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 100 of 119
10. Section 5.2, Schedule of  study assessments (Table 5-1)
Old text:
Table 5-1. Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call 
(home 
administration)
or visit (clinic 
administrationb
Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
6, 10, 18, 22, 
30, 34, 42, 46 
14, 26, 38, 50
52
62
Written informed consent
X
Assessment of inclusion/ exclusion 
criteria
X
Demography
X
Life style
C87035
Crohn’s disease history
C87035
Medical and surgical history
C87035
Assessment of childbearing potential
C87035
X
X
Pregnancy teste
C87035
X
X
X
Physical examination
C87035
X
X
X
TB test
X
TB questionnaire
X
X
X
X
Tanner stage
C87035
X
X
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 101 of 119
Table 5-1. Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call 
(home 
administration)
or visit (clinic 
administrationb
Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
6, 10, 18, 22, 
30, 34, 42, 46 
14, 26, 38, 50
52
62
Height
C87035
X
X
Weight
C87035
X
X
Vital signsf
C87035
X
X
X
X
X
Adverse eventsa
C87035
X
X
X
X
X
X
Concomitant medicationsa
C87035
X
X
X
X
X
X
Concurrent medical procedures
C87035
X
X
X
X
X
X
PCDAI
C87035
X
X
ESR/hematocrit/albumin for PCDAI
C87035
X
X
CRP
C87035
X
X
Hematology/chemistry/urinalysis
C87035
X
X
X
IMPACT III
C87035
X
X
WPAI:CDg
C87035
X
X
Certolizumab pegol plasma concentrationh
C87035
X
X
X
Anti-CZP antibody plasma concentrationi
C87035
X
X
X
Autoantibodies (ANA and anti-dsDNA)
C87035
X
X
X
Bone markers (osteocalcin, bone specific 
C87035
X
X
X
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 102 of 119
Table 5-1. Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call 
(home 
administration)
or visit (clinic 
administrationb
Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
6, 10, 18, 22, 
30, 34, 42, 46 
14, 26, 38, 50
52
62
alkaline phosphatase, n-telopeptides)
Study drug administrationj
X
X
X
Reinductionk
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.
Reinduction Week 0 (first reinduction dose) is followed by Reinduction Week 2 (second dose, 2 
weeks after first dose), and Reinduction Week 4 (third dose, 2 weeks after second dose). Subjects 
should return to the clinic for each Reinduction. 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.
Reinduction Week 0 assessments: PCDAI: ESR, hematocrit, and albumin; IMPACT-III; 
WPAI:CD
Reinduction Week 2 assessments: PCDAI: ESR, hematocrit, and albumin
Reinduction Week 4 assessments: PCDAI: ESR, hematocrit, and albumin; WPAI:CD
ANA=antinuclear antibody; CRP=C-reactive protein; CZP=certolizumab pegol; dsDNA=double-stranded deoxyribonucleic acid (antibody); 
ESR=erythrocyte sedimentation rate; ET=Early Termination; PCDAI=Pediatric Crohn’s Disease Activity Index; SFU=Safety Follow-Up; TB=tuberculosis; 
WPAI:CD=Work Productivity and Activity Impairment Questionnaire for CD
a.
Week 0 of CR0012 is equivalent to Week 62 (status evaluation) of C87035 with the following exceptions: written informed consent, assessment of 
inclusion/exclusion criteria, demography, TB testing, and TB questionnaire. Ongoing AEs and concomitant medications from C87035 will continue to 
be followed in CR0012. Other assessments will be taken from the C87035 database by UCB.
b.
After Week 2, subjects or parents/caregivers have the option of home administration of CZP upon appropriate training during a previous clinic visit(s) 
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 103 of 119
Table 5-1. Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call 
(home 
administration)
or visit (clinic 
administrationb
Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
6, 10, 18, 22, 
30, 34, 42, 46 
14, 26, 38, 50
52
62
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 in order to capture potential AEs 
and changes in concomitant medications, and to check compliance with home dosing. Subjects will have the option to either switch to home dosing or 
switch back to site administration at anytime during the study.
c.
Vital signs, concomitant medication, and AEs must be assessed at every Unscheduled Visit. 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.
d.
The SFU Visit should be performed 12 weeks after the final dose of study medication. For subjects continuing directly onto commercial CZP, a SFU 
Visit should be completed prior to the first dose of commercial drug administration.
e.
For all females post menses, a urine pregnancy test will be conducted at all regularly scheduled clinic visits except Week 2.
f.
Vital signs will be collected 15 minutes prior to dosing with a ±5 minute window.
g.
Days missed from school will be assessed using the WPAI:CD for children. The time missed from work will be assessed using the WPAI:CD for 
working individuals with CD. The effect of the child’s CD on the caregiver’s productivity will be assessed using the WPAI:CD for caregivers of 
children with CD.
h.
Plasma samples will be collected to determine the concentration of CZP every 12 weeks starting at Week 14, and at the Completion/Early Termination 
and SFU Visits. Samples will be collected before dosing (except for the Completion/ET and SFU Visits when there is no dosing).
i.
Anti-CZP antibody concentrations in plasma will be collected every 12 weeks starting at Week 14, and at the Completion/ET and SFU Visits (anti-CZP 
antibody measurements will be made using the samples taken for PK measurements at these time points, so additional blood draws will not be required).
j.
If home administration is performed, sufficient study drug will be dispensed at the scheduled every 12-week clinic visit to last until the next scheduled 
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 104 of 119
Table 5-1. Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call 
(home 
administration)
or visit (clinic 
administrationb
Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
6, 10, 18, 22, 
30, 34, 42, 46 
14, 26, 38, 50
52
62
clinic visit.
k.
If a subject has not been previously reinduced in C87035, the subject is eligible for 1 reinduction due to loss of response in CR0012.
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 105 of 119
New text:
Table 5-1. Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call (home 
administration)or visit 
(clinic administrationb
Regular Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
Every 4 weeks beginning 
at Week 6 and in 
between regular clinic 
visits
Every 12 weeks 
beginning at Week 14
+12 weeks 
after last 
dose of 
study drug
Written informed consent
X
Assessment of inclusion/ 
exclusion criteria
X
Demography
X
Life style
C87035
Crohn’s disease history
C87035
Medical and surgical history
C87035
Assessment of childbearing 
potential
C87035
X
X
Pregnancy teste
C87035
X
X
X
Physical examination
C87035
X
X
X
TB test
X
TB questionnaire
X
X
X
X
Tanner stage
C87035
X
X
Height
C87035
X
X
Weight
C87035
X
X
Vital signsf
C87035
X
X
X
X
X
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 106 of 119
Table 5-1. Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call (home 
administration)or visit 
(clinic administrationb
Regular Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
Every 4 weeks beginning 
at Week 6 and in 
between regular clinic 
visits
Every 12 weeks 
beginning at Week 14
+12 weeks 
after last 
dose of 
study drug
Adverse eventsa
C87035
X
X
X
X
X
X
Concomitant medicationsa
C87035
X
X
X
X
X
X
Concurrent medical procedures
C87035
X
X
X
X
X
X
PCDAI
C87035
X
X
ESR/hematocrit/albumin for 
PCDAI
C87035
X
X
CRP
C87035
X
X
Hematology/chemistry/urinalys
is
C87035
X
X
X
IMPACT III
C87035
Xl
X
WPAI:CDg
C87035
Xl
X
Certolizumab pegol plasma 
concentrationh
C87035
X
X
X
Anti-CZP antibody plasma 
concentrationi
C87035
X
X
X
Autoantibodies (ANA and anti-
dsDNA)
C87035
X
X
X
Bone markers (osteocalcin, 
bone specific alkaline 
phosphatase, n-telopeptides)
C87035
Xl
X
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 107 of 119
Table 5-1. Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call (home 
administration)or visit 
(clinic administrationb
Regular Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
Every 4 weeks beginning 
at Week 6 and in 
between regular clinic 
visits
Every 12 weeks 
beginning at Week 14
+12 weeks 
after last 
dose of 
study drug
Study drug administrationj
X
X
X
Reinductionk
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.
Reinduction Week 0 (first reinduction dose) is followed by Reinduction Week 2 (second dose, 2 weeks after first dose), and 
Reinduction Week 4 (third dose, 2 weeks after second dose). Subjects should return to the clinic for each Reinduction. 
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.
Reinduction Week 0 assessments: PCDAI: ESR, hematocrit, and albumin; IMPACT-III; WPAI:CD
Reinduction Week 2 assessments: PCDAI: ESR, hematocrit, and albumin
Reinduction Week 4 assessments: PCDAI: ESR, hematocrit, and albumin; WPAI:CD
ANA=antinuclear antibody; CRP=C-reactive protein; CZP=certolizumab pegol; dsDNA=double-stranded deoxyribonucleic acid (antibody); 
ESR=erythrocyte sedimentation rate; ET=Early Termination; PCDAI=Pediatric Crohn’s Disease Activity Index; SFU=Safety Follow-Up; TB=tuberculosis; 
WPAI:CD=Work Productivity and Activity Impairment Questionnaire for CD
aWeek 0 of CR0012 is equivalent to the last visit (Week 62; status evaluation) of C87035 with the following exceptions: written informed consent, 
assessment of inclusion/exclusion criteria, demography, TB testing, and TB questionnaire. Ongoing AEs and concomitant medications from C87035 will 
continue to be followed in CR0012. Other assessments will be taken from the C87035 database by UCB. 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.
bAfter Week 2, subjects 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 in order to capture potential AEs and 
changes in concomitant medications, and to check compliance with home dosing. Subjects will have the option to either switch to home dosing or switch 
back to site administration at anytime during the study.
cVital signs, concomitant medication, and AEs must be assessed at every Unscheduled Visit. Other safety and PK assessments (eg, CZP plasma sample) may 
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 108 of 119
Table 5-1. Schedule of study assessments
Treatment Period
Visit or phone call 
(+/-7 days)
Entry a
Visit
Phone call (home 
administration)or visit 
(clinic administrationb
Regular Clinic Visitsb
Completion/ 
Early 
Termination
Unscheduled 
Visitc
SFUd
Week
0
2
Every 4 weeks beginning 
at Week 6 and in 
between regular clinic 
visits
Every 12 weeks 
beginning at Week 14
+12 weeks 
after last 
dose of 
study drug
be performed at the discretion of the Investigator as related to the nature of the visit.
dThe SFU Visit should be performed 12 weeks after the final dose of study medication. For subjects continuing directly onto commercial CZP, a SFU Visit 
should be completed prior to the first dose of commercial drug administration.
eFor all females post menses, a urine pregnancy test will be conducted at all regularly scheduled clinic visits except Week 2.
fVital signs will be collected 15 minutes prior to dosing with a ±5 minute window.
gDays missed from school will be assessed using the WPAI:CD for children. The time missed from work will be assessed using the WPAI:CD for working 
individuals with CD. The effect of the child’s CD on the caregiver’s productivity will be assessed using the WPAI:CD for caregivers of children with CD.
hPlasma samples will be collected to determine the concentration of CZP every 12 weeks starting at Week 14, and at the Completion/Early Termination and 
SFU Visits. Samples will be collected before dosing (except for the Completion/ET and SFU Visits when there is no dosing).
iAnti-CZP antibody concentrations in plasma will be collected every 12 weeks starting at Week 14, and at the Completion/ET and SFU Visits (anti-CZP 
antibody measurements will be made using the samples taken for PK measurements at these time points, so additional blood draws will not be required).
jIf home administration is performed, sufficient study drug will be dispensed at the scheduled every 12-week clinic visit to last until the next scheduled clinic 
visit.
kIf a subject has not been previously reinduced in C87035, the subject is eligible for 1 reinduction due to loss of response in CR0012.
lMeasured at Weeks 14, 26, 38, 50 and then every 12 months thereafter.
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 109 of 119
11. Section 5.3, Schematic diagram (figure)
Old text:
New text:
ED 
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08
08 M


UCB
08 May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 110 of 119
CZP=certolizumab pegol; Q4W=every 4 weeks
COPY 
This document cannot be used to support any marketi
eting authorization application and 
y 
any extensions or variations 
on thereof.
08
08 M


UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 111 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 112 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)
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 113 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)
•
Urine pregnancy test (female subjects of childbearing potential only)
•
Physical examination
•
TB questionnaire
•
Tanner stage
•
Weight and height
•
Vital signs
•
Adverse events
•
Concomitant medications
•
Concurrent medical procedures
•
PCDAI
•
ESR/hematocrit/albumin for PCDAI
•
CRP
•
Hematology, clinical chemistry, and urinalysis
•
IMPACT III
•
WPAI:CD (for children, for working individuals with CD and for caregivers)
•
Certolizumab pegol plasma concentration
•
Anti-CZP antibody plasma concentration
•
Autoantibody concentrations (ANA and anti-dsDNA)
•
Bone markers (osteocalcin, bone specific alkaline phosphatase, n-telopeptides)
•
Study drug administration (including training and self-injection under supervision, as 
appropriate)
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 114 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)
−
Week 26 (for Weeks 30 and 34)
−
Week 38 (for Weeks 42 and 46)
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)
•
Urine pregnancy test (female subjects of childbearing potential only)
•
Physical examination
•
TB questionnaire
•
Tanner stage
•
Weight and height
•
Vital signs
•
Adverse events
•
Concomitant medications
•
Concurrent medical procedures
•
PCDAI
•
ESR/hematocrit/albumin for PCDAI
•
CRP
•
Hematology, clinical chemistry, and urinalysis
•
IMPACT III
•
WPAI:CD (for children, for working individuals with CD and for caregivers)
•
Certolizumab pegol plasma concentration
•
Anti-CZP antibody plasma concentration
•
Autoantibody concentrations (ANA and anti-dsDNA)
•
Bone markers (osteocalcin, bone specific alkaline phosphatase, n-telopeptides)
•
Study drug administration (including training and self-injection under supervision, as 
appropriate)
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 115 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)
−
Week 26 (for Weeks 30 and 34)
−
Week 38 (for Weeks 42 and 46)
•
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
•
Congestive heart failure
•
Demylinating-like disorders
•
Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leucopenia
•
Serious bleeding events
•
Lupus and lupus-like syndrome
•
Serious skin reactions (eg, Stevens Johnson Syndrome, toxic epidermal necrosis, and 
erythema multiforme)
New text:
Section heading-
Adverse events of interest
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 116 of 119
Bullet list-
•
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)
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.
Instructions on blood sample collection, processing, storage, and shipping will be provided in 
the laboratory manual for this study.
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.
Instructions on blood sample collection, processing, storage, and shipping will be provided in 
the laboratory manual for this study.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 117 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. 
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 118 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.
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UCB
08  May 2012
Clinical Study Protocol
Certolizumab pegol
CR0012
Confidential
Page 119 of 119
18
DECLARATION AND SIGNATURE OF INVESTIGATOR
I 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 
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SAP_001.pdf: 
UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
STATISTICAL ANALYSIS PLAN 
Study: CR0012
Product: Certrolizumab pegol
An open-label, multi-center study to assess the safety of Certrolizumb 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
SAP/Amendment Number
Date
Draft SAP
<30 Sep 2015>
Final SAP
<01 Jan 2018>
Confidentiality Statement
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 COPY 
This document 
en cannot be used to support any 
01 Jan
01 Ja
marketing 
ep 20
ep 2
authorization application
zu
or we
or we
UCB
UCB
and 
umb 
umb
any extensions or variations thereof. 


UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
TABLE OF CONTENTS
LIST OF ABBREVIATIONS ................................................................................................... 4
1
INTRODUCTION............................................................................................................. 5
2
PROTOCOL SUMMARY................................................................................................. 5
2.1
Study objective(s).................................................................................................... 5
2.1.1
Primary objective(s) ...................................................................................... 5
2.1.2
Secondary objective(s) .................................................................................. 5
2.2
Study variable(s)...................................................................................................... 5
2.2.2
Efficacy variable(s) ....................................................................................... 5
2.2.2.1
Primary efficacy variable(s) ................................................................ 5
2.2.2.2
Secondary efficacy variable(s) ............................................................ 5
2.2.2.3
Other efficacy variable(s) .................................................................... 5
2.2.3
Pharmacokinetic/pharmacodynamic variable(s) ........................................... 6
2.3
Study design and conduct........................................................................................ 6
2.3.1
Study duration per subject............................................................................. 7
2.3.2
Anticipated regions and countries ................................................................. 7
2.4
Determination of sample size .................................................................................. 7
3
DATA ANALYSIS CONSIDERATIONS........................................................................ 8
3.1
General presentation of summaries and analyses.................................................... 8
3.2
General study level definitions................................................................................ 8
3.3
Definition of Baseline values .................................................................................. 9
3.4
Protocol deviations .................................................................................................. 9
3.5
Analysis sets ............................................................................................................ 9
3.6
Center pooling strategy............................................................................................ 9
3.7
Coding dictionaries.................................................................................................. 9
4
STATISTICAL/ANALYTICAL ISSUES....................................................................... 10
4.1
Adjustments for covariates.................................................................................... 10
4.2
Handling of dropouts or missing data.................................................................... 10
4.3
Interim analyses and data monitoring.................................................................... 10
4.4
Examination of subgroups..................................................................................... 10
5
STUDY POPULATION CHARACTERISTICS ............................................................ 10
5.1
Subject disposition................................................................................................. 10
5.2
Protocol deviations ................................................................................................ 11
6
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................ 11
6.1
Demographics........................................................................................................ 11
6.2
Medical history and concomitant diseases ............................................................ 11
6.3
Prior and concomitant medications ....................................................................... 11
7
MEASUREMENTS OF TREATMENT COMPLIANCE .............................................. 12
8
SAFETY ANALYSES .................................................................................................... 12
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
8.1
Extent of exposure................................................................................................. 12
8.2
Adverse events....................................................................................................... 12
8.3
Clinical laboratory evaluations.............................................................................. 14
8.4
Vital signs, physical findings, and other observations related to safety................ 15
8.4.1
Vital signs.................................................................................................... 15
8.4.2
Height and Weight....................................................................................... 15
8.4.3
Electrocardiograms...................................................................................... 15
8.4.4
Other safety variable(s) ............................................................................... 15
9
EFFICACY ANALYSES................................................................................................ 15
10
PHARMACOKINETICS AND PHARMACODYNAMICS.......................................... 17
10.1
Pharmacokinetics................................................................................................... 17
10.2
Pharmacodynamics................................................................................................ 17
11
OTHER ANALYSES...................................................................................................... 17
12
REFERENCES ................................................................................................................ 18
13
APPENDICES................................................................................................................. 19
13.1
Markedly abnormality criteria for laboratory data ................................................ 19
13.2
Impact III Questionnaire Scoring .......................................................................... 21
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE..................................................... 23
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
LIST OF ABBREVIATIONS
AE
adverse event
ATC
Anatomical Therapeutic Chemical classification system
BMI
body mass index
CSR
Clinical Study Report
CZP
Certrolizumab pegol
CV
coefficient of variance
EudraCT
European Clinical Trials Database
MedDRA®
Medical Dictionary for Regulatory Activities®
PCDAI
Pediatric Crohn’s Disease Activity Index
PK
Pharmacokinetic
PT
Preferred Term
Q2W
every 2 weeks
Q4W
every 4 weeks
SAP
Statistical Analysis Plan
SD
standard deviation
SOC
System Organ Class
TEAE
Treatment Emergent Adverse Event
WHODRL
World Heath Organization Drug Reference List
WPAI
Work Productivity and Activity Impairment Questionnaire
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
1
INTRODUCTION
This SAP supports the final analysis for CR0012 CSR.
2
PROTOCOL SUMMARY
2.1
Study objective(s)
2.1.1
Primary objective(s)
The primary objective of the study is to assess the long-term safety and tolerability of CZP in 
children and adolescents with moderately to severely active CD.
2.1.2
Secondary objective(s)
Secondary objectives include further assessment of the long-term efficacy, PK, and immunogenicity 
of CZP treatment in this population.
2.2
Study variable(s)
2.2.1
Safety variable(s)
•
Adverse Events
•
Laboratory parameters (hematology, biochemistry, urinalysis)
•
Vital signs
•
Autoantibodies (ANA and anti-dsDNA antibody)
2.2.2
Efficacy variable(s)
2.2.2.1
Primary efficacy variable(s)
The primary efficacy variable is the proportion of subjects in clinical remission where clinical 
remission is defined as a PCDAI score ≤10.
2.2.2.2
Secondary efficacy variable(s)
Secondary variables include:
•
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
2.2.2.3
Other efficacy variable(s)
Other efficacy variables include:
•
ESR values
•
Change from Baseline (Week 0 of C87035) in ESR values
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
•
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
•
Absolute IMPACT-III scores
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Change from Baseline (Week 0 of C87035) in IMPACT-III score
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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)
•
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•
Actual scores of WPAI:CD for caregivers
•
Change from Baseline (Week 0 of C87035) in scores of WPAI:CD for caregivers
2.2.3
Pharmacokinetic/pharmacodynamic variable(s)
•
Plasma concentrations of CZP
•
Detection of anti-CZP antibodies
2.3
Study design and conduct
This 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.
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.
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01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
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.
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.
2.3.1
Study duration per subject
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.
The end of the study is defined as the date of the last SFU visit of the last subject in the study.
2.3.2
Anticipated regions and countries
This study will be conducted in the US, Canada, Australia, and New Zealand.
2.4
Determination of sample size
This is an open-label study for subjects who completed Week 62 of C87035 or who were 
terminated from C87035 when the study was stopped by UCB (and completed all assessments 
required for Week62/Visit 23 at the time of termination) and as such no formal sample size has 
been determined.
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
3
DATA ANALYSIS CONSIDERATIONS
3.1
General presentation of summaries and analyses
Statistical analysis and generation of tables, figures, subject data listings, and statistical output will 
be performed using SAS Version 9.1 or higher. All tables and listings will use Courier New font size 
9.
Descriptive statistics will be displayed to provide an overview of the study results. For categorical 
parameters, the number and percentage of subjects in each category will be presented. The 
denominator for percentages will be based on the number of subjects appropriate for the purpose of 
analysis. Unless otherwise noted, all percentages will be displayed to 1 decimal place. No 
percentage will be displayed for zero counts, and no decimal will be presented when the percentage 
is 100%. For continuous parameters, descriptive statistics will include number of subjects with 
available measurements (n), mean, standard deviation (SD), median, minimum, and maximum. 
Pharmacokinetic variables may also present the geometric mean, coefficient of variance, and 95% 
CI for the geometric mean as appropriate.
Decimal places for descriptive statistics will always apply the following rules:
•
“n” will be an integer.
•
Mean, SD, and median will use 1 additional decimal place compared to the original data.
•
Coefficient of variance (CV[%]) will be presented with 1 decimal place.
•
Minimum and maximum will have the same number of decimal places as the original value.
3.2
General study level definitions
CZP dose groups will be identified as “Low Dose” and “High Dose”, respectively on column 
headers.  These are defined 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
Table 1-1.
Doses of CZP in CR0012
CZP dose (mg) injections
Treatment group
High Dose Group
Low Dose Group
Dose frequency
Q4W
Q4W
Subject weight
20 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
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
For all by-visit AE and medication summaries, if a subject in the Low Dose group is re-induced, the 
subject will be summarized under the High Dose column from the time of re-induction onwards. 
The population N’s in the column headers will indicate the number of subjects who entered CR0012 
on their respective High/Low dose groups despite whether a subject changed doses within the study.  
By-visit tables will show the number of subjects at each visit.
Reinduction visits will be included in table summaries only if they occur during a scheduled study 
week. A ‘(R)’ will be used to indicate a visit summary that includes any reinduction visits (eg, Week 
14 (R)).
3.3
Definition of Baseline values
For data which were collected at Week 0 of C87035 and prior to receiving any study treatment, the 
last nonmissing value collected prior to receiving first dose of study medication of C87035 will be 
defined as the Baseline value. For data such as Crohn’s disease history which was collected only at 
the Screening Visit of C87035, Baseline will be defined as the Screening Visit of C87035.
3.4
Protocol deviations
No 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 to decide how to handle problems in the subject’s data 
(eg, missing values, withdrawals, dropouts, protocol deviations). In addition, the review will be used 
to identify the use of rescue therapy. The pre-analysis reviewers should ensure that the results of this 
review are communicated to the study team before locking the database.
After the pre-analysis review, resolution of all issues and documentation of all decisions, the 
database will be locked.
3.5
Analysis sets
The 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.
3.6
Center pooling strategy
No pooling of centers is planned for this study.
3.7
Coding dictionaries
All AEs and medical history will be coded and classified by primary System Organ Class (SOC) and 
Preferred Term (PT) according to Version 20.1 of the Medical Dictionary for Regulatory Activities 
(MedDRA®).
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01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
All medications will be coded using World Health Organization Drug Reference List (WHO-DRL). 
Medical procedures will not be coded.
4
STATISTICAL/ANALYTICAL ISSUES
4.1
Adjustments for covariates
No inferential statistics will be performed for the efficacy analysis. However, descriptive statistics 
for clinical response and clinical remission will be presented by subgroup variables of interest as 
defined in Section 4.4.
4.2
Handling of dropouts or missing data
For 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.
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.
4.3
Interim analyses and data monitoring
A DSMB reviews CR0012 safety data on an annual basis and can recommend modifying or stopping 
the study.
No formal interim analyses are planned. Should a regulatory authority request an interim analysis, 
this analysis will be performed according to the request.
4.4
Examination of subgroups
No subgroup analysis for efficacy is planned since the total number of subjects participating in this 
study is small (n=16).
5
STUDY POPULATION CHARACTERISTICS
5.1
Subject disposition
The number of subjects who received any study medication, completed, prematurely discontinued 
the study along with reasons for discontinuation, and the number of subjects re-induced in C87035 
and in CR0012 will be summarized by dose group and overall for the Safety Population. In addition,
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
discontinuations due to AEs will be presented in a separate table. Disposition information will also 
be listed.
5.2
Protocol deviations
The number and percentage of subjects with at least one protocol deviation and the number and 
percentage of subjects by type of deviation (inclusion criteria, exclusion criteria, withdrawal criteria, 
prohibited medication use, incorrect dose received, treatment non-compliance, and procedural non-
compliance) will be presented by dose group and overall. All protocol deviations will be listed.
6
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS
6.1
Demographics
Demographics will be summarized for the Safety Population by dose group and overall and will 
include age, age category (<12, ≥12 years), gender, race, ethnicity, height, weight, and body mass 
index (BMI). Note that for European Clinical Trials Database (EudraCT) regulatory requirements, 
age will also be presented categorically as (12 to <18, and 18 to 65 years). Demographic information 
will also be listed.
6.2
Medical history and concomitant diseases
Medical history and concomitant diseases will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA, Version 20.1) and summarized for the Safety Population. The 
number and percentage of subjects by system organ class and preferred term will be presented.
Medical history and concomitant diseases will also be listed.
Procedure history and concomitant medical procedures will not be coded and summarized in tabular 
form, but will be listed for the Safety Population.
6.3
Prior and concomitant medications
Prior and concomitant medication will be coded according to the WHO Drug Reference List 
(SEP/2017).
Medications will be separated into prior and concomitant medications. If the imputed start and stop 
dates of medication are before the date of first administration of study medication, the medication 
will be classified as a prior medication. Medications that were taken after start of CZP treatment or 
medications which started prior to the first administration of CZP treatment  but are still ongoing at 
the time of first administration of CZP will be defined as concomitant medications.  
Start dates will be imputed as follows:
•
Missing day will be imputed as the first day of the month. Missing month will be imputed as 
January
Stop dates will be imputed as follows:
•
Missing day will be imputed as the last day of the month. Missing month will be imputed as 
December
Concomitant medications will be summarized for the Safety Population. Tables will present the 
Anatomical Therapeutic Chemical classification system (ATC) anatomical main group (Level 2) and 
therapeutic/pharmacological subgroup (Level 4) by dose group and overall. 
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01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
Prior and concomitant medications will be listed.
7
MEASUREMENTS OF TREATMENT COMPLIANCE
The number of weeks completed, number of expected doses, and number of doses received will be 
listed for the Safety Population. Definitions are provided below:
•
Total weeks completed = [(last dose date – first dose date + 1) / 7]
o
If total weeks completed is <2, then total expected doses = 0 since first study dose 
administration begins at the Week 2
•
If the subject did not re-induce, then
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total expected doses = (total #weeks completed/4) + 1 rounded down to the nearest 
integer
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If the subject did re-induce, then 
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total expected doses = (total #weeks/4) + 2 rounded down to the nearest integer
8
SAFETY ANALYSES
All safety summaries will be based on the Safety Population and presented by dose group (separate 
columns for High Dose and Low Dose), and presented by weight category, and by age category, as 
appropriate.
For all by-visit AE and medication summaries, if a subject in the Low Dose group is re-induced, the 
subject will be summarized under the High Dose column from the time of re-induction onwards.
8.1
Extent of exposure
Descriptive statistics for the duration of CZP exposure (in years), and for CZP exposure (in mg) 
during the study will be presented by dose group and Total.
8.2
Adverse events
Treatment-emergent adverse events (TEAEs) will be summarized descriptively by primary
SOC and PT. Table columns will include dose groups of CZP Low Dose, CZP High Dose, 
CZP Re-induction 400mg, and All CZP Doses, and report incidence, percent, and number of 
TEAEs. AEs will be defined as related to treatment if the relationship is recorded as possible, 
probable, highly probable, or missing. AEs will be defined as not related if the relationship is 
recorded as unlikely or none.
An overall summary of TEAEs, including the number of events, the number and percentage of 
subjects with any TEAE, with each severity, with each relationship to treatment, treatment 
related (defined as possible, probable, highly probable, or missing), SAEs, any TEAEs leading 
to withdrawal from the study, any TEAEs requiring dose change, and any TEAEs leading to 
death will be presented by dose group.
Other treatment-emergent adverse event tables will include:
•
All TEAEs by primary SOC and PT
•
All TEAEs by primary SOC, PT, and severity
•
All TEAEs by primary SOC, PT, and relationship to study drug
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01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
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•
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•
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•
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•
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•
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•
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PT, and relationship
•
Adverse Events of interest
Adverse events (AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 20.1. AEs of interest and the approach to summarize them will be briefly 
described below. Further information is provided in the guidance document (AE’s of Interest –
Cimzia Program 5January2018).
1. Serious infections, including opportunistic infections will be manually identified by a 
study physician using the Serious TEAE table. A separate table does not need to be 
produced. Opportunistic infections (including tuberculosis) will be summarized in a 
stand-alone table using UCB-defined search criteria.
2. Malignancies, including lymphoma will be presented in 2 tables using the Standardized 
MedDRA Query (SMQ) criteria “Malignant or unspecified tumours” and “Malignant 
tumours” respectively.
3. Serious cardiovascular events will be presented in a table using the following search 
criteria
a.
Serious cardiovascular events will be presented in a table using the following 
search criteria
i. Serious cardiovascular events will be presented in a table using the 
following search criteria:
1. Conditions associated with central nervous system haemorrhages 
and cerebrovascular accidents (SMQ)
2. Haemorrhagic central nervous system vascular conditions (SMQ) 
3. Ischaemic central nervous system vascular conditions (SMQ)
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artery disorders” except events coding to PT “Chest Pain” or “Chest discomfort”
c.
All serious TEAEs which code to a PT included in any of the following HLTs: 
“Heart Failures NEC”, “Left Ventricular Failures”, or “Right Ventricular 
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
Failures” and which also code to the SOC of “Cardiac Disorders” as Primary 
SOC
4. Congestive heart failure AEs (defined as all AEs which code to a PT of “Cardiac failure 
congestive”) will be manually identified by the study physician using the “Any TEAE” 
table.  A separate table does not need to be produced to summarize this event.  
5. Demyelinating-like disorders will be presented in a stand-alone table which is based on 
the SMQ = “Demyelination”. The SMQ search should include all TEAEs which code to 
a PT included in Scope=Narrow group within the SMQ. TEAEs which code to a PT 
included in the Scope=Broad group within the SMQ should be excluded from the 
search.
6. Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia and leucopenia will be 
presented in a stand alone tables based on the SMQ = “Haematopoietic cytopenias”. The 
SMQ search should include all serious TEAEs which code to a PT included in the 
Scope=Broad and/or Scope=Narrow groups within the SMQ.
7. Serious bleeding events will be presented in a stand-alone table that is based on the 
SMQ = “Haemorrhage terms (excl laboratory terms) (SMQ)”. The SMQ search should 
include all serious TEAEs which code to a PT included in the SMQ. 
8. Lupus and lupus-like illness will be manually identified by the study physician using the 
“Any TEAE” table.  A separate table does not need to be produced to summarize these 
types of events.
9. Serious skin reactions (eg, Stevens Johnson Syndrome, toxic epidermal necrosis, and
erythema multiforme) will be manually identified by the study physician using the “Any 
SAE” table.  A separate table does not need to be produced to summarize these types of 
events.
8.3
Clinical laboratory evaluations
Actual laboratory values will be summarized descriptively by week, by dose group and Total.
Change from Baseline to last available visit with laboratory values will be summarized descriptively
by dose group and Total. If multiple laboratory assessments are taken at the last visit with available 
data, the last assessment will be used.
Shift tables that cross-tabulate Baseline (low, normal, high relative to normal range, and missing) by 
end of trial status will be presented by dose group and Total for each laboratory parameter.
The incidence rate of treatment-emergent markedly abnormal laboratory values (based on Common 
Terminology Criteria for Adverse Events criteria) will be presented by dose group and Total for 
hematology and biochemistry laboratory parameters only. See Section 13.1 for markedly abnormal 
criteria.
All laboratory values will be listed with markedly abnormal laboratory values flagged.
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
8.4
Vital signs, physical findings, and other observations related to 
safety
8.4.1
Vital signs
Actual vital signs values (systolic blood pressure, diastolic blood pressure, and pulse rate) will be 
summarized descriptively by week, by dose group and Total. Change from Baseline to last available 
visit with vital signs values will be summarized descriptively by dose group and Total. If multiple 
vital sign values are taken at the last visit with available data, the last assessment will be used.
Vital sign values will also be listed.
8.4.2
Height and Weight
Actual height and weight values will be summarized descriptively by week, by dose group and
Total. Change from baseline to last available visit with height and weight values will be summarized 
descriptively by dose group and Total. If multiple height and weight values are taken at the last visit 
with available data, the last assessment will be used.
Height and weight values will also be listed.  
8.4.3
Electrocardiograms
Not applicable as electrocardiograms were not collected in this study.
8.4.4
Other safety variable(s)
The number and percent of autoantibody levels (ANA and anti-dsDNA antibody) will be presented 
as normal or antibodies present for ANA, and as negative or positive for anti-dsDNA antibodies. 
This table will be presented for the CZP Low Dose group, CZP High Dose group, and for the All 
CZP Doses group. A similar table will be presented by age group.
9
EFFICACY ANALYSES
As the primary objective of this study is to evaluate safety, no primary or secondary efficacy 
variables are defined. Rather, efficacy variables will be measured to evaluate efficacy of long-term 
open label treatment with CZP.
All efficacy summaries, where applicable, will be presented by visit, dose group, weight, (20 to 
<40kg [44 to <88lbs] and ≥40kg [≥88lbs]) and age category (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 by 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.
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
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. Higher 
scores indicate greater impairment and less productivity. The summaries will be presented separately
for the WPAI:CD for children, WPAI:CD for working individuals with CD, and WPAI:CD for 
caregivers. Each of these 3 questionnaires have 6 questions with the WPAI for working individuals 
and for caregivers having similar questions, and the WPAI for children having questions which 
assess time missed and productivity at school rather than at work. In general, the 6 questions are 
(note that for children, the questions will be similar but related to school):
Questions:
The 4 domains are labeled and calculated as (note: domain labels for children will reflect time at 
school, but domain scores are calculated similarly): 
•
: Q2/(Q2+Q4)
•
: Q5/10
•
 Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4))x(Q5/10)]
•
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If appropriate for WPAI, indirect costs parameters will be summarized using descriptive statistics by 
period of onset.
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
10
PHARMACOKINETICS AND PHARMACODYNAMICS 
10.1
Pharmacokinetics
Plasma concentrations of CZP at each visit will be summarized by anti-CZP antibody status (all 
subjects, antibody-positive, and antibody negative) for each age category, the overall population, 
and for each dose group. In addition, plasma concentrations will be summarized by weight category
(<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 category and by 
dose 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. If there are more than 1 concentration available for 
the same timepoint, data will be listed as per the guidance found in the global convention document.
10.2
Pharmacodynamics
Not applicable.
11
OTHER ANALYSES 
Not applicable
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
12
REFERENCES
Not Applicable
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
13
APPENDICES
13.1
Markedly abnormality criteria for laboratory data
Markedly abnormal laboratory values will be defined as those categorized as Grade 3 or 4 based on 
the Common Terminology Criteria for Adverse Events v3.0. Definitions of markedly abnormal 
values using the Grade 3 and Grade 4 cut points are given for hematology in Table 1 and Table 2, 
respectively. Definitions of markedly abnormal values using the Grade 3 and Grade 4 cut points are 
given for biochemistry in Table 3 and Table 4, respectively.
Table 1
Definitions of Grade 3 markedly abnormal hematology values
Parameter (units)
Markedly Abnormal Definition
Low
High
Hemoglobin (g/L)
<80 - 65
N/A
Platelets (X10E9/L)
<50.0 – 25.0
N/A
White blood cells (X10E9/L)
<2.0 – 1.0
N/A
Neutrophils (X10E9/L)
<1.0 - 0.5
N/A
Lymphocytes (X10E9/L)
<0.5 – 0.2
N/A
N/A=Not Applicable
Table 2
Definitions of Grade 4 markedly abnormal hematology values
Parameter (units)
Markedly Abnormal Definition
Low
High
Hemoglobin (g/L)
<65
N/A
Platelets (X10E9/L)
<25.0
N/A
White blood cells (X10E9/L)
<1.0
N/A
Neutrophils (X10E9/L)
<0.5
N/A
Lymphocytes (X10E9/L)
<0.2
N/A
N/A=Not Applicable
Table 3
Definitions of Grade 3 markedly abnormal biochemistry values
Parameter (units)
Markedly Abnormal Definition
Low
High
Sodium (mmol/L)
<130 - 120
>155 - 160
Potassium (mmol/L)
<3.0 – 2.5
>6.0 – 7.0
Calcium (mmol/L)
<1.75 – 1.5
>3.1 – 3.4
Glucose (mmol/L)
<2.2 – 1.7
>13.9 – 27.8
Creatinine
N/A
>3.0 – 6.0 x ULN
Albumin (g/L)
<20
N/A
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
Confidential
Page 20 of 23
Alkaline phosphatase
N/A
>5.0 – 20.0 x ULN
Gamma glutamyl transferase
N/A
>5.0 – 20.0 x ULN
Aspartate aminotransferase
N/A
>5.0 – 20.0 x ULN
Alanine aminotransferase
N/A
>5.0 – 20.0 x ULN
Bilirubin
N/A
>3.0 – 10.0 x ULN
N/A=Not Applicable
Table 4
Definitions of Grade 4 markedly abnormal biochemistry values
Parameter (units)
Markedly Abnormal Definition
Low
High
Sodium (mmol/L)
<120
>160
Potassium (mmol/L)
<2.5
>7.0
Calcium (mmol/L)
<1.5
>3.4
Glucose (mmol/L)
<1.7
>27.8
Creatinine
N/A
>6.0 x ULN
Albumin (g/L)
N/A
N/A
Alkaline phosphatase
N/A
>20.0 x ULN
Gamma glutamyl transferase
N/A
>20.0 x ULN
Aspartate aminotransferase
N/A
>20.0 x ULN
Alanine aminotransferase
N/A
>20.0 x ULN
Bilirubin
N/A
>10.0 x ULN
N/A=Not Applicable.
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
Confidential
Page 21 of 23
13.2
Impact III Questionnaire Scoring
The Impact III questionnaire is a 35-item measure of health-related quality of life in children 
with inflammatory bowel disease with a total score ranging from 35 (poor) to 175 (best). Total 
score is calculated as the sum of all 35 questions. Scores for the 6 domain scores of IBD 
Symptoms, Systemic Symptoms, Emotional Functioning, Social Functioning, Body Image, and 
Treatment/Interventions are calculated by summing the responses for questions within a domain 
(see table below).
Domain
Question (actual question number in parentheses)
IBD Symptoms
•
 (1)
•
 (3)
•
 (10)
•
 (19)
•
 (21)
•
 (25)
•
 (31)
Systemic Symptoms
•
 (6)
•
 (28)
•
 (32)
Emotional Functioning
•
up (4)
•
 (5)
•
 (11)
•
 (12)
•
(13)
•
 (16)
•
 (29)
Social Functioning
•
 (8)
•
 (9)
•
 (14)
•
 (17)
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
Confidential
Page 22 of 23
•
riends (18)
•
 (20)
•
 (23)
•
 (27)
•
 (26)
•
ies (30)
•
 (34)
•
 (35)
Body Image
•
 (33)
•
 (7)
•
 (15)
Treatment/Interventions
•
 (2)
•
(22)
•
 (24)
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UCB
01 Jan 2018
Statistical Analysis Plan
Certrolizumab pegol
{StudyNumber}
Confidential
Page 23 of 23
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution.
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ELECTRONIC SIGNATURES
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