Clinical trial NCT01550003
Conditions: Polyarticular-course Juvenile Idiopathic Arthritis (JIA)
Keywords: Cimzia JIA Polyarticular Oligoarticular Enthesitis-related-Arthritis Juvenile Idiopathic Arthritis Juvenile Psoriatic Arthritis Certolizumab Pegol PASCAL CDP870
Sponsor: UCB BIOSCIENCES GmbH
Start date: 2012-03-08; Completion date: 2024-04-08
Enrollment: 193 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Multicenter, Open-label Study to Assess the Pharmacokinetics, Safety and Efficacy of Certolizumab Pegol in Children and Adolescents With Moderately to Severely Active Polyarticular-course Juvenile Idiopathic Arthritis (JIA).

Detailed description:
The overall study consists of a Screening Period of up to 4 weeks and an Open-Label Treatment Period which will continue until the approval of the marketing application for the Polyarticular-course Juvenile Idiopathic Arthritis (JIA) indication in the study participant's country or region or until further notice from UCB (approximately 4-6 years duration; depending on region). A Final Visit will be conducted 12 weeks after last dose of study medication. Overall, study visits will occur monthly during the first 6 months and every 2 months afterwards. All patients will receive active treatment with Certolizumab Pegol. The dose will depend on actual weight. Home dosing will be allowed between study visits.

If less than 50 % of the study population achieves an adequate response to the treatment (American College of Rheumatology Pediatric 30 % (PedACR30) response) at Week 16, the study will be entirely discontinued.

Arms: arm 1: Active treatment with Certolizumab Pegol; dose adjustment is based on weight.
Interventions: intervention 1: Certolizumab Pegol (CZP) intervention 2: Certolizumab Pegol (CZP)
Intervention descriptions: intervention 1: CZP will be administered subcutaneously as a fixed dose based on weight every 2 weeks (Q2W) or every 4 weeks (Q4W) throughout the study.

CZP will be provided by UCB as a CZP 200 mg/ml solution for single subcutaneous (sc) injection, in a single use prefilled syringe (PFS). Each PFS contains an extractable volume of 0.25 mL, 0.5 mL or 1 mL of CZP solution.

Eligible subjects will begin with 3 loading doses of CZP followed by a treatment dose for the duration of the study based on the weight range.

Reduced CZP regimen (after implementation of protocol amendments 4 and 5):

* 10 to \< 20 kg: Loading dose = 50 mg Q2W (1 x 0.25 mL sc); treatment dose = 50 mg Q4W (1 x 0.25 mL sc);
* 20 to \< 40 kg: Loading dose = 100 mg Q2W (1 x 0.5 mL sc,); treatment dose = 50 mg Q2W (1 x 0.25 mL sc);
* ≥ 40 kg: Loading dose = 200 mg Q2W (1 x 1.0 mL sc); treatment dose = 100 mg Q2W (1 x 0.5 mL sc); intervention 2: CZP will be administered subcutaneously as a fixed dose based on weight every 2 weeks (Q2W) or every 4 weeks (Q4W) throughout the study.

CZP will be provided by UCB as a CZP 200 mg/ml solution for single subcutaneous (sc) injection, in a single use prefilled syringe (PFS). Each PFS contains an extractable volume of 0.25 mL, 0.5 mL or 1 mL of CZP solution.

Eligible subjects will begin with 3 loading doses of CZP followed by a treatment dose for the duration of the study based on the weight range.

Original CZP regimen (prior to implementation of protocol amendments 4 and 5 and after implementation of protocol amendment 9):

* 10 to \< 20 kg: Loading dose = 100 mg Q2W (1 x 0.5 mL sc); treatment dose = 50 mg Q2W (1 x 0.25 mL sc);
* 20 to \< 40 kg: Loading dose = 200 mg Q2W (1 x 1.0 mL sc,); treatment dose = 100 mg Q2W (1 x 0.5 mL sc);
* ≥ 40 kg: Loading dose = 400 mg Q2W (2 x 1.0 mL sc); treatment dose = 200 mg Q2W (1 x 1.0 mL sc);

Protocol documents:
Prot_000.pdf: 
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PROTOCOL RA0043 AMENDMENT 9 
A MULTICENTER, OPEN-LABEL STUDY TO ASSESS THE 
PHARMACOKINETICS, SAFETY, AND EFFICACY OF 
CERTOLIZUMAB PEGOL IN CHILDREN AND 
ADOLESCENTS WITH MODERATELY TO SEVERELY 
ACTIVE POLYARTICULAR-COURSE JUVENILE IDIOPATHIC 
ARTHRITIS 
PASCAL (Pediatric Arthritis Study of CertolizumAb pegoL) 
PHASE 3 
EudraCT-Number: 2009-018027-33 
IND Number: 9869 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Strasse 10 
40789 Monheim  
GERMANY 
Protocol/Amendment Number 
Date 
Type of amendment 
Final 
14 Jan 2010 
N/A 
Amendment 1 
26 Aug 2011 
Substantial 
Amendment 2 
02 Jul 2012 
Nonsubstantial 
Amendment 3 
06 May 2013 
Substantial 
Amendment 4 
01 Aug 2013 
Substantial 
Amendment 5 
20 Jan 2014 
Substantial 
Amendment 6 
17 Sep 2015 
Nonsubstantial 
Amendment 7 
22 Sep 2016 
Substantial 
Amendment 8 
24 Jun 2019 
Substantial 
Amendment 9 
27 Apr 2020 
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. 
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STUDY CONTACT INFORMATION 
Sponsor 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Clinical Program Director  
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
 
 
Sponsor Study Physician 
Name: 
 
Address: 
UCB 
208 Bath Road 
Slough 
SL1 3WE  
Phone: 
Fax: 
 
Clinical Project Manager 
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
Germany 
Phone: 
Fax: 
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Clinical Trial Biostatistician  
Name: 
 
Address: 
UCB 
208 Bath Road 
Slough 
SL1 3WE 
Phone: 
 
Fax: 
N/A 
 
Clinical Monitoring Contract Research Organization  
Name: 
Pharmaceutical Research Associates, Inc. 
Address: 
4130 Park Lake Avenue, Suite 
 
Raleigh, NC 27612 
USA 
Phone: 
+1 919 786 8200 
Fax: 
+1 919 786 8201 
 
Medical Monitor (all regions) 
E-mail: 
PASCAL@praintl.com 
 
Medical Monitor North America 
Name: 
Phone: 
Fax: 
 
Medical Monitor Europe 
Name: 
Phone: 
Fax: 
 
 
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SERIOUS ADVERSE EVENT REPORTING 
 
Serious adverse event reporting (24h)  
Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA and Canada: +1 800 880 6949 or +1 866 890 3175 
E-mail 
Global: DS_ICT@ucb.com  
 
 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 11 
1 
SUMMARY ..................................................................................................................... 15 
2 
INTRODUCTION ........................................................................................................... 18 
3 
STUDY OBJECTIVES .................................................................................................... 20 
3.1 
Primary study objectives .............................................................................................. 20 
3.2 
Secondary study objective ........................................................................................... 20 
3.3 
Other objectives ........................................................................................................... 20 
4 
STUDY VARIABLES ..................................................................................................... 21 
4.1 
Primary variables ......................................................................................................... 21 
4.1.1 
Pharmacokinetic and immunological variables ................................................... 21 
4.1.2 
Safety variables .................................................................................................... 21 
4.2 
Secondary variables ..................................................................................................... 21 
4.3 
Other variables ............................................................................................................. 21 
5 
STUDY DESIGN ............................................................................................................. 23 
5.1 
Study description ......................................................................................................... 23 
5.1.1 
Study duration per study participant .................................................................... 24 
5.1.2 
Planned number of study participants and sites ................................................... 24 
5.1.3 
Anticipated regions and countries ....................................................................... 24 
5.2 
Schedule of study assessments..................................................................................... 25 
5.3 
Schematic diagram ....................................................................................................... 29 
5.4 
Rationale for study design and selection of dose ......................................................... 30 
5.4.1 
Study design ......................................................................................................... 30 
5.4.2 
Dose selection ...................................................................................................... 30 
5.4.2.1 
Original CZP dose regimen ....................................................................... 31 
5.4.2.2 
Reduced CZP dose regimen ...................................................................... 32 
6 
SELECTION AND WITHDRAWAL OF STUDY PARTICIPANTS ........................... 34 
6.1 
Inclusion criteria .......................................................................................................... 34 
6.2 
Exclusion criteria ......................................................................................................... 35 
6.3 
Retesting and rescreening ............................................................................................ 39 
6.4 
Liver Chemistry Stopping Criteria ............................................................................... 39 
6.5 
Withdrawal criteria ...................................................................................................... 40 
7 
STUDY TREATMENTS ................................................................................................. 42 
7.1 
Description of IMP ...................................................................................................... 42 
7.2 
Treatments to be administered ..................................................................................... 42 
7.2.1 
Procedure for dose change (Protocol Amendment 9) .......................................... 44 
7.3 
Packaging ..................................................................................................................... 45 
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7.4 
Labeling ....................................................................................................................... 45 
7.5 
Handling and storage requirements ............................................................................. 45 
7.6 
Drug accountability ...................................................................................................... 46 
7.7 
Procedures for monitoring study participant compliance ............................................ 46 
7.8 
Concomitant medication(s)/treatment(s) ..................................................................... 47 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 47 
7.8.2 
Rescue medication ............................................................................................... 48 
7.8.3 
Prohibited concomitant treatments (medications and therapies) ......................... 49 
7.9 
Lost to follow up .......................................................................................................... 49 
7.10 
Enrollment and numbering of study participants ......................................................... 50 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 50 
8.1 
Visit 1 (Week -4 to 0) Screening ................................................................................. 50 
8.2 
Visit 2 (Week 0) Baseline ............................................................................................ 52 
8.3 
Visits 3 and 4 (Weeks 1 and 2) .................................................................................... 53 
8.4 
Visits 5 to 10 (Weeks 4, 8, 12, 16, 20, and 24) ............................................................ 54 
8.5 
Visits 11 and continuing (Week 32 and every 8 weeks thereafter) ............................. 55 
8.6 
Unscheduled Visit ........................................................................................................ 57 
8.6.1 
Unscheduled Visit related to dose change ........................................................... 57 
8.7 
Early Discontinuation/End of Treatment Visit ............................................................ 57 
8.8 
Final Visit..................................................................................................................... 58 
9 
ASSESSMENT OF PHARMACOKINETICS AND IMMUNOLOGICAL 
VARIABLES ................................................................................................................... 59 
10 ASSESSMENT OF SAFETY .......................................................................................... 60 
10.1 
Adverse events ............................................................................................................. 60 
10.1.1 
Definition of AE .................................................................................................. 60 
10.1.2 
Procedures for reporting and recording AEs ....................................................... 60 
10.1.3 
Description of AEs .............................................................................................. 60 
10.1.4 
Follow-up on AEs ................................................................................................ 60 
10.1.5 
Rule for repetition of an AE ................................................................................ 61 
10.1.6 
Reporting requirements for events relating to TB ............................................... 61 
10.1.7 
Pregnancy ............................................................................................................ 61 
10.1.8 
Suspected transmission of an infectious agent via a medicinal product .............. 62 
10.1.9 
Overdose of IMP .................................................................................................. 62 
10.1.10 
Ongoing safety data review and oversight ........................................................... 62 
10.2 
Serious adverse events ................................................................................................. 63 
10.2.1 
Definition of SAE ................................................................................................ 63 
10.2.2 
Procedures for reporting SAEs ............................................................................ 64 
10.2.3 
Follow-up of SAEs .............................................................................................. 64 
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10.3 
AEs of special interest ................................................................................................. 65 
10.4 
Immediate reporting of AEs......................................................................................... 65 
10.5 
Anticipated serious adverse events .............................................................................. 66 
10.6 
Laboratory measurements ............................................................................................ 66 
10.7 
Other safety measurements .......................................................................................... 69 
10.7.1 
Vital signs ............................................................................................................ 69 
10.7.2 
Growth (height and weight) ................................................................................. 69 
10.7.3 
Tanner stages ....................................................................................................... 70 
10.7.4 
Physical examination ........................................................................................... 70 
10.7.5 
Demographics, JIA history, prior JIA medication, and general medical and 
procedure history ................................................................................................. 71 
10.7.6 
Reproductive potential and birth control ............................................................. 71 
10.7.7 
Pregnancy testing ................................................................................................. 71 
10.7.8 
Autoantibody (ANA and anti-dsDNA antibodies) concentrations ...................... 71 
10.7.9 
Assessment and management of TB and TB risk factors .................................... 71 
10.7.9.1 
Physical examination ................................................................................. 72 
10.7.9.2 
IGRA test conversion ................................................................................ 72 
10.7.9.3 
Latent TB infection ................................................................................... 73 
10.7.9.4 
Active TB or NTMB infection .................................................................. 73 
10.7.9.5 
TB assessment by IGRA or tuberculin skin test (TST) ............................. 73 
10.7.9.6 
TB assessment by chest x-ray ................................................................... 74 
10.7.9.7 
TB risk factors via the TB questionnaire ................................................... 74 
10.7.9.8 
TB management ........................................................................................ 75 
11 ASSESSMENT OF EFFICACY AND HEALTH OUTCOMES VARIABLES ............ 76 
11.1 
PedACR30, PedACR50, PedACR70, and PedACR90 clinical response .................... 76 
11.2 
PRINTO/PRCSG standard joint examination .............................................................. 76 
11.3 
Number of joints with active arthritis and number of joints with limitation of 
range of motion ............................................................................................................ 77 
11.4 
Physician’s Global Assessment of Disease Activity (VAS) ........................................ 77 
11.5 
Childhood Health Assessment Questionnaire (CHAQ) ............................................... 77 
11.6 
Parent’s Assessment of Arthritis Pain (VAS) .............................................................. 78 
11.7 
Parent’s Global Assessment of Overall Well-Being (VAS) ........................................ 78 
11.8 
C-reactive protein (CRP) ............................................................................................. 78 
11.9 
JADAS ......................................................................................................................... 79 
11.10 Clinically Inactive Disease and clinical remission ...................................................... 79 
11.11 Duration of morning stiffness (DMS) .......................................................................... 80 
11.12 Faces Pain Scale-Revised (FPS-R) .............................................................................. 80 
11.13 Patient’s Assessment of Arthritis Pain (JIA Pain VAS) .............................................. 81 
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11.14 Fatigue Assessment Scale (NRS)................................................................................. 81 
11.15 Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey ........ 82 
12 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 82 
12.1 
Adherence to protocol .................................................................................................. 82 
12.2 
Monitoring ................................................................................................................... 82 
12.2.1 
Definition of source data ..................................................................................... 83 
12.2.2 
Source data verification ....................................................................................... 83 
12.3 
Data handling ............................................................................................................... 84 
12.3.1 
Case report form completion ............................................................................... 84 
12.3.2 
Database entry and reconciliation ........................................................................ 84 
12.3.3 
Study participant screening and enrollment log/Study participant 
identification code list .......................................................................................... 84 
12.4 
Termination of the study .............................................................................................. 84 
12.5 
Archiving and data retention ........................................................................................ 85 
12.6 
Audit and inspection .................................................................................................... 85 
12.7 
Good Clinical Practice ................................................................................................. 86 
13 STATISTICS ................................................................................................................... 86 
13.1 
Definition of analysis sets ............................................................................................ 86 
13.2 
General statistical considerations ................................................................................. 86 
13.2.1 
Data presentation ................................................................................................. 86 
13.2.2 
Multicenter studies ............................................................................................... 87 
13.2.3 
Coding dictionaries .............................................................................................. 87 
13.3 
Planned safety analyses................................................................................................ 87 
13.4 
Planned PK, PD, and immunological variable analysis ............................................... 88 
13.5 
Planned efficacy and health outcomes analyses .......................................................... 89 
13.6 
Handling of dropouts or missing data .......................................................................... 90 
13.7 
Interim analysis and data monitoring ........................................................................... 91 
13.8 
Determination of sample size ....................................................................................... 92 
14 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 93 
14.1 
Informed consent ......................................................................................................... 93 
14.2 
Study participant identification cards .......................................................................... 94 
14.3 
Institutional Review Boards and Independent Ethics Committees .............................. 95 
14.4 
Study participant privacy ............................................................................................. 95 
14.5 
Protocol amendments ................................................................................................... 96 
15 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 96 
16 REFERENCES ................................................................................................................ 96 
17 APPENDICES ................................................................................................................. 98 
17.1 
Childhood Health Assessment Questionnaire (CHAQ) ............................................... 99 
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17.2 
Parent’s Assessment of Arthritis Pain (VAS) ............................................................ 101 
17.3 
Parent’s Global Assessment of Overall Well-Being (VAS) ...................................... 101 
17.4 
Faces Pain Scale-Revised .......................................................................................... 102 
17.5 
Patient’s Assessment of Arthritis Pain (JIA Pain VAS, acute version) ..................... 103 
17.6 
Patient’s Assessment of Arthritis Pain (JIA Pain VAS, standard version) ................ 103 
17.7 
Fatigue Assessment Scale (NRS)............................................................................... 103 
17.8 
Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey ...... 104 
17.9 
TB questionnaire ........................................................................................................ 110 
17.10 Liver Safety – Suggested Actions and Follow-up Assessments ................................ 111 
17.10.1 
Evaluation of PDILI .......................................................................................... 111 
17.10.1.1 
Consultation with Medical Monitor and local hepatologist .................... 114 
17.10.1.2 
Immediate action: determination of IMP discontinuation ....................... 114 
17.10.1.3 
Testing: identification/exclusion of alternative etiology ......................... 114 
17.10.1.4 
Follow-up evaluation ............................................................................... 116 
17.11 Protocol Amendment 1 .............................................................................................. 117 
17.12 Protocol Amendment 2 .............................................................................................. 119 
17.13 Protocol Amendment 3 .............................................................................................. 121 
17.14 Protocol Amendment 4 .............................................................................................. 169 
17.15 Protocol Amendment 5 .............................................................................................. 185 
17.16 Protocol Amendment 6 .............................................................................................. 201 
17.17 Protocol Amendment 7 .............................................................................................. 204 
17.18 Protocol Amendment 8 .............................................................................................. 212 
17.19 Protocol Amendment 9 .............................................................................................. 226 
18 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 279 
19 SPONSOR DECLARATION ........................................................................................ 280 
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LIST OF TABLES 
Table 5-1 
Schedule of study assessments......................................................................... 25 
Table 5-2 
PK estimates of CZP exposure in adult study participants with RA 
based on population PK modeling ................................................................... 32 
Table 6-1 
Prohibited medications at entry (Baseline) ...................................................... 36 
Table 7-1 
Dosing administration of CZPa ........................................................................ 43 
Table 10-1 
Anticipated serious adverse events for JIA population.................................... 66 
Table 10-2 
Laboratory measurements ................................................................................ 68 
Table 13-1 
PK simulation results for 125-study participant study sample size ................. 93 
Table 17‒1: 
Required investigations and follow up for PDILI.......................................... 112 
Table 17‒2: 
PDILI laboratory measurements .................................................................... 115 
Table 17‒3: 
PDILI information to be collected ................................................................. 116 
Table 17‒1 
Proposed revised dosing recommendation based on PopPK model 
simulations ..................................................................................................... 169 
Table 17‒2 
Proposed revised dosing recommendation based on PopPK model 
simulations ..................................................................................................... 185 
Table 17-1 
Dosing administration of CZPa ...................................................................... 254 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse events of special interest 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ADA 
adalimumab 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
AST 
aspartate aminotransferase 
anti-dsDNA 
anti-double-stranded deoxyribonucleic acid 
BCG 
Bacille Calmette-Guérin 
CDMS 
clinical data management system 
CDC 
Centers for Disease Control and Prevention 
CDP870 
certolizumab pegol 
CHAQ 
Childhood Health Assessment Questionnaire 
CI 
confidence interval 
CID 
Clinically Inactive Disease 
COX-2 
cyclooxygenase-2 
CRF 
case report form 
CPM 
Clinical Project Manager 
CRM 
clinical remission on medication 
CRO 
contract research organization 
CRP 
C-reactive protein 
CTS 
Clinical Trial Supplies 
CZP 
certolizumab pegol 
DIP 
distal interphalangeals 
DMARD 
disease-modifying antirheumatic drug 
DMS 
duration of morning stiffness 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
EAIR 
exposure-adjusted incidence rate 
ECG 
electrocardiogram 
ECLIA 
electrochemiluminescence immunoassay 
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ELISA 
enzyme-linked immunosorbent assay 
ERA 
enthesitis-related arthritis 
ES 
Enrolled Set  
ETN 
etanercept 
Fab′ 
fragment antigen binding  
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FPS-R 
Faces Pain Scale-Revised 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ia 
intra-articular 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IGRA 
interferon-gamma release assay 
im 
intramuscular 
IMP 
investigational medicinal product 
INH 
isonicotinic acid hydrazide/isoniazid 
IRB 
institutional review board 
iv 
intravenous(ly) 
IXRS 
interactive voice/web response system 
JADAS 
Juvenile Arthritis Disease Activity Score  
JIA 
juvenile idiopathic arthritis 
LOCF 
last observation carried forward 
LOM 
limitation of motion 
LTB 
latent tuberculosis 
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LTBI 
latent tuberculosis infection 
MAR 
missing at random 
MCP 
metacarpal 
MedDRA® 
Medical Dictionary of Regulatory Activities 
MSD 
Meso Scale Discovery 
MTP 
metatarsophalangeal 
MTX 
methotrexate 
NRS 
numeric rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
NTMB 
nontuberculous mycobacteria 
OC 
observed case 
PD 
Pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
PedACR30, 50, 70, 90 
American College of Rheumatology Pediatric 30%, 50%, 70%, 90% 
PEG 
polyethylene glycol 
PFS 
prefilled syringe(s) 
PIP 
proximal interphalangeal 
PK 
pharmacokinetics 
PK-PD 
Pharmacokinetic-Pharmacodynamic 
PK-PP 
Pharmacokinetic Per-Protocol 
POM 
pain on motion 
PopPK 
population pharmacokinetic 
PRN 
as needed 
PRINTO/PRCSG 
Paediatric Rheumatology INternational Trials Organisation/ Pediatric 
Rheumatology Collaborative Study Group 
Q2W, Q4W 
every 2 weeks, every 4 weeks 
RA 
rheumatoid arthritis 
RBC 
red blood cell 
RDC 
remote data capture 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
subcutaneous(ly) 
SDV 
source data verification 
SOP 
standard operating procedures 
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SS 
Safety Set 
TB 
tuberculosis 
TNF 
tumor necrosis factor 
TNFα 
tumor necrosis factor alpha 
USA 
United States of America 
VAS 
visual analog scale 
WBC 
white blood cell 
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1 
SUMMARY 
This is a Phase 3, multicenter, open-label study to assess the pharmacokinetics (PK), safety, 
and efficacy of certolizumab pegol (CDP870, CZP, Cimzia®) in children and adolescents 
with moderately to severely active polyarticular-course juvenile idiopathic arthritis (JIA). 
Certolizumab pegol, the investigational medicinal product (IMP), is a humanized antibody 
fragment antigen binding (Fab′), with specificity for human tumor necrosis factor alpha 
(TNFα), conjugated to polyethylene glycol (PEG). The drug intended for use in this study is 
the liquid formulation in a prefilled syringe (PFS). 
The study population will consist of study participants 2 to 17 years of age upon enrollment 
with a minimum weight of 10kg (22lb). Study participants must have had onset of signs and 
symptoms consistent with polyarticular-course JIA and initiation of JIA treatment for at least 
6 months prior to Baseline. Active polyarticular-course JIA disease is defined as ≥5 joints 
with active arthritis including: polyarthritis rheumatoid factor-positive, polyarthritis 
rheumatoid factor-negative, extended oligoarthritis, juvenile psoriatic arthritis, and 
enthesitis-related arthritis (ERA). Study participants cannot have had active uveitis within the 
last 6 months prior to Baseline. In addition, study participants must have had an inadequate 
response to, or intolerance to, at least 1 disease-modifying antirheumatic drug (DMARD). 
The study consists of a Screening Period of up to 4 weeks; eligible study participants will 
then enter an open-label Treatment Period which will continue until the approval of the 
marketing application for the indication of polyarticular-course JIA in the study participant’s 
country or region or until further notice from UCB. A Final Visit will be conducted 12 weeks 
after last dose of study medication. 
Approximately 195 study participants are planned to be screened to enroll 156 study 
participants in this study, as follows: 
 A minimum of 10 study participants will be enrolled on the reduced CZP dose regimen 
(Protocol Amendment 5) in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg 
(44 to <88lb), and ≥40kg (≥88lb).  
 A minimum of 10 study participants will be enrolled in each age category of 2 to 5 years, 
6 to 11 years, and 12 to 17 years, irrespective of the dose regimen.  
 A minimum of 25 study participants will be enrolled who receive CZP as monotherapy 
(ie, study participants with established intolerability or inadequate response to MTX), 
irrespective of the dose regimen. 
 A minimum of 10 study participants with ERA will be enrolled, irrespective of the dose 
regimen.  
Each of these categories is assessed independently. In order to further support the safety 
assessment of the original CZP dose, as more of the safety data collected in the study to date 
has been on the reduced dose, an additional 30 study participants will be enrolled on the 
original dose regimen with the aim to enroll at least 5 study participants in each weight range 
of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and ≥40kg (≥88lb) following 
Protocol Amendment 9. 
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A full interim analysis will be performed after all active study participants have completed 
the Week 24 (Visit 10) assessments.  
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4, followed by maintenance doses 
Q2W. The original minimum and maximum loading doses in the study were CZP 100mg 
Q2W and CZP 400mg Q2W, respectively, and the original minimum and maximum 
maintenance doses were CZP 50mg Q2W and CZP 200mg Q2W, respectively. Based on an 
interim PopPK analysis of RA0043 data, the minimum and maximum loading doses in the 
study were adjusted to CZP 50mg Q2W and CZP 200mg Q2W, respectively, and the 
minimum and maximum maintenance doses were adjusted to CZP 50mg Q4W and 
CZP 100mg Q2W, respectively, following implementation of Protocol Amendments 4 and 5. 
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPK analysis and 
simulations that informed the dose reduction in Protocol Amendment 4 and 5 unusable from a 
regulatory standpoint. Accordingly, PK samples were no longer collected for study 
participants on the reduced CZP dose regimen following implementation of Protocol 
Amendment 8.  
An electrochemiluminescence immunoassay (ECLIA) method, for which selectivity had 
previously been assessed in the RA matrix, has now been validated to meet the standards set 
in the regulatory guidance for analytical procedures and methods validations for drugs and 
biologics. 
Based on 24-week interim results from the first 163 participants enrolled in RA0043, both the 
original and reduced dose regimens showed safety profiles similar to the approved CZP dose 
regimen in the adult RA population. The overall clinical response in this analysis (taking both 
dose regimens into account) was American College of Rheumatology Pediatric 30% 
(PedACR30) and PedACR50 responses of 77.3% and 67.5%, respectively at Week 12. The 
response from the original dose regimen was 75.6% for PedACR30 and 64.1% for 
PedACR50. PedACR50 response demonstrates a highly clinically relevant decrease in 
disease activity. 
Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
JIA at both the reduced and original CZP dose regimens and also adequately support the 
safety assessment of the original CZP dosing regimen, as more of the safety data collected in 
the study to date has been on the reduced dose, 30 additional study participants will be 
enrolled on the original CZP dose regimen following Protocol Amendment 9. All study 
participants enrolled following Protocol Amendment 9 will have plasma concentrations of 
CZP and anti-CZP antibodies analyzed using the ECLIA method. In addition, PK and ADA 
samples (for which sufficient volume is available) collected in this study prior to Protocol 
Amendment 9 will be analyzed with the ECLIA method. The collective ECLIA-based PK 
data for this study will form the basis of any future CZP modeling and simulation work. 
The primary objectives of the study are to evaluate the PK and safety including the 
immunogenicity of CZP administered subcutaneously (sc) in children and adolescents with 
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moderate to severe polyarticular-course JIA. The primary PK and immunological variables 
are CZP plasma concentrations and anti-CZP antibody levels at Week 16 and Week 48.  
The primary safety variables are the incidence of serious treatment-emergent adverse events 
(TEAEs) and TEAEs leading to permanent withdrawal of IMP. Other safety variables to be 
assessed are the incidence of TEAEs, vital signs and measurements of laboratory parameters 
including hematology, biochemistry, and urinalysis. Physical examination findings (except 
joint examination) are recorded in the case report form (CRF) only at Screening. Subsequent 
physical examinations are performed to assess clinically significant changes and thus, only 
abnormal findings are recorded in the CRF as AEs. Tanner stages (except growth) and 
growth (height, weight) over the course of the study will be assessed. Autoantibody 
(antinuclear antibodies [ANA] and anti-double-stranded deoxyribonucleic acid [anti-dsDNA] 
antibodies) concentrations will be evaluated. The secondary objective of the study is to assess 
the effectiveness of CZP on the clinical response in children and adolescents with moderate 
to severe polyarticular-course JIA. 
The following efficacy variables are defined as secondary variables: PedACR30, PedACR50, 
PedACR70, and PedACR90 response rates at Week 16 (compared to Baseline). Other 
efficacy and health outcomes variables include: PedACR30, PedACR50, PedACR70, and 
PedACR90 response rates at other timepoints than Week 16 (compared to Baseline), change 
from Baseline in number of joints with active arthritis, change from Baseline in number of 
joints with limitation of range of motion, change from Baseline in Physician’s Global 
Assessment of Disease Activity (visual analog scale [VAS]), change from Baseline in 
Childhood Health Assessment Questionnaire (CHAQ, parent/caregiver reported) total score, 
change from Baseline in Parent's Assessment of Arthritis Pain (VAS), change from Baseline 
in Parent’s Global Assessment of Overall Well-Being (VAS), ratio to Baseline in C-reactive 
protein (CRP), change from Baseline in Juvenile Arthritis Disease Activity Score (JADAS), 
percentage of study participants meeting criteria of Clinically Inactive Disease (CID) and 
clinical remission on medication (CRM), time to CID, time to CRM, change from Baseline in 
duration of morning stiffness (DMS), change from Baseline in Faces Pain Scale-Revised 
(FPS-R, child reported, ages 5 to 11 years), change from Baseline in Patient’s Assessment of 
Arthritis Pain (JIA Pain VAS, child reported, ages 12 to 17 years), change from Baseline in 
Fatigue Assessment Scale, and Juvenile Arthritis School Attendance and Caregiver Work 
Productivity Survey (parent/caregiver reported).
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2 
INTRODUCTION 
Certolizumab pegol (CDP870, CZP, Cimzia®) is approved in the United States of America 
(USA), the European Union, and a number of other countries worldwide for the treatment of 
moderately to severely active RA in adults.  
Juvenile idiopathic arthritis is the clinical presentation of persistent arthritis (≥6 weeks in 
duration) of unknown etiology due to chronic inflammation of the synovium (Ravelli and 
Martini, 2007; Nigrovic and White, 2006). Juvenile idiopathic arthritis is the most commonly 
diagnosed rheumatic disease affecting children less than 16 years of age with a prevalence of 
approximately 100 in 100,000 children (Zitelli et al, 2012). Disease onset is typically by 
5 years of age but rarely before 6 months, and females are affected approximately twice as 
frequently as males. Juvenile idiopathic arthritis leads to significant functional and emotional 
disability with 50% of affected children continuing to suffer from persistent inflammation 
and disability as adults. 
The disease is characterized by B-cell, T-cell, and macrophage infiltration and expansion 
which leads to the release of proinflammatory cytokines and promotes synovial proliferation, 
resulting in thickened pannus and subsequently joint destruction. Patients with 
polyarticular-course JIA have ≥5 inflamed joints over the course of the disease. For the 
purpose of this study, polyarticular-course is defined as ≥5 joints at the time of enrollment. In 
addition to the articular manifestations, children with JIA commonly present with 
constitutional symptoms such as anorexia, weight loss, and growth failure. 
The introduction of TNF-antagonists represented a major advance in the drug treatment of 
RA for adults and subsequently, JIA in children and adolescents. Two TNF-antagonists, 
etanercept (ETN) and adalimumab (ADA), are currently registered in both the USA and 
Europe for the treatment of JIA. The therapeutic response to these available TNF-antagonists 
is variable. This is also true for tolerability and is in keeping with the well known 
idiosyncratic response to traditional DMARDs. Therefore, a medical need remains for 
additional effective TNF-antagonists in the treatment of JIA. 
TNFα blockers appear to be less effective in patients with systemic JIA compared to other 
JIA subtypes (Lovell et al, 2000). Recent evidence suggests that, unlike other JIA subtypes, 
abnormalities in the cytokines IL-1 and IL-6 play a major role in the pathogenesis of systemic 
JIA (Vastert et al, 2009). The IL-6 blocker tocilizumab is currently approved in the EU for 
systemic JIA (Tocilizumab [RoActemra®] Summary of Product Characteristics, 2010). 
Certolizumab pegol is a humanized antibody antigen-binding fragment (Fab′), with 
specificity for human TNFα, which is conjugated to PEG. Certolizumab pegol has a high 
affinity for TNFα with a Kd of 0.9x10-10M and has been shown to be an effective 
TNF-inhibitor, preventing the development of arthritis as assessed by both disease activity 
and joint histology in a transgenic mouse model of progressive arthritis. Certolizumab pegol 
does not neutralize TNF beta (lymphotoxin) and does not effect antibody-dependent 
cell-mediated cytotoxicity (ADCC) or activate complement-mediated lysis in vitro.  
Single-dose and subchronic toxicity studies in animal models indicate that CZP was well 
tolerated and had no safety issues. Genotoxicity (in vitro and in vivo) and reproductive 
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toxicity (animal models) studies support the safety of the product, demonstrating no adverse 
effects from CZP. 
Single intravenous (iv) and sc doses of CZP have been shown to have predictable 
dose-related exposure with an approximately linear relationship between the dose 
administered and both the maximum plasma concentration (Cmax) and the area under the CZP 
plasma concentration versus time curve (AUC). The terminal elimination phase half-life is 
approximately 14 days. Certolizumab pegol has been demonstrated to have good 
bioavailability (~80%) when given sc. 
No clinically meaningful drug-drug interactions between CZP and methotrexate (MTX) or its 
metabolite, 7-hydroxy MTX, have been detected. Population PK analyses have shown that 
concomitant administration of MTX (or other immunosuppressants), corticosteroids, 
aminosalicylic acid analogs, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, or 
anti-infectives do not impact the PK of CZP. Age and gender had no effect on the PK of CZP 
in these studies. The influence of renal impairment was not studied as almost 80% of the 
study participants had a normal creatinine clearance and less than 2% of the study 
participants exhibited moderate to severe renal impairment. 
The overall clinical efficacy of CZP studied both as monotherapy as well as concomitantly 
with MTX in MTX-inadequate responders, in the treatment of adult study participants with 
moderate to severe active RA, was demonstrated in four Phase 3 placebo-controlled RA 
studies. The dosing regimens tested included CZP 400mg sc at Weeks 0, 2, and 4 followed by 
CZP 200mg or CZP 400mg given Q2W with MTX and CZP 400mg every 4 weeks with and 
without MTX. Inhibition of the progression of structural damage was demonstrated in the two 
Phase 3 studies in which it was evaluated. Significant improvements in physical function, 
health-related quality of life (including pain and tiredness), and productivity within and 
outside the home were demonstrated with CZP compared with the control groups in all four 
Phase 3 studies. 
Overall, the incidence and pattern of the treatment-emergent AEs observed in the Phase 3 
studies of CZP in RA are consistent with those expected for RA patients on TNF-antagonist 
therapy and for this population as a whole and demonstrate that CZP has a favorable 
risk-to-benefit profile. 
The risks of the present study are essentially those of experiencing an AE following 
administration of CZP and for progressive disability if the study participant does not respond 
to CZP. 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 patients treated with currently 
available TNF-antagonists including CZP include congestive heart failure, drug-induced 
lupus, demyelinating disorders, and pancytopenia. 
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In a placebo-controlled clinical study of study participants with RA, no meaningful difference 
was detected in antibody response to vaccine between CZP and placebo treatment groups 
when the pneumococcal polysaccharide vaccine and influenza vaccine were administered 
concurrently with CZP. Similar proportions of study participants developed protective levels 
of anti-vaccine antibodies between CZP and placebo treatment groups. Study participants 
receiving MTX had a lower humoral response compared with study participants not receiving 
MTX, with or without CZP. The clinical significance of this is unknown. Certolizumab pegol 
does not suppress the humoral immune response to the pneumococcal polysaccharide vaccine 
or influenza vaccine.  
No data are available on the response to live vaccinations or the secondary transmission of 
infection by live vaccines in study participants receiving CZP. Live or live attenuated 
vaccines should not be administered concurrently with CZP. 
Additional information on the nonclinical and clinical data for CZP in RA is available in the 
current version of the CZP Investigator’s Brochure (IB). 
Conducting placebo-controlled studies in pediatric populations requires special consideration. 
These include ethical concerns associated with denying active treatment to a population of 
patients that cannot make their own fully-informed choices about healthcare, the enrollment 
difficulties commonly encountered for placebo-controlled pediatric studies, and the limited 
size of the patient population from which to recruit. Studies in JIA are no exception for these 
considerations. 
For the 2 TNF-antagonists (ETN and ADA) approved in the USA and Europe for the 
treatment of JIA, similarities between the adult RA and the JIA population were shown in the 
placebo-controlled clinical studies with respect to efficacy, safety, and dosing. In light of 
these results and the efficacy of CZP demonstrated in the 4 adequate and well-controlled 
studies in adult RA, it is appropriate to extrapolate these efficacy data to the intended JIA 
population if similar results are obtained for PK and safety in JIA as seen for adult RA. The 
opinion within the pediatric rheumatology community supports that extrapolation from 
open-label PK/safety data is acceptable for additional members of the class of 
TNF-antagonists. 
3 
STUDY OBJECTIVES 
3.1 
Primary study objectives 
The primary objectives of the study are to evaluate the PK and safety including the 
immunogenicity of CZP administered sc in children and adolescents with moderate to severe 
polyarticular-course JIA. 
3.2 
Secondary study objective 
The secondary objective of the study is to assess the effectiveness of CZP on the clinical 
response in children and adolescents with moderate to severe polyarticular-course JIA. 
3.3 
Other objectives 
Other objectives of the study are to further assess safety as well as efficacy and health 
outcomes. 
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4 
STUDY VARIABLES 
See Section 13.1 for the definition of analysis sets. 
4.1 
Primary variables 
4.1.1 
Pharmacokinetic and immunological variables 
Certolizumab pegol plasma concentrations and anti-CZP antibody levels at Week 16 and 
Week 48 will be assessed and data will be summarized. 
4.1.2 
Safety variables 
The primary safety variables will be the incidence of serious TEAEs and TEAEs leading to 
permanent withdrawal of IMP. 
Adverse events will be solicited at every visit, recorded and coded according to Medical 
Dictionary for Regulatory Activities (MedDRA®) criteria.  
4.2 
Secondary variables 
Efficacy will be assessed by the PedACR30, PedACR50, PedACR70, and PedACR90 
response rates at Week 16 as compared to Baseline (see Section 11.1 for definition). 
4.3 
Other variables 
Other PK and immunological variables are: 
 Certolizumab pegol plasma concentrations and anti-CZP antibody levels at other study 
timepoints 
Other safety variables are: 
 Incidence of TEAEs, TEAEs of interest, TEAEs by relatedness, TEAEs by severity, and 
TEAEs by duration of exposure 
 Clinical laboratory values (hematology, biochemistry, and urinalysis) will be collected 
and assessed at every visit except Visits 3 and 4 and Unscheduled Visits. 
 Vital sign abnormalities will be evaluated at every visit. 
 Assessments of study participant’s developmental stages and growth (height, weight) will 
be performed to determine Tanner stages at Baseline, every 24 weeks thereafter, and the 
Early Discontinuation/End of Treatment Visit (weight at every visit through Final Visit). 
For study participants enrolled prior to Protocol Amendment 9, Tanner stages assessment 
will be performed every 48 weeks following Protocol Amendment 8, and only for those 
subjects who have not reached Tanner stage V. 
 Autoantibody (antinuclear antibodies [ANA] and anti-double-stranded deoxyribonucleic 
acid [anti-dsDNA] antibodies) concentrations will be evaluated at Baseline (testing for 
anti-dsDNA antibodies only if ANA is positive), Weeks 16 and 48, and at the Early 
Discontinuation/End of Treatment Visit. 
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Other efficacy and health outcomes variables are: 
 PedACR30, PedACR50, PedACR70, and PedACR90 response rates at every visit except 
Week 16 and Final Visit as compared to Baseline (see Section 11.1 for definition). 
 Change from Baseline in number of joints with active arthritis at every visit except Final 
Visit. 
 Change from Baseline in number of joints with limitation of range of motion at every 
visit except Final Visit.  
 Change from Baseline in Physician’s Global Assessment of Disease Activity (VAS) at 
every visit except Final Visit. 
 Change from Baseline in CHAQ at every visit except Final Visit. 
 Change from Baseline in Parent's Assessment of Arthritis Pain (VAS) at every visit 
except Final Visit. 
 Change from Baseline in Parent’s Global Assessment of Overall Well-Being (VAS) at 
every visit except Final Visit. 
 Ratio to Baseline in CRP at every visit except Final Visit. 
 Change from Baseline in JADAS at every visit except Final Visit.  
 Percentage of study participants with Clinically Inactive Disease (CID), as defined in 
Section 11.10, at every post-Baseline visit except Final Visit. 
 Percentage of study participants with clinical remission on medication (CRM), as defined 
in Section 11.10, at every post-Baseline visit from Week 24 onwards except Final Visit. 
 Time (in days) to CID. 
 Time (in days) to CRM. 
 Change from Baseline in DMS at every visit except Final Visit. 
 Change from Baseline in FPS-R (child-reported, ages 5 to 11 years), daily during the first 
week of treatment; Weeks 4, 12, 16, 24, and then every 8 weeks thereafter through the 
Early Discontinuation/End of Treatment Visit. For study participants enrolled prior to 
Protocol Amendment 9, visit frequency changes to every 16 weeks instead of every 
8 weeks following implementation of Protocol Amendment 8. 
 Change from Baseline in JIA Pain VAS, daily during the first 7 days of the study (acute 
and standard versions); and at Weeks 4, 12, 16, 24, and then every 8 weeks thereafter 
through the Early Discontinuation/End of Treatment Visit (standard version) for study 
participants ages 12 to 17 years. For study participants enrolled prior to Protocol 
Amendment 9, visit frequency changes to every 16 weeks instead of every 8 weeks 
following implementation of Protocol Amendment 8. 
 Change from Baseline in Fatigue Assessment Scale at every visit except Weeks 12 and 
20, and Final Visit. 
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 Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey responses 
at Baseline, Week 4, and every visit thereafter except Final Visit. 
5 
STUDY DESIGN 
5.1 
Study description 
This is a Phase 3, multicenter, open-label study to assess the PK, safety, and efficacy of CZP 
in children and adolescents with moderately to severely active polyarticular-course JIA. 
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. 
The overall study consists of a Screening Period of up to 4 weeks (between Weeks -4 to 0 
[Visits 1 and 2]) and an open-label Treatment Period which will continue until the approval 
of the marketing application for the polyarticular-course JIA indication in the study 
participant’s country or region or until further notice from UCB. A Final Visit will be 
conducted 12 weeks after last dose of study medication. 
A Screening Visit is used to initiate assessments of eligibility. Certolizumab pegol will be 
administered as a fixed dose based on weight throughout the study (see Table 7-1 for doses 
administered and Section 5.4.2 for the rationale for the different dose regimens). At Baseline 
(Week 0, Visit 2) eligible study participants will begin with 3 loading doses of CZP at Weeks 
0, 2, and 4 followed by a maintenance dose for the duration of the study. After Week 4 
(Visit 5), home-based CZP administration by the study participant or parent/caregiver will be 
permitted between scheduled study visits. 
Interim analyses were performed as described in Section 13.7. A full interim analysis will be 
performed after all active study participants have completed the Week 24 (Visit 10) 
assessments.  
Pharmacokinetic data from this study that were assayed with an enzyme-linked 
immunosorbent assay (ELISA) technique will not be used for submission to the Food and 
Drug Administration (FDA) to complete the Pediatric Research Equity Act commitment, 
primarily due to deficiencies detected with the use of the bioanalytical assay within RA0043. 
All study participants enrolled following Protocol Amendment 9 will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using an ECLIA method that meets 
current regulatory standards. In addition, PK and ADA samples (for which sufficient volume 
is available) collected in this study prior to Protocol Amendment 9 will be analyzed with the 
ECLIA method. The collective ECLIA-based PK data for this study will form the basis of 
any future CZP modeling and simulation work. 
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5.1.1 
Study duration per study participant 
For each study participant, there will be a Screening Period of up to 4 weeks (Weeks -4 to 0). 
Eligible study participants will subsequently initiate open-label treatment with CZP at 
Baseline (Week 0, Visit 2) and be permitted to continue until the approval of the marketing 
application for the polyarticular-course JIA indication in the study participant’s country or 
region, or until further notice from UCB. The Final Visit will be conducted 12 weeks after the 
last dose of study medication. 
The end of the study is defined as the date of the last study participant’s Final Visit. 
First Study participant, First Visit – 1Q 2012 
Planned Last Study participant, First Visit – 3Q 2021  
5.1.2 
Planned number of study participants and sites  
Approximately 195 study participants are planned to be screened at about 55 centers in order 
to enroll 156 study participants in this study, as follows:  
 A minimum of 10 study participants will be enrolled on the reduced CZP dose regimen in 
each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and ≥40kg 
(≥88lb) (See Section 7.2 for the doses administered in the study and Section 5.4.2.2 for 
the rationale for the reduced CZP dose regimen).  
 A minimum of 10 study participants will be enrolled in each age category of 2 to 5 years, 
6 to 11 years, and 12 to 17 years, irrespective of the dose regimen.  
 A minimum of 25 study participants will be enrolled who receive CZP as monotherapy 
(ie, study participants with established intolerability or inadequate response to MTX), 
irrespective of the dose regimen. 
 A minimum of 10 study participants with ERA will be enrolled, irrespective of the dose 
regimen. 
 The enrollment per site is limited to a maximum of 15 study participants. 
Recruitment based on all protocol amendments prior to Protocol Amendment 9 is complete. 
Following Protocol Amendment 9, an additional 30 study participants will be enrolled on the 
original dose regimen with the aim to enroll at least 5 study participants in each weight range 
of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and ≥40kg (≥88lb) (See Section 7.2 
for the doses administered in the study and Section 5.4.2.1 for the rationale for the original 
CZP dose regimen).  
Each of these categories is assessed independently. For instance, a 12kg, 3-year old study 
participant unable to tolerate MTX contributes to the enrollment goals for the 10 to <20kg 
(22 to <44lb) weight group, the 2- to 5-year-old age group, and the CZP as monotherapy 
group. 
5.1.3 
Anticipated regions and countries 
The regions planned for participation in this study are North and South America and Russia, 
with possible extension to other regions.  
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5.2 
Schedule of study assessments 
Table 5-1 
Schedule of study assessments  
Study period 
Screening 
Baseline 
 
 
 
 
 
 
 
Week 
-4 to 0(a) 
0 
1 
2 
4, 8, 12, 16, 
(17(u)), 20, 24 
32 and every 
8 weeks 
thereafter (z) 
Unsch. 
Visit(b) 
Early Disc/ 
End of 
Treatment 
Final 
Visit(c) 
Visit (+/-3 days)(a) 
1 
2 
3 
4 
5 to 10 
11 onwards 
 
 
FV 
Written informed consent/assent 
X 
 
 
 
 
 
 
 
 
Assessment of inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demography, JIA history, prior JIA medication, 
general medical and procedure history 
X 
 
 
 
 
 
 
 
 
Vital signs(d) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X(e) 
X 
 
 
X(f) 
X(f)  
 
X(f) 
 
Weight(g)  
X(e) 
X 
X 
X 
X 
X 
 
X 
X 
Tanner stages (except growth) 
 
X 
 
 
X(f) 
X(f)  
 
X(f) 
 
Physical examination(h) 
X 
X 
 
 
X 
X 
 
X 
X 
TB questionnaire 
X 
X 
 
 
X(i) 
X(i) 
 
X(i) 
 
Hematology/biochemistry/urinalysis(j)  
X(k) 
X(l) 
 
 
X 
X 
 
X 
X 
Reproductive potential and birth control 
X 
X 
 
 
X 
X 
 
X 
X 
Pregnancy testing(m) 
X 
X 
 
 
X(m) 
X 
 
X 
X 
C-reactive protein(j) 
X 
X 
X 
X 
X 
X 
 
X 
 
TB screening(n) and chest x-ray(o) 
X 
 
 
 
 
X(n) 
 
 
 
PRINTO/PRCSG standard joint examination  
X 
X 
X 
X 
X 
X 
 
X 
 
Physician’s Global Assessment of Disease Activity 
X 
X 
X 
X 
X 
X 
 
X 
 
CHAQ-parent reported 
X 
X 
X 
X 
X 
X 
 
X 
 
Parent’s Assessment of Arthritis Pain 
X 
X 
X 
X 
X 
X 
 
X 
 
Parent’s Global Assessment of Overall Well-Being 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinically Inactive Disease and clinical remission(p)  
 
 
X 
X 
X 
X 
 
X 
 
Duration of morning stiffness 
 
X 
X 
X 
X 
X 
 
X 
 
JADAS 
 
X 
X 
X 
X 
X 
 
X 
 
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Table 5-1 
Schedule of study assessments  
Study period 
Screening 
Baseline 
 
 
 
 
 
 
 
Week 
-4 to 0(a) 
0 
1 
2 
4, 8, 12, 16, 
(17(u)), 20, 24 
32 and every 
8 weeks 
thereafter (z) 
Unsch. 
Visit(b) 
Early Disc/ 
End of 
Treatment 
Final 
Visit(c) 
Visit (+/-3 days)(a) 
1 
2 
3 
4 
5 to 10 
11 onwards 
 
 
FV 
Faces Pain Scale-Revised(q) 
 
X 
 
 
X 
X 
 
X 
 
Patient’s Assessment of Arthritis Pain(r), acute 
 
X 
 
 
 
 
 
 
 
Patient’s Assessment of Arthritis Pain(r), standard 
 
X 
 
 
X(r) 
X 
 
X 
 
Fatigue Assessment Scale 
 
X 
X 
X 
X(s) 
X 
 
X 
 
Juvenile Arthritis School Attendance and Caregiver 
Work Productivity Survey (parent/caregiver-
reported) 
 
X 
 
 
X 
X 
 
X 
 
Concomitant medications and procedures(t) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IXRS contact 
X 
X 
X 
X 
X 
X 
 
X 
X 
CZP plasma concentrations  
 
X 
X 
 
X(u)  
X(v) 
 
 
 
Anti-CZP antibodies 
 
X 
X 
 
X(u)  
X(v) 
 
 
 
Autoantibodies (ANA and anti-dsDNA 
antibodies)(j) 
 
X(w) 
 
 
X(x) 
X(x) 
 
X 
 
CZP administration(y) 
 
X 
 
X 
X 
X 
 
 
 
ANA=antinuclear antibody; anti-dsDNA=anti-double-stranded deoxyribonucleic acid; BCG=Bacille Calmette-Guérin; CHAQ=Childhood Health Assessment 
Questionnaire; CZP=certolizumab pegol; Disc=discontinuation; IGRA=interferon-gamma release assay; IXRS=interactive voice/web response system; 
JADAS=Juvenile Arthritis Disease Activity Score; JIA= juvenile idiopathic arthritis; PRINTO/PRCSG=Paediatric Rheumatology INternational Trials 
Organisation/Pediatric Rheumatology Collaborative Study Group; TB=tuberculosis; TST=tuberculin skin test; Unsch=Unscheduled 
a 
Screening Visit must be completed at least 4 to 12 working days prior to the Baseline Visit, depending on regional requirements and laboratory assessments 
required for the study participant (please refer to Section 10.6 and the laboratory manual). For all other visits, the Visit window is ±3 days relative to 
Baseline.  
b 
Vital signs, concomitant medications, concomitant procedures, and AEs must be assessed at every Unscheduled Visit. Other PK and safety assessments 
should be performed as related to nature of the visit. For Unscheduled Visits related to the dose changes, see Sections 7.2.1 and 8.6.1. For these Unscheduled 
Visits, the same visit window applies, ie, ±3 days. 
c 
Final Visit should be performed 12 weeks after the final dose of CZP. 
d 
Pulse, systolic/diastolic blood pressure, and temperature to be measured within approximately 15 minutes prior to dosing and in addition (pulse and blood 
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Table 5-1 
Schedule of study assessments  
Study period 
Screening 
Baseline 
 
 
 
 
 
 
 
Week 
-4 to 0(a) 
0 
1 
2 
4, 8, 12, 16, 
(17(u)), 20, 24 
32 and every 
8 weeks 
thereafter (z) 
Unsch. 
Visit(b) 
Early Disc/ 
End of 
Treatment 
Final 
Visit(c) 
Visit (+/-3 days)(a) 
1 
2 
3 
4 
5 to 10 
11 onwards 
 
 
FV 
pressure only) approximately 30 minutes after dosing. 
e 
Change in height and weight over the last 6 months and over the last year will be collected via parent-/self-report, if not available from medical records.  
f 
Height and Tanner stages to be measured at Week 24 and 48, every 24 weeks thereafter (for study participants enrolled prior to Protocol Amendment 9, 
Tanner stages assessment will be performed every 48 weeks following Protocol Amendment 8, and only for those subjects who have not reached Tanner 
stage V) and at Early Discontinuation/End of Treatment. 
g 
From Week 2 onwards, weight measurements will be used to readjust the CZP dose as needed according to Table 7-1. 
h 
Physical examination findings (except joint examination) are recorded in the CRF only at Screening. Subsequent physical examinations are to be recorded in 
the source documentation and clinically significant findings recorded as AEs. 
i 
TB questionnaire to be completed at Weeks 12 and 24 and every 16 weeks thereafter, and Early Discontinuation/End of Treatment. If the Investigator 
suspects latent TB or active TB, TB testing and/or a chest x-ray should be performed as outlined in Section 10.7.9. 
j 
Hematology/biochemistry/urinalysis will be performed by a central laboratory, except urine dipsticks, which will be done locally at the site. Study 
participants do not have to be fasting. 
k 
At Screening, laboratory testing includes testing for hepatitis B core antibody, hepatitis B surface antibody, hepatitis B surface antigen, hepatitis C virus 
antibody, and HIV 1/2. Study participants with a positive hepatitis B virus test will not be allowed in the study (except for anti-hepatitis B surface positive 
only, in case study participant is immune due to well-documented hepatitis B vaccination or isolated false-positive anti-hepatitis B core test confirmed with a 
confirmatory test such as hepatitis B virus deoxyribonucleic acid [DNA]). A positive hepatitis C antibody test will be confirmed by a confirmatory test (such 
as hepatitis C virus ribonucleic acid [RNA]) and those with a positive confirmatory test will not be allowed in the study. 
l 
At Baseline, hematology/chemistry/urinalysis only need to be done if in the Investigator’s opinion there is a change in the study participant’s status 
compared to the Screening Visit.  
m 
Pregnancy testing for postmenarcheal female study participants. Serum testing by a central laboratory at Screening and urine testing locally at the site at 
Baseline, Weeks 8, 16, 24, and every visit thereafter. 
n 
TB screening: Interferon-gamma release assay (IGRA) testing (QuantiFERON®) is required to be performed by the central lab for all study participants from 
5 to 17 years of age. TST and IGRA testing at Screening is mandatory for study participants less than 5 years of age in this study unless written 
documentation of BCG vaccination is available (refer to Section 6.2 [exclusion criterion 11] and Section 10.7.9). Following implementation of Protocol 
Amendment 7, IGRA testing (QuantiFERON) should be done once a year (approximately every 48 weeks) for all study participants.  
o 
Chest radiographic imaging is done at Screening and results must be available at Baseline before first drug administration, unless a chest x-ray or CT is 
available within 2 months prior to Screening. 
p 
Clinical remission on medication will be assessed at every post-Baseline visit from Week 24 onwards only. 
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Table 5-1 
Schedule of study assessments  
Study period 
Screening 
Baseline 
 
 
 
 
 
 
 
Week 
-4 to 0(a) 
0 
1 
2 
4, 8, 12, 16, 
(17(u)), 20, 24 
32 and every 
8 weeks 
thereafter (z) 
Unsch. 
Visit(b) 
Early Disc/ 
End of 
Treatment 
Final 
Visit(c) 
Visit (+/-3 days)(a) 
1 
2 
3 
4 
5 to 10 
11 onwards 
 
 
FV 
q 
For study participants ages 5 to 11 years. Daily assessment during the first week (Baseline and Day 1 to Day 7, to be collected at Week 1). In addition, to be 
completed at Weeks 4, 12, 16, 24, and then every 8 weeks thereafter (for study participants enrolled prior to Protocol Amendment 9, visit frequency changes 
to every 16 weeks instead of every 8 weeks following implementation of Protocol Amendment 8) through the End of Treatment/Early Discontinuation Visit. 
r 
For study participants ages 12 to 17 years. Daily assessment of acute VAS version during the first week (at Baseline and Day 1 to Day 7, to be collected at 
Week 1). In addition, standard VAS version to be completed at Baseline, Weeks 4, 12, 16, 24, and then every 8 weeks thereafter (for study participants 
enrolled prior to Protocol Amendment 9, visit frequency changes to every 16 weeks instead of every 8 weeks following implementation of Protocol 
Amendment 8) through the End of Treatment/Early Discontinuation Visit for study participants ages 12 to 17 years. 
s 
Fatigue Assessment Scale performed at Weeks 4, 8, 16, and 24. 
t 
Concomitant procedures are collected starting at Baseline. 
u 
CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 4, 12, 16, and 24. A postdose CZP plasma sample will be collected at 
approximately 5 to 7 days following the Week 16 Visit (ie, requires an additional clinic site visit for blood collection at Week 17). Samples for CZP plasma 
concentration and anti-CZP antibodies will be collected as separate samples.  
v 
CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 32, 40, 48, and every 24 weeks thereafter for study participants enrolled 
following Protocol Amendment 9. For study participants enrolled prior to Protocol Amendment 9, samples for CZP plasma concentration and anti-CZP 
antibodies will no longer be collected. Samples for CZP plasma concentration and anti-CZP antibodies will be collected as separate samples. 
w 
At Baseline, testing for anti-dsDNA antibodies will only be done if ANA is positive. 
x 
ANA and anti-dsDNA antibodies performed at Week 16 and Week 48. 
y 
After Week 4 (Visit 5) study participants/caregivers may administer CZP Q2W (or Q4W for the lowest weight group) at home between scheduled study 
visits. See Section 7.2 regarding training and option for continued site administration. 
z 
For study participants enrolled prior to Protocol Amendment 9, on-site CZP administration, safety sampling, and efficacy assessment frequency changes to 
every 16 weeks instead of every 8 weeks following implementation of Protocol Amendment 8, provided that compliance is maintained with the CZP dosing 
schedule using at-home administration. The option to come to the site for CZP administration between scheduled visits is available as needed.   
 
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5.3 
Schematic diagram  
 
 
 
 
 
a 
a Following Week 32, visits will be every 8 weeks. For study participants enrolled prior to Protocol Amendment 9, visit 
frequency changes to every 16 weeks instead of every 8 weeks following implementation of Protocol Amendment 8. 
b The futility analysis of PedACR30 after all study participants on the reduced CZP dose completed Week 16 has 
already been completed. A further futility analysis will not be performed using the additional study participants that 
will be enrolled on the original CZP dose regimen following the implementation of Protocol Amendment 9.   
b 
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5.4 
Rationale for study design and selection of dose 
5.4.1 
Study design 
Following the US approval of CZP for the treatment of moderately to severely active RA in 
adults, the FDA has required a postmarketing pediatric study. The following open-label study 
has been accepted to fulfill the FDA postmarketing requirement to investigate CZP PK, 
dosing, safety, and immunogenicity in the pediatric population (2 to 17 years old, inclusive) 
with JIA.  
Conducting placebo-controlled studies in pediatric populations requires special consideration. 
These include ethical concerns associated with denying active treatment to a population of 
patients that cannot make their own fully-informed choices about healthcare, the enrollment 
difficulties commonly encountered for placebo-controlled pediatric studies, and the limited 
size of the patient population from which to recruit. Studies in JIA are no exception for these 
considerations. 
Currently, 2 TNF-antagonists (ETN and ADA) have been approved in the USA and Europe 
for the treatment of JIA. For both TNF-antagonists, similarities between the adult RA and the 
JIA population were shown in the placebo-controlled clinical studies with respect to efficacy, 
safety and dosing. Through extensive interactions between the FDA and external experts, 
culminating in a collaborative workshop in October 2019 entitled “Accelerating Drug 
Development for polyarticular Juvenile Idiopathic Arthritis (pJIA)”, a therapeutic bridging 
approach from RA to pJIA was strongly supported for TNF-α inhibitors based on the 
relationship between RA and pJIA and the extensive knowledge of TNF-α inhibitors as 
therapeutic agents in these two populations. This approach (based on "Pharmacokinetic (PK) 
matching") directs that the therapeutic effect of TNF-α inhibitors (such as CZP) in pJIA 
patients can be expected if the pediatric systemic exposure for the drug is within the 
therapeutic range for adult RA patients.  
Study RA0043 is being undertaken in support of the pJIA Pediatric Research Equity Act 
(PREA) requirement for CZP. The pJIA development program for CZP will be based on PK 
data generated with the newly validated MSD ECLIA method for pediatric study participants 
in (Section 7.2 and Section 5.4.2). To enable this approach, an additional 30 study 
participants will be enrolled in RA0043 following Protocol Amendment 9 at the original CZP 
dosing regimen.  
Central to application of this approach is the existence of a reference systemic exposure (PK) 
range which is associated with therapeutic benefit of the drug in adult RA population. A 
supporting adult reference PK dataset for "PK matching" in the pJIA program will also need 
to be based on data generated with the ECLIA method. Accordingly, a separate study is being 
undertaken in order to generate ECLIA-based CZP PK data for CZP in adults with RA.    
5.4.2 
Dose selection 
The original minimum and maximum loading doses in the study were CZP 100mg Q2W and 
CZP 400mg Q2W, respectively, and the original minimum and maximum maintenance doses 
were CZP 50mg Q2W and CZP 200mg Q2W, respectively (see Section 5.4.2.1 for the 
rationale for the original CZP dose regimen). Based on an interim PopPK analysis of RA0043 
data, the minimum and maximum loading doses in the study were adjusted to CZP 50mg 
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Q2W and CZP 200mg Q2W, respectively, and the minimum and maximum maintenance 
doses were adjusted to CZP 50mg Q4W and CZP 100mg Q2W, respectively, following 
implementation of Protocol Amendments 4 and 5 (see Section 5.4.2.2 for the rationale for the 
reduced CZP dose regimen).  
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPK analysis and 
simulations that informed the dose reduction in Protocol Amendment 4 and 5 unusable from a 
regulatory standpoint. Accordingly, PK samples were no longer collected for study 
participants on the reduced CZP dose regimen following implementation of Protocol 
Amendment 8.  
An ECLIA method, for which selectivity had previously been assessed in the RA matrix, has 
now been validated to meet the standards set in the regulatory guidance for analytical 
procedures and methods validations for drugs and biologics (FDA, Guidance for Industry – 
Bioanalytical Method Validation, 2018). The ECLIA assay consists of a homogeneous 
bridging immunoassay on the MSD platform. 
Based on 24-week interim results from RA0043 (Section 13.7), both the original and reduced 
dose regimens showed safety profiles similar to the approved CZP dose regimen in the adult 
RA population. The overall clinical response in the study (taking both dose regimens into 
account) was PedACR30 and PedACR50 responses of 77.3% and 67.5%, respectively at 
Week 12. The response from the original dose regimen was 75.6% for PedACR30 and 64.1% 
for PedACR50. PedACR50 response demonstrates a highly clinically relevant decrease in 
disease activity. 
Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
pJIA at both the reduced and original CZP dose regimens and also adequately support the 
safety assessment of the original CZP dosing regimen, as more of the safety data collected in 
the study to date has been on the reduced dose, 30 additional study participants will be 
enrolled on the original CZP dose regimen following Protocol Amendment 9. All study 
participants enrolled following Protocol Amendment 9 will have plasma concentrations of 
CZP and anti-CZP antibodies analyzed using the ECLIA method. In addition, PK and ADA 
samples (for which sufficient volume is available) collected in this study prior to Protocol 
Amendment 9 will be analyzed with the ECLIA method. The collective ECLIA-based PK 
data for this study will form the basis of any future CZP modeling and simulation work. 
5.4.2.1 
Original CZP dose regimen 
The recommended dosing regimen for CZP in adult study participants with moderate to 
severe RA is CZP 400mg sc at Weeks 0, 2, and 4 followed by CZP 200mg Q2W thereafter. 
This dose regimen was evaluated for safety and efficacy in 2 double-blind, placebo-
controlled, Phase 3 clinical studies (C87027 and C87050) and supported by population 
PK/pharmacodynamic (PD) modeling (C87079). The PK/PD model estimated EC50 Cavg 
plasma concentration (the CZP concentration that produces one-half of the maximum effect 
for ACR20 response) to be 16.8µg/mL (95% confidence interval [CI] = 10.2 to 23.4). 
Population PK analysis on data from adult study participants with RA (C87068) showed that 
there was a less than proportional inverse relationship between body weight and PK. The 
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adult PopPK model was used to predict the effect of extreme body weights on PK exposure in 
typical adult study participants with RA at steady state using the recommended dose regimen 
as shown in Table 5-2. 
Table 5-2 
PK estimates of CZP exposure in adult study participants with RA 
based on population PK modeling 
Body weight (kg) 
Cmax (µg/mL) 
Ctrough (µg/mL) 
AUC (µg.day/mL) 
40 
53 
34 
616 
70 
41 
22 
457 
120 
33 
14 
334 
AUC=area under the curve; Cmax=maximum serum concentration; Ctrough=trough serum concentration; 
CZP=certolizumab pegol; PK=pharmacokinetic; RA=rheumatoid arthritis 
The therapeutic plasma concentration of CZP in children and adolescents with JIA was 
expected to be similar to that required for the adult population with RA. In adults with RA, 
effective plasma concentrations are achieved with doses of CZP 400mg at Weeks 0, 2, and 4, 
followed by CZP 200mg Q2W thereafter. The intention in RA0043 is to study the equivalent 
dose regimen in children and adolescents with JIA. Initial predictions, based on allometric 
scaling of PK data from adults, suggested that this could be achieved by reducing the dose of 
CZP for pediatric study participants with body weights between 20 to <40kg (44 to <88lb) to 
CZP 200mg at Weeks 0, 2, and 4 followed by CZP 100mg Q2W (ie, 50% of the 
recommended adult dose), and by reducing the dose further to 25% of the adult dose for 
study participants with body weights 10 to <20kg (22 to <44lb) (ie, CZP 100mg at Weeks 0, 
2, and 4 followed by CZP 50mg Q2W).  
The original choice of dose and the weight-based dose-adjustment algorithm was supported 
by simulations of the PK exposure and response rates in children using the PopPK model and 
PK/PD exposure response model developed in adult RA study participants, corrected for 
pediatric demographics (C87079 addendum 08 Oct 2008). Results of these simulations 
showed that all age groups exhibit similar exposures (Cmax and AUCT) to those of adults over 
the Week 14 to Week 16 dosing interval, with the pediatric/adult ratio of the median 
predicted values of PK parameters ranging from 1.03 to 1.19 for Cmax and from 0.97 to 1.18 
for AUCT. The similarities in exposures were reflected in the probability of ACR20 response, 
which are similar for all age groups at Week 16 (pediatric/adult ratio of the median predicted 
values ranging from 1.08 to 1.10). These simulations were performed upon the assumption 
that disease progression and response rate for a given exposure are similar in children and 
adults.  
The original CZP dose regimen is the regimen that will be used for study participants 
enrolled following Protocol Amendment 9.  
5.4.2.2 
Reduced CZP dose regimen 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicated that no change to the dosing algorithm was required. The protocol stated that if 
future analyses indicate that plasma concentrations were outside of the exposure range of 
those observed in previous studies with adults, the dosing algorithm could have been changed 
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via a protocol amendment, and if necessary, additional interim analyses including PopPK, 
could have been performed.  
Results of an interim PopPK analysis conducted following Protocol Amendment 3 (in 
Jun 2013) suggested that while observed CZP plasma concentrations remained in the adult 
range, they were at the upper end of the distribution. Simulations predicted that for some 
study participants in RA0043 receiving the originally determined loading doses up to Week 4 
(Visit 5), plasma concentrations were likely to exceed the range previously seen in adult 
study participants receiving CZP 400mg Q2W. Furthermore, plasma concentrations of study 
participants receiving the originally determined maintenance dose after Week 4 (Visit 5) were 
predicted to exceed the concentration range observed in adults receiving CZP 200mg Q2W. 
Based on these findings, the dosing regimen was changed with Protocol Amendments 4 and 
5, and the doses to be administered were reduced by 50% for all weight groups. This dose 
change was intended to achieve plasma concentrations that were similar to the effective 
concentrations observed in previous studies in adult study participants with RA.  
Subsequently, the maintenance doses in this study were reduced with Protocol Amendment 4 
so that study participants with body weights between 20 and <40kg (44 to <88lb) received 
CZP 50mg Q2W, and study participants with body weights of ≥40kg (≥88lb) received 
CZP 100mg Q2W (see Table 7-1). The optimal maintenance dose estimated in the PopPK 
model for the lowest weight group was CZP 25mg Q2W, however, the lowest available dose 
size is CZP 50mg. Thus, study participants with body weights of 10 to <20kg (22 to <44lb) 
received CZP 50mg Q4W to achieve this 50% reduction. In addition, with Protocol 
Amendment 5, the loading dose in the study was reduced by 50% for newly enrolled study 
participants, so that study participants with body weights of 10 to <20kg (22 to <44lb) 
received CZP 50mg at Weeks 0, 2, and 4, study participants with body weights between 20 to 
<40kg (44 to <88lb) received CZP 100mg at Weeks 0, 2, and 4, and study participants with 
body weights ≥40kg (≥88lb) will receive CZP 200mg at Weeks 0, 2, and 4. 
The rationale behind selecting the equivalent of the adult therapeutic dose was based on the 
following: 
 There is no metabolic rationale to expect a difference in the PK/PD of CZP in a younger 
population, particularly as there is no involvement of cytochrome P450. 
 Evaluation of a previous anti-TNF antibody (CDP571, a whole antibody) in a pediatric 
population (administered iv) confirmed that the PK and safety were similar to that of an 
adult population. 
 Doses in excess of CZP 400mg (up to CZP 800mg) have been administered to healthy 
adult study participants and study participants with RA without any dose-limiting 
toxicities being identified. 
 A conservative approach to dose reduction was chosen because the body weight of 
pediatric study participants may be influenced largely by frame size while the range of 
body weight of adults may be more influenced by percent body fat. 
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPK analysis and 
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simulations that informed the dose reduction in Protocol Amendment 4 and 5 unusable from a 
regulatory standpoint. Study participants enrolled prior to the implementation of Protocol 
Amendment 9 can remain on the reduced CZP dose or may be switched to the original CZP 
dose at the discretion of the Investigator and in consultation with the medical monitor. 
Additional dose changes are not allowed (Section 7.2.1).  
6 
SELECTION AND WITHDRAWAL OF STUDY 
PARTICIPANTS 
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 study participant or by the 
parent(s) or legal representative. The Consent form or a specific Assent form, where 
required, will be signed and dated by minors. 
2. Study participant/legal representative/parent is considered reliable and capable of 
adhering to the protocol, visit schedule or medication intake according to the judgment of 
the Investigator. 
3. Study participant must be able and willing to comply with the requirements of the study. 
4. Study participant is 2 to 17 years of age (inclusive) at Baseline (Visit 2). 
5. Study participants must weigh ≥10kg (22lb) at Baseline (Visit 2). 
6. Study participants must have had onset of signs and symptoms consistent with a diagnosis 
of JIA (according to the International League of Associations for Rheumatology 
Classification of Juvenile Idiopathic Arthritis, 2001) and initiation of JIA treatment for at 
least 6 months prior to Baseline (Visit 2). Eligible JIA categories include: polyarthritis 
rheumatoid factor-positive, polyarthritis rheumatoid factor-negative, extended 
oligoarthritis, juvenile psoriatic arthritis, and ERA.  
7. Study participants must have active polyarticular-course disease, defined as ≥5 joints with 
active arthritis at Screening and at Baseline.  
8. Study participants must have had an inadequate response to, or intolerance to, at least 
1 DMARD (nonbiologic or biologic). For example, study participant had prior inadequate 
response to MTX (based on the Investigator’s clinical judgment).  
9. If the study participant is using MTX, then the study participant must have been on MTX 
for a minimum of 3 months at Screening. In addition, the dose must have been stable for 
at least 1 month before Screening at ≥10 to ≤15mg/m2 per week. If the study participant is 
not using MTX, then the treatment must have been previously withdrawn for documented 
reasons of intolerability or inadequate response. 
10. If the study participant is using oral corticosteroid therapy, the dose must have been stable 
for at least 7 days prior to the Baseline arthritis assessment at a maximum dose of 10mg 
or 0.2mg/kg prednisone (or equivalent) per day, whichever is the smaller dose. 
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6.2 
Exclusion criteria 
Study participants are not permitted to enroll in the study if any one of the following criteria 
is met: 
1. Study participant has previously been exposed to more than 2 biologic agents. 
2. Study participant previously failed to respond to treatment with more than one tumor 
necrosis factor alpha (TNFα) antagonist drug. Lack of response to treatment is defined as 
no clinical disease improvement within the first 12 weeks of treatment. (Study 
participants who demonstrated clinical response within 12 weeks of treatment and 
subsequently lost response after 12 weeks of treatment are eligible.) 
3. Study participant is currently receiving or has received any experimental (biological or 
non-biological) therapy (within or outside a clinical study) in the 3 months or 5 half-lives 
prior to Baseline (Visit 2), whichever is longer. 
4. Study participant had previous treatment with a biological therapy for JIA that resulted in 
a severe hypersensitivity reaction or an anaphylactic reaction. 
5. Study participant previously participated in this study or has previously been treated with 
CZP (whether in a study or not). 
6. Study participant has received any prohibited medication as detailed in Table 6-1. 
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Table 6-1 
Prohibited medications at entry (Baseline) 
Drug class 
Prohibited dose  
Exclusion criteria 
Oral corticosteroids 
Any dose greater than 10mg 
or 0.2mg/kg prednisone (or 
equivalent) per day, 
whichever is the smaller dose  
Any change in dose in the 7 days prior to 
the Baseline arthritis assessment.  
im/iv/ia corticosteroids 
Any dose 
Use within 28 days prior to the Baseline 
arthritis assessment. 
Non-biologic DMARDs 
(eg, sulfasalazine, 
hydroxychloroquine, 
cyclosporine) 
Any dose 
For MTX, any dose <10 or 
>15mg/m2 per week 
Use within 28 days prior to the Baseline 
arthritis assessment.  
For MTX, any change in dose in the 
1 month prior to Screening. 
Use of cyclosporine within 7 days prior to 
the Baseline arthritis assessment. 
Use of leflunomide within 6 months prior 
to the Baseline arthritis assessment if a 
cholestyramine washout is not performed 
(and 28 days prior if performed). 
Biologic DMARDs 
Any dose 
Prior or current exposure to more than 
2 biologic DMARDs and/or primary 
failure (defined as a complete lack of 
response) to more than 1 TNF inhibitor. 
Use of anakinra or rilonacept within 
7 days prior to the Baseline arthritis 
assessment. 
Use of etanercept within 28 days prior to 
the Baseline arthritis assessment. 
Use of adalimumab within 56 days prior 
to the Baseline arthritis assessment. 
Use of infliximab or abatacept within 
60 days prior to the Baseline arthritis 
assessment. 
Use of rituximab within 180 days prior to 
the Baseline arthritis assessment. 
Use of any other biological response 
modifier therapy (eg, tocilizumab, 
canakinumab) within 90 days or 
5 half-lives prior to the Baseline arthritis 
assessment, whichever is longer. 
(All aforementioned drugs are prohibited 
during the study.) 
DMARDs=disease-modifying antirheumatic drugs; ia=intra-articular; im=intramuscular; iv=intravenous; 
JIA=juvenile idiopathic arthritis; TNF=tumor neucrosis factor 
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7. Study participant has a history of systemic JIA, with or without systemic features. 
8. Study participant has a secondary, noninflammatory type of rheumatic disease or of joint 
pains (eg, fibromyalgia) that in the Investigator’s opinion is symptomatic enough to 
interfere with evaluation of the effect of study medication. 
9. Study participant has other inflammatory arthritis (eg, systemic lupus erythematosus, 
inflammatory bowel disease-related). 
10. Study participant has active uveitis or a history of active uveitis within the preceding 6 
months. 
11. Participant has: 
a. Known active TB disease 
b. History of active TB involving any organ system  
c. History of or current latent tuberculosis infection (LTBI) 
d. High risk of exposure to TB infection 
e. Current nontuberculous mycobacterial (NTMB) infection or history of NTMB 
infection. For further information relating to definitions of known active TB, past 
history of TB, LTBI, high risk of acquiring TB infection and NTMB infection, refer 
to Section 10.7.9 (Assessment and management of TB and TB risk factors). 
12. Study participant has a current sign or symptom which may indicate infection (eg, fever, 
cough), a history of chronic or recurrent infections within the same organ system (more 
than 3 episodes requiring antibiotics/antivirals during the 12 months prior to Screening 
[Visit 1]), had a recent (within the 6 months prior to Screening [Visit 1]) serious or 
life-threatening infection (including herpes zoster), or is at a high risk of infection in the 
Investigator’s opinion (eg, study participants with leg ulcers, indwelling urinary catheter, 
and persistent or recurrent chest infections or permanently bed-ridden or wheelchair 
bound).  
13. Study participant has a history of or current hepatitis B or C virus or HIV 1/2 or has any 
of the following laboratory abnormalities during the Screening Period:  
a. Hepatitis B surface (HBs) antigen, hepatitis B core (HBc) antibody (except for 
isolated, false-positive anti-HBc confirmed with a confirmatory test such as hepatitis 
B virus [HBV]-deoxyribonucleic acid [DNA] [refer to Table 5-1 footnote k and 
Section 10.6 (Clinical Laboratory Tests) table footnote c]): Positive to any of these 
b. Hepatitis C virus (HCV) positive: defined as hepatitis C antibody (anti-HCV Ab) 
positive confirmed via a confirmatory test (for example, HCV polymerase chain 
reaction) 
c. HIV antigen or antibody: Positive to either test 
14. Study participant has received any live, including attenuated, vaccination within 8 weeks 
prior to Baseline (Visit 2) and/or is scheduled for live vaccination during the course of 
study participation. Non-live vaccinations are permitted at any time prior to and during 
the study. 
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15. Study participant has a history of chronic alcohol or drug abuse based on the 
Investigator’s clinical judgment within the last 1 year. 
16. Study participant is breast-feeding, pregnant or plans to become pregnant during the study 
or within 12 weeks following the last dose of study medication (or longer if required by 
local regulations). Female study participants of childbearing potential (ie, 
postmenarcheal) must have a negative result at Screening and Baseline (Visits 1 and 2) 
pregnancy tests to be eligible for study entry. 
17. Study participant is a sexually active female of childbearing potential (ie, 
postmenarcheal) and is not practicing or will not agree to practice an effective means of 
birth control. For postmenarcheal female study participants not currently sexually active, 
the study participant and parent or legal representative should agree that the study 
participant will employ an effective means of birth control consistently and correctly 
should the study participant become sexually active. Effective methods of birth control 
are: oral/parenteral/implantable hormonal contraceptives (stable at least 2 months prior to 
Screening (Visit 1) if initiated prior to entering the study) or a combination of barrier and 
spermicide. Study participants must agree to use effective contraception during the study 
and for 12 weeks after their last dose of study medication (or longer if required by local 
regulations). Male study participants who are sexually active must agree to ensure they or 
their female partner(s) uses adequate contraception during the study and for 12 weeks 
after the study participant receives their last dose of study medication (or longer if 
required by local regulations). (Sexually active means engaging in sexual intercourse, 
regardless of frequency). 
18. Study participant has a history of an adverse reaction to PEG. 
19. Study participant has a history of a lymphoproliferative disorder including lymphoma or 
signs and symptoms at any time suggestive of lymphoproliferative disease. 
20. Study participant has a concurrent malignancy, or a history of any malignancy. 
21. Study participant has a current or recent history (within 6 months prior to Screening [Visit 
1]) of severe, progressive, and/or uncontrolled renal, hepatic, hematological, 
gastrointestinal, endocrine, pulmonary, cardiac, neurological, or cerebral disease 
including blood dyscrasia (eg, pancytopenia, aplastic anemia), demyelinating disease (eg, 
multiple sclerosis, myelitis, optic neuritis). 
22. Study participant has any other medical or psychiatric condition that, in the opinion of the 
Investigator or Sponsor, could jeopardize or would compromise the study participant’s 
ability to participate in the study or which otherwise make the study participant unsuitable 
for inclusion in the study. 
23. Study participant has any clinically significant laboratory abnormalities which, in the 
Investigator’s judgment, would make the study participant unsuitable for inclusion in the 
study, with specific exclusion of study participants with values of: liver function tests that 
are >2×upper limit of normal (ULN), serum creatinine that are >1.5 ×ULN, and white 
blood cells that are <3.0x109/L or 3000/mm3. 
24. Study participant is wheelchair-bound at the time of enrollment. 
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25. Study participant with a history of or active systemic/respiratory infection due to fungal, 
parasitic, or mycotic pathogens including but not limited to histoplasmosis, coccidiosis, 
paracoccidiosis, pneumocystis, blastomyces, and aspergillus.  
Radiographic evidence suggestive of any of these infections is sufficient grounds for 
exclusion. 
6.3 
Retesting and rescreening 
Retesting of laboratory assessments within the Screening Period is allowed as per the 
following: 
 Study participants with isolated exclusionary laboratory assessments at Screening may 
have this laboratory assessment repeated once if, in the Investigator’s opinion, the value 
is not reflective of the study participant’s previous clinical and laboratory pattern. 
Retesting must be completed within the stated Screening Period. If the repeat values are 
within the acceptable ranges of the study and the study participant remains eligible during 
the Baseline Visit (Week 0), the study participant may be dosed. 
Rescreening is only allowed after consultation with the Medical Monitor as per the following: 
 Study participants who failed Screening (eg, due to transient out-of-range safety 
laboratory values or in the Investigator’s judgment mild acute illness, eg, a cold) may be 
rescreened after complete recovery of the mild acute illness and/or normalization of the 
out-of-range safety laboratory values. 
 Study participants who fulfilled all eligibility criteria but were registered as Screen 
failures due to suspension of enrollment as of 17 Jul 2013 are allowed to be rescreened. 
 Rescreening might be allowed more than once but not in case of repeated occurrence of 
the same illness. All Screening assessments must be repeated as applicable in case of 
Rescreening. The maximum duration of the Rescreening Period is 28 days or 4 weeks. 
Rescreening must only be scheduled after an appropriate time period after the initial 
Screening Visit allowing for repetition of blood collection (depending on local 
requirements for maximum blood volumes; depending on study participant weight). 
 All study participants who failed to be enrolled within the Screening Period of 28 days 
must be registered as Screen Failure in the interactive voice/web response system (IXRS). 
Study participants approved to be rescreened must be registered with a new study 
participant number. 
6.4 
Liver Chemistry Stopping Criteria 
Participants with potential drug-induced liver injury (PDILI) must be assessed to determine if 
IMP must be discontinued. In addition, all concomitant medications and herbal supplements 
that are not medically necessary should be discontinued. The PDILI criteria below require 
immediate and permanent discontinuation of IMP:  
 Participants with either of the following:  
- 
ALT or AST ≥5xULN 
- 
ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
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The PDILI criterion below requires immediate discontinuation of IMP:  
 Participants with ALT or AST ≥3xULN who exhibit temporally associated symptoms 
of hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, 
and right upper quadrant pain or tenderness. Hypersensitivity symptoms include fever 
(without clear alternative cause), rash, and eosinophilia (ie, >5%).  
The PDILI criterion below allows participants to continue on IMP at the discretion of the 
Investigator:  
 Participants with ALT or AST ≥3xULN (and ≥2x baseline) and <5xULN, total 
bilirubin <2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of 
hepatitis (eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness).  
Evaluation of PDILI must be initiated as described in Section 17.10. If participants are unable 
to comply with the applicable monitoring schedule, IMP must be discontinued immediately.  
Investigators should attempt to obtain information on participants in the case of IMP 
discontinuation to complete the final evaluation. Participants with PDILI should not be 
withdrawn from the study until investigation and monitoring are complete. All results of 
these evaluations and observations, as well as the reason(s) for IMP discontinuation and 
participant withdrawal (if applicable), must be recorded in the source documents. The eCRF 
must document the primary reason for IMP discontinuation. 
6.5 
Withdrawal criteria 
Study participants are free to withdraw from the study at any time, without prejudice to their 
continued care. Where possible, study participants discontinuing study medication should be 
encouraged to remain in the study. 
A study participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
If the study participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
If a study participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
See the Schedule of Activities for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
Study participants should be withdrawn from the study if any of the following events occur: 
1. Study participant or legal representative withdraws his/her consent. 
2. The sponsor or a regulatory agency requests withdrawal of the study participant. 
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Study participants must be permanently discontinued from study medication (but not 
necessarily from the study) if any of the following occurs: 
1. Study participant/caregiver is noncompliant with the study procedures or medications in 
the opinion of the Investigator or Sponsor. 
2. A study participant considered as having either a suspected new LTBI or who develops 
active TB or NTMB infection during the study (including but not limited to, conversion 
demonstrated by interferon-gamma release assay [IGRA] or other diagnostic means) must 
be immediately discontinued from IMP (refer to Section 10.7.9.8 for further details). 
a) The study participant must be permanently withdrawn from the study if further 
examinations result in a diagnosis of active TB, NTMB infection, or if the study 
participant is diagnosed with LTBI. An Early Discontinuation visit must be scheduled 
as soon as possible, but not later than the next regular visit. 
Any confirmed diagnosis or suspicion of a latent or active TB infection is a reportable 
event. Either type of infection must be reported as an adverse event of special interest 
(AESI) and must be captured on an AE report form, ticking the appropriate AESI and, if 
applicable, serious adverse event (SAE) field(s) on the form to clearly indicate the level 
of seriousness. A UCB TB follow-up form also must be completed. 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 requirements until such time as the TB 
infection resolves. 
3. Study participant is found to be persistently noncompliant (missing 2 or more consecutive 
scheduled CZP doses or missing 3 or more doses over a 12-month period), the Sponsor in 
conjunction with the Investigator will make a decision as to whether the study participant 
should be withdrawn from the study (see Section 7.7).  
This rule does not apply when CZP is discontinued if the study participant is in CRM or if 
CZP is temporarily discontinued due to an AE. In the case of temporary discontinuation 
due to an AE, the Sponsor in conjunction with the Investigator will make a decision as to 
whether the study participant should be withdrawn from the study. 
4. Study participant takes prohibited concomitant medications as defined in this protocol 
(see Section 7.8.3). 
Study participants may be discontinued from study medication (but not necessarily from the 
study) if any of the following occurs, but may be restarted after consultation with the Medical 
Monitor: 
1. Study participant develops an illness that would interfere with continued participation (eg, 
malignancies). 
2. If there is a positive pregnancy test, study medication will be held. If there is confirmed 
pregnancy, study medication must be discontinued until end of the pregnancy. In case the 
study participant intends to breastfeed after a pregnancy study medication must be further 
discontinued until end of breastfeeding.  
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Investigators should attempt to obtain information on study participants, in the case of 
withdrawal or discontinuation. All results of these evaluations and observations, together 
with a narrative description of the reason(s) for removing the study participant, must be 
recorded in the source documents. For study participants considered as lost to follow-up the 
Investigator should make an effort (at least 1 phone call and 1 written message to the study 
participant), 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. The CRF must 
document the primary reason for withdrawal or discontinuation. 
Investigators should contact the Medical Monitor whenever possible to discuss the 
withdrawal of a study participant in advance. 
7 
STUDY TREATMENTS 
7.1 
Description of IMP 
Supplies of CZP will be provided by UCB as a CZP 200mg/mL solution for single sc 
injection, in a single use PFS for sc injection (administered in accordance with Table 7-1). 
Each PFS contains an extractable volume of 0.25mL, 0.5mL, or 1mL of CZP solution. 
The IMP will be supplied under the responsibility of UCB. The frequency at which the IMP 
will be supplied to each individual center will be adapted based on the recruitment capacity 
of that center, availability, and expiry date of the IMP. Study medication supplies will be 
managed by the IXRS in order to ensure all sites have sufficient quantities of study 
medication available. 
7.2 
Treatments to be administered 
Throughout the study, CZP dosing is fixed dose based on weight and given Q2W, with the 
exception of the lowest weight group on the reduced CZP regimen who will receive the 
maintenance dose Q4W. The loading dose, maintenance dose, and range of exposures in each 
weight category for both the original and reduced CZP regimens are presented in Table 7-1. 
Study participants start with 3 loading doses of CZP at Weeks 0, 2, and 4 followed by a 
maintenance dose for the duration of the study. After Week 4 (Visit 5), home-based CZP 
administration by the study participant or parent/caregiver will be permitted between 
scheduled study visits. 
A study participant’s dosing category will only be changed after the confirmation of a weight 
change by the Investigator at a scheduled clinic visit.  
The study participant will receive the dose of the next weight category once their weight 
crosses the 40kg/88lb boundary or crosses the 20kg/44lb boundary at a scheduled clinic visit. 
The study participant will continue on the dose of the new weight category regardless of 
potential decrease of the weight below the boundary. In case of significant weight 
fluctuations the Investigator should contact the Medical Monitor to discuss and confirm 
potential change in dosing if medically advised or discontinuation of treatment (eg, if related 
to AE).  
The injection should be administered at either the lateral abdominal wall or upper outer thigh. 
Treatment of the injection site with an anesthetic cream prior to dosing is permitted. 
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Table 7-1 
Dosing administration of CZPa  
Weight range 
Loading dose – Weeks 0, 2, and 4 
(mg/kg dose range) 
IMP Description 
Maintenance – Week 6 and onwards 
(mg/kg dose range) 
IMP Description 
Original CZP regimen 
10 to <20kg 
(22 to <44lb) 
100mg Q2W 
(5-10mg/kg) 
1 x 0.5mL inj 
50mg Q2W 
(2.5-5mg/kg) 
1 x 0.25 mL inj 
20 to <40kg 
(44 to <88lb) 
200mg Q2W 
(5-10mg/kg) 
1 x 1mL inj 
100mg Q2W 
(2.5-5mg/kg) 
1 x 0.5mL inj 
≥40kg 
(≥88lb) 
400mg Q2W 
(<10mg/kg) 
2 x 1mL inj 
200mg Q2W 
(<5mg/kg) 
1 x 1mL inj 
Reduced CZP regimen 
10 to <20kg 
(22 to <44lb) 
50mg Q2W 
(2.5-5mg/kg) 
1 x 0.25mL inj  
50mg Q4W 
(2.5-5mg/kg) 
1 x 0.25mL inj  
20 to <40kg 
(44 to <88lb) 
100mg Q2W 
(2.5-5mg/kg) 
1 x 0.5mL inj  
50mg Q2W 
(1.25-2.5mg/kg) 
1 x 0.25mL inj  
≥40kg 
(≥88lb) 
200mg Q2W 
(<5mg/kg) 
1 x 1mL inj  
100mg Q2W 
(<2.5mg/kg) 
1 x 0.5mL inj  
CZP=certolizumab pegol; inj=injection; Q2W=every 2 weeks; Q4W=every 4 weeks 
Note: A study participant should change dosing category during the course of the study if their weight crosses 
the 40kg/88lb boundary or crosses the 20kg/44lb boundary. 
a Note that the original CZP regimen describes the dosing administration of CZP prior to the implementation of 
Protocol Amendments 4 and 5 and for study participants enrolled following the implementation of Protocol 
Amendment 9. The reduced CZP regimen describes the dosing administration of CZP after implementation of 
Protocol Amendments 4 and 5. Refer to Section 7.2.1 for the procedure to be taken for study participants who 
are undergoing a dose change.  
Site staff will administer the study participant’s injection at Week 0 to demonstrate the 
correct injection technique. At Weeks 2 and 4, study participants/caregivers 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 study participants/caregivers have 
been trained, the study medication may be administered at home. Prior to CZP administration 
at home, study participants/caregivers will be trained by the site staff and provided written 
instructions on the fixed dose for injection and the correct sc injection technique including 
0.25mL, 0.5mL, and 1mL injections, as appropriate. If administered at home, the study 
participant/caregiver is requested to document the container number, date, and time point of 
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administration of study medication and return this documentation together with any 
used/unused or partially used containers at the next scheduled clinic visit. Study participants 
who are unable to self-administer the study treatment or those without a family 
member/friend/caregiver who can help, will not be withdrawn from the study but may 
continue to visit the site for study treatment administration between regular scheduled visits. 
In addition, if needed, home dosing can be performed by qualified health care professionals 
according to the written instructions for the correct sc injection technique provided by the site 
staff. Study participants will have the option to either switch to home-based CZP injection or 
switch back to administration at the study site at anytime during the study. 
The method of injection (ie, qualified site personnel-injection at study site; injection by the 
study participant/caregiver or qualified health care professional at the study site or at home) 
and the site of injection (abdomen, thigh) will be recorded in the CRF at each visit. 
Study participants achieving clinical remission on medication (CRM), ie, after 6 months of 
continuous CID, may discontinue CZP treatment at the Investigator’s discretion following 
consultation with the Sponsor to confirm remission status. Study participants who have 
discontinued CZP due to achieving CRM will be allowed to remain in the study and continue 
with scheduled study visits. Study participants not maintaining persistent CID following 
achievement of CRM will be allowed to resume CZP treatment at any time at the 
Investigator’s discretion and consultation with the Sponsor. If a study participant is on 
concomitant MTX treatment, the Investigator may decide to decrease and ultimately 
discontinue the MTX dose after complete discontinuation of CZP. Study participants not 
maintaining persistent CID following achievement of CRM and resuming treatment will 
restart the fixed-dose CZP dosing based on their current weight with 3 loading doses of CZP 
administered Q2W over 6 weeks, followed by a maintenance dose administered Q2W, or 
Q4W for the lowest weight group on the reduced CZP regimen for the duration of the study 
(see Table 7-1). 
7.2.1 
Procedure for dose change (Protocol Amendment 9) 
Following Protocol Amendment 9, study participants will only be enrolled on the original 
CZP dose regimen. With Protocol Amendment 4, the maintenance dose in the study was 
reduced by 50% for all weight groups (not applicable for study participants enrolled on the 
reduced CZP dose regimen per Protocol Amendment 5). Participants on the reduced CZP 
dose regimen can remain on the reduced CZP dose or may be switched to the original CZP 
dose regimen at the discretion of the Investigator and in consultation with the medical 
monitor. Additional dose changes are not allowed. The procedure for dose change is as 
follows:  
 The timepoint of the dose change is the next scheduled time of injection after the 
Informed Consent form related to the dose change was signed. In case the next scheduled 
injection was planned for home dosing, the study participant will be requested to return to 
the clinic for an Unscheduled Visit for signing the Informed Consent form related to the 
dose change, administration of CZP, and to dispense the new supplies. Unused IMP 
dispensed previously needs to be returned. 
In case the study participant is not able to visit the site for that next scheduled injection, 
then the dose change must be performed at the next scheduled injection. 
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 Study participants will be monitored at least every 4 weeks over a period of 12 weeks 
after the dose change, either at the regularly scheduled visits or at additional Unscheduled 
Visits. The Unscheduled Visits will be scheduled to match with the dosing schedule, ie, 
the study medication will be administered at the day of the Unscheduled Visit. The 
Investigator should consult with the Medical Monitor in case of any questions related to 
the timing of the dose change or the Unscheduled Visits.   
 Study participants undergoing the dose change at an Unscheduled Visit between the 
regular visits will be required to return at the latest after 4 weeks for an Unscheduled 
Visit in case no regular visit is scheduled within 4 weeks. These study participants 
will be monitored at least every 4 weeks over a period of 12 weeks.  
 At Unscheduled Visits when the dose change occurs and following the dose change, the 
following will be assessed: AEs, concomitant medications and procedures, vital signs, 
hematology/biochemistry, as well as CRP, PRINTO/PRCSG standard joint examination, 
Physician’s Global Assessment of Disease Activity, CHAQ, and Parent’s Global 
Assessment of Overall Well-Being to determine PedACR response rates. Assessments at 
regular visits will be done as scheduled, except for PK sampling (see below). 
7.3 
Packaging 
Certolizumab pegol is packaged and labeled according to Good Manufacturing Practice 
(GMP) guidelines and applicable laws or regulations. They are suitably packaged in such a 
way as to protect the IMPs from deterioration during transport and storage. 
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will include 
any locally required statements. If necessary, labels will be translated into the local language. 
Details on Labeling will be provided in the Pharmacy manual. 
7.5 
Handling and storage requirements 
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the 
site. All IMPs must be stored in a secured, limited access area between 2 and 8°C (35.6 and 
46.4°F) and protected from light. 
Appropriate storage conditions must be ensured either by controlled temperature or by 
completing a temperature log in accordance with local requirements, but at least once a day 
with minimum and maximum temperatures reached over the time interval. A temperature 
out-of-range can be noted during storage at a site or during shipment at any time during the 
study.  
In case a temperature out-of-range is noted during storage at a site, it must be immediately 
communicated to the Clinical Program Manager (CPM) (or designee) via the monitor before 
further use of the IMP. Site personnel have to complete the temperature excursion form 
during storage and fax it together with the temperature log form to the monitor. The monitor 
immediately has to inform Clinical Trial Supplies (CTS) at UCB who will place the affected 
medication in quarantine during the evaluation of the temperature excursion. 
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In case a temperature out-of-range is noted during shipment to a site, it must be immediately 
put in quarantine by contacting the IXRS and informing the monitor during the evaluation of 
the temperature excursion. For the maximum of information the temperature monitoring 
device has to be sent back immediately to the distributor. 
After the evaluation of the temperature excursion, CTS will provide the monitor and the 
IXRS with instructions regarding further use of the product at the site. 
For IMP dispensed to the study participant/caregiver for injection at home, the Investigator 
(or designee) will instruct the study participant/caregiver to store the IMP following the 
instructions on the label. 
7.6 
Drug accountability 
A drug accountability form will be used to record IMP dispensing and return information on 
a by-study participant 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. 
Periodically and at the end of the study, all unused and expired investigational product (PFSs 
and containers) 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. For CZP administration at home, the study 
participant/caregiver will receive a disposal (sharps) container in order to return used PFSs to 
the site for disposal. 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, unused, and partially used 
containers of IMP until returned or destroyed. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the 
study site to an appropriate pharmacist/designee. 
The Investigator must ensure that the IMP is used only in accordance with the protocol. 
7.7 
Procedures for monitoring study participant compliance 
At each visit after IMP is dispensed, study participants must return all used, unused, and 
partially used IMP containers together with the documentation on home dosing, if applicable. 
Drug accountability must be done in the study participant’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. 
If a study participant is found to be persistently noncompliant (missing 2 or more consecutive 
scheduled CZP doses or missing 3 or more doses over a 12-month period), the Sponsor in 
conjunction with the Investigator will make a decision as to whether the study participant 
should be withdrawn from the study. 
This rule does not apply when CZP is discontinued if the study participant is in CRM or if 
CZP is temporarily discontinued due to an AE. The study participant will continue with 
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scheduled study visits even if not dosed. In the case of temporary discontinuation due to an 
AE, the Sponsor in conjunction with the Investigator will make a decision as to whether the 
study participant should be withdrawn from the study.  
7.8 
Concomitant medication(s)/treatment(s) 
The sections below describe the following categories of concomitant medications/treatments: 
concomitant medications that are permitted during the study, rescue medications that are 
allowed before Week 16, rescue medications that are allowed after Week 16 and may be used 
for the remainder of the study, and concomitant medications that are prohibited at any time 
during the study. 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
The following are permitted: 
 MTX, if being used:  
 Must have been stable for at least 1 month before Screening (Visit 1) at ≥10 to 
≤15mg/m2 per week.  
 During the study, an increase is allowed only after Week 16 and to a maximum dose 
of 15mg/m2 per week.  
 Prior to Week 16, route of administration must not change. After Week 16, the route 
of administration may be changed. 
 During the study, the MTX dose may be decreased, but not discontinued. 
Methotrexate may be discontinued only for documented reasons of intolerance or 
toxicity, or in study participants who achieve CRM (persistent CID over a period of 6 
months, as defined in Section 11.10) and only after discontinuation of CZP. 
 Study participants who do not maintain persistent CID following achievement of 
CRM can reinitiate therapy with MTX.  
 Scheduled and as needed (PRN) use of NSAIDs, cyclooxygenase-2 (COX-2) inhibitors, 
acetaminophen (paracetamol), and other analgesics are permitted.  
 Folic acid or folinic acid. 
 Topical anesthetic creams (eg, lidocaine/prilocaine creams, licensed NSAID creams). 
 Corticosteroids:  
 At study entry, the dose should have been stable for at least 7 days prior to the 
Baseline joint examination at a maximum dose of 10mg or 0.2mg/kg prednisone (or 
equivalent) per day, whichever is the smaller dose. 
 During the study, the dose of oral corticosteroids may be decreased but not initiated or 
increased above 10mg or 0.2mg/kg prednisone (or equivalent) per day, whichever is 
the smaller dose. The dose must be stable in the 7 days prior to a joint examination. 
 Initiation of topical corticosteroids is allowed for treatment of uveitis if developed 
during the course of the study. 
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 Intra-articular (ia) corticosteroids may be administered no more frequently than every 
4 months and no more than up to 3 times in 1 year and only into up to 2 joints at a 
single time point. 
 Any joint injected with ia corticosteroids will be excluded from the efficacy analysis 
for a period of 3 months. 
 Intravenous (iv) corticosteroid use is permitted only for stress dosing for the purposes 
of surgery. 
 Oral/parenteral/implantable hormonal contraceptives (stable for at least 2 months prior to 
Screening [Visit 1] if initiated prior to entering the study). 
 Non-live and therefore permitted vaccinations include: intramuscular polio, Hepatitis A, 
Hepatitis B, pneumococcal conjugate vaccine (PCV), pneumococcal polysaccharide 
vaccine (PPSV), diphtheria-tetanus-pertussis (DTaP/DTP), Hemophilus influenzae type b 
(Hib), injectable (but not nasal) influenza, meningococcus, and human papilloma virus. 
The effectiveness of vaccines administered while on CZP treatment is currently unknown. 
(Live or live attenuated vaccines are prohibited during the course of the study.) 
7.8.2 
Rescue medication 
Rescue medication use is defined as any initiation of treatment or increase in dose of a 
medication used to treat JIA (in addition to the IMP) that is considered to impact the efficacy 
analyses. A study participant requiring rescue medication after first administration of IMP is 
considered as a treatment failure from that time point forward for the purpose of efficacy 
analyses. Exception: A study participant initiating rescue medication use after the Week 56 
visit will not be considered a treatment failure and the efficacy data will be analyzed as 
observed without imputation. 
A study participant requiring rescue medication may remain on study medication if the 
benefit/risk assessment of the study participant’s continued participation is still favorable 
based on the Investigator’s clinical assessment.  
The use of rescue medication should be specifically avoided during the first 4 months 
(16 weeks) of treatment, if possible. 
The following medications are defined as rescue medication in the first 16 weeks of this 
study: 
 Initiation of MTX (if not being used at study entry), or increase of MTX above Baseline. 
 Initiation of oral corticosteroids, or increase above Baseline.  
The following medications are defined as rescue medication after Week 16: 
 Initiation of MTX (if not being used at study entry), and increase of MTX above 15mg/m2 
per week at any time. 
 Initiation of oral corticosteroids, or increase to >10mg or 0.2mg/kg prednisone (or 
equivalent) per day, whichever is the smaller dose. 
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The following medications are defined as rescue medication when given at any time during 
the study: 
 Injection of intra-articular (ia) corticosteroids into more than 2 joints at a single time 
point. 
 Injection of intra-articular (ia) corticosteroids into the same joint more frequently than 
3 times in a 12-month period.  
 Intravenous (iv) corticosteroids (any dose), if not used for stress dosing for the purposes 
of surgery. 
 Intramuscular (im) corticosteroids. 
Use of the following medications only results in efficacy data at the next scheduled visit 
being treated as missing/nonresponse: 
 Higher than Baseline dose of NSAIDs and COX-2 inhibitors including PRN use within 
72 hours prior to scheduled study visit.  
 Higher than Baseline dose of analgesics or opioids including PRN use within 48 hours 
prior to scheduled study visit. 
 Any increase in dose of oral corticosteroids within 7 days prior to scheduled study visit. 
All concomitant medications and procedures must be recorded on the CRF. Rescue 
medication will not be supplied by the Sponsor. 
7.8.3 
Prohibited concomitant treatments (medications and therapies) 
See Table 6-1 for prohibitions prior to study entry. The following are prohibited at any time 
during the study: 
 Nonbiologic DMARDs (other than MTX; see Section 7.8.1) and biologic DMARDs. 
 Any experimental (biological or non-biological) therapy (within or outside a clinical 
study). 
 Live and live attenuated vaccinations including, but not limited to, oral polio, chicken pox 
(varicella), measles-mumps-rubella (MMR), nasal influenza, and rotavirus. No data are 
available on the response to live vaccinations or the secondary transmission of infection 
by live vaccines in study participants receiving CZP. 
The concomitant use of these must result in the study participant’s immediate discontinuation 
of CZP dosing and the study participant must be withdrawn from the study. 
7.9 
Lost to follow up 
For study participants considered as lost to follow up, the Investigator should make an effort 
(at least 1 phone call and 1 written message to the participant), 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.  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
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The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:  
 The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.  
 Before a participant is deemed lost to follow up, the Investigator or designee must 
make every effort to regain contact with the participant (at least 1 phone call and 1 
written message to the participant), 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 participant, must be recorded 
in the source documents. The eCRF must document the primary reason for 
withdrawal.  
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up documented in the 
eCRF. 
7.10 
Enrollment and numbering of study participants 
To enroll a study participant, the Investigator must contact the IXRS and provide brief details 
of the study participant to be enrolled, eg, age, weight, and concomitant MTX use. The 
Investigator will enter the unique study participant number assigned to each study participant, 
based on a predefined range of study participant numbers assigned to the Investigator’s site. 
This unique study participant number will be required in all communications between the 
Investigator (or designee) and the IXRS regarding a particular study participant. The IXRS 
will allocate container numbers to the study participants based on the unique study participant 
number during the course of the study. Study participant numbers and container numbers will 
be tracked via the IXRS and also will be required to be entered into the CRF. 
The IXRS will allocate containers of study medication as appropriate to the visit schedule. 
8 
STUDY PROCEDURES BY VISIT 
During the study, the visits will take place in the timeframe as described in the study schedule 
(Schedule of study assessments, Section 5.2). The acceptable window between all the study 
visits is +/-3 days relative to Baseline (Week 0, Visit 2). 
8.1 
Visit 1 (Week -4 to 0) Screening 
Prior to any study activities and at least 4 days prior to the Baseline Visit (Visit 2), study 
participants and parent(s)/legal representative, as applicable, will be asked to read and sign an 
Informed Consent/Assent Form that has been approved by an IRB/IEC and which complies 
with regulatory requirements. Study participants and parent(s)/legal representative 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, study participants and 
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parent(s)/legal representative will be given the opportunity to ask the Investigator any 
questions regarding potential risks and benefits of participation in the study. 
Assessments at this visit will include: 
 Obtain written informed consent/assent 
 Assessment of inclusion/exclusion criteria 
 Demographic data including date of birth, gender, and race/ethnicity 
 JIA history and prior JIA medication 
 Review of general medical and procedure history, concomitant diseases, and previous and 
concomitant medications 
 Vital signs 
 Height* 
 Weight* 
 Physical examination 
• TB questionnaire 
 Hematology/biochemistry/urinalysis (including hepatitis and HIV testing) 
 Reproductive potential and birth control 
 Pregnancy (serum) test for postmenarcheal females 
 CRP 
 Chest radiographic imaging and results must be available at Baseline before first IMP 
administration unless a chest X-ray or CT scan is available from 2 months prior to 
Screening.   
 TB screening: TST and IGRA for study participants from 2 to 4 years of age (unless the 
study participant is located in a country with high TST positivity and/or written 
documentation for BCG vaccination is available) or IGRA (to be performed by the central 
lab) for study participants from 5 to 17 years of age. Note that the TST may be positive 
due to BCG vaccination, however, UCB will not permit enrollment of pediatric study 
participants <5 years old into the study without written approval from a physician with 
expertise in pediatric TB** 
 TB questionnaire (study participant and parent/caregiver)**  
 PRINTO/PRCSG standard joint examination 
 Physician’s Global Assessment of Disease Activity (VAS) 
 CHAQ-parent reported  
 Parent’s Assessment of Arthritis Pain (VAS) 
 Parent’s Global Assessment of Overall Well-Being (VAS) 
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 Adverse events 
 IXRS contact (to register study participant with unique study participant number) 
*Change in height and weight over the last 6 months and over the last year will be collected 
via parent-/self-report, if not available from medical records. 
**For details of TB screening and testing, see Section 10.7.9. 
8.2 
Visit 2 (Week 0) Baseline 
 Assessment of inclusion/exclusion criteria 
 Vital signs (within approximately 15 minutes prior to dosing and [pulse and blood 
pressure only] approximately 30 minutes after dosing) 
 Height 
 Weight (measurement used to determine CZP dose according to Table 7-1) 
 Tanner stages (except growth) 
 Physical examination 
 TB questionnaire (study participant and parent/caregiver) 
 Hematology/biochemistry/urinalysis (only if in the Investigator’s opinion there is a 
change in the study participant’s status compared to the Screening Visit, ie, any valid 
result from hematology, biochemistry, or urinalysis obtained at the Screening Visit will 
be used as the Baseline value) 
 Reproductive potential and birth control 
 Pregnancy (urine) test for postmenarcheal females 
 CRP 
 PRINTO/PRCSG standard joint examination 
 Physician’s Global Assessment of Disease Activity (VAS) 
 CHAQ-parent reported 
 Parent’s Assessment of Arthritis Pain (VAS) 
 Parent’s Global Assessment of Overall Well-Being (VAS) 
 DMS 
 JADAS 
 FPS-R for study participants ages 5 to 11 years (at Baseline and daily assessment on Day 
1 to Day 7) 
 JIA Pain VAS for study participants ages 12 to 17 years; acute and standard versions 
(both at Baseline and daily assessment of the acute version on Day 1 to Day 7)  
 Fatigue Assessment Scale  
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 Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey 
 Concomitant medications and procedures 
 Adverse events 
 IXRS contact (to receive assigned container number[s]) 
 CZP plasma concentrations  
 Anti-CZP antibodies 
 Autoantibodies (ANA antibodies and, if ANA is positive, anti-dsDNA antibodies) 
 CZP administration (Injection by site personnel including demonstration for training.) 
Documentation of the assessment of all 6 core set measures of PedACR response 
(PRINTO/PRCSG standard joint examination, Physician’s Global Assessment of Disease 
Activity [VAS], CHAQ-parent reported, Parent’s Assessment of Arthritis Pain [VAS], 
Parent’s Global Assessment of Overall Well-Being [VAS] and CRP) will be submitted to 
UCB or designee for immediate review of completeness, while the study participant is 
still on site. 
8.3 
Visits 3 and 4 (Weeks 1 and 2) 
 Vital signs (within approximately 15 minutes prior to dosing and [pulse and blood 
pressure only] approximately 30 minutes after dosing) 
 Weight (at Week 2 measurement used to reassess CZP dose according to Table 7-1) 
 CRP 
 PRINTO/PRCSG standard joint examination 
 Physician’s Global Assessment of Disease Activity (VAS) 
 CHAQ-parent reported 
 Parent’s Assessment of Arthritis Pain (VAS) 
 Parent’s Global Assessment of Overall Well-Being (VAS) 
 Collection of JIA Pain VAS or FPS-R completed on Day 1 to Day 7 
 Clinically Inactive Disease 
 DMS 
 JADAS 
 Fatigue Assessment Scale  
 Concomitant medications and procedures 
 Adverse events 
 IXRS contact 
 CZP plasma concentrations (Week 1 only) 
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 Anti-CZP antibodies (Week 1 only) 
 CZP administration (Week 2 only. Self/or parent/caregiver-administration under the 
supervision of the site staff for training.) 
8.4 
Visits 5 to 10 (Weeks 4, 8, 12, 16, 20, and 24) 
 Vital signs (within approximately 15 minutes prior to dosing and [pulse and blood 
pressure only] approximately 30 minutes after dosing) 
 Height (Week 24 only) 
 Weight (measurement used to reassess CZP dose according to Table 7-1) 
 Tanner stages (except growth; Week 24 only) 
 Physical examination 
 TB questionnaire (study participant and parent/caregiver) (Weeks 12 and 24 only) 
 Hematology/biochemistry/urinalysis 
 Reproductive potential and birth control 
 Pregnancy (urine) test for postmenarcheal females (Weeks 8, 16, and 24 only) 
 CRP 
 PRINTO/PRCSG standard joint examination 
 Physician’s Global Assessment of Disease Activity (VAS) 
 CHAQ-parent reported 
 Parent’s Assessment of Arthritis Pain (VAS) 
 Parent’s Global Assessment of Overall Well-Being (VAS) 
 Clinically Inactive Disease 
 Clinical remission on medication (at Week 24 only) 
 DMS 
 JADAS 
 FPS-R for study participants ages 5 to 11 years (Weeks 4, 12, 16, and 24 only) 
 JIA Pain VAS (standard version, Weeks 4, 12, 16, and 24 only for study participants ages 
12 to 17 years) 
 Fatigue Assessment Scale (Weeks 4, 8, 16, and 24 only) 
 Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey 
 Concomitant medications and procedures 
 Adverse events 
 IXRS contact (Assignment of all required study medication until next scheduled visit.) 
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 CZP plasma concentrations (predose at Weeks 4, 12, 16, and 24.  
Study participants will return to the clinic site for a postdose CZP plasma sample 
approximately 5 to 7 days following the Week 16 visit.) 
 Anti-CZP antibodies (predose at Weeks 4, 12, 16, and 24) 
 Autoantibodies (ANA and anti-dsDNA antibodies) (Week 16 only) 
 CZP administration (At Week 4, self/parent/caregiver-administration under the 
supervision of the site staff for training. After Week 4, administration of study medication 
either by site personnel [for those not performing home-based administration] or 
self/parent/caregiver-administration under supervision of site personnel to ensure proper 
injection technique.) 
Between scheduled visits (Weeks 6, 10, 14, 18, 22, 26, 28, 30), CZP will be administered at 
home by the study participant or parent/caregiver or study participants may visit the site for 
CZP administration by staff personnel. 
Documentation of the Week 24 assessment of all 6 core set measures of PedACR response 
(PRINTO/PRCSG standard joint examination, Physician’s Global Assessment of Disease 
Activity [VAS], CHAQ-parent reported, Parent’s Assessment of Arthritis Pain [VAS], 
Parent’s Global Assessment of Overall Well-Being [VAS] and CRP) will be submitted to 
UCB or designee for immediate review of completeness, while the study participant is 
still on site. 
8.5 
Visits 11 and continuing (Week 32 and every 8 weeks 
thereafter)  
For study participants enrolled prior to Protocol Amendment 9, visit frequency changes to 
every 16 weeks instead of every 8 weeks following implementation of Protocol 
Amendment 8, provided that compliance is maintained with the CZP dosing schedule using 
at-home administration.   
 Vital signs (within approximately 15 minutes prior to dosing and [pulse and blood 
pressure only] approximately 30 minutes after dosing) 
 Height (Week 48 and every 24 weeks thereafter; for study participants enrolled prior to 
Protocol Amendment 9, height assessment will be performed every 48 weeks following 
Protocol Amendment 8) 
 Weight (measurement used to reassess CZP dose according to Table 7-1) 
 Tanner stages (except growth; for study participants enrolled prior to Protocol 
Amendment 9, Tanner stages assessment will be performed every 48 weeks following 
Protocol Amendment 8, and only for those subjects who have not reached Tanner stage 
V) 
 Physical examination 
 TB screening once a year (at least every 48 weeks) 
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 TB questionnaire (study participant and parent/caregiver) (Week 40 and every 16 weeks 
thereafter) 
 Hematology/biochemistry/urinalysis 
 Reproductive potential and birth control 
 Pregnancy (urine) test for postmenarcheal females 
 CRP 
 PRINTO/PRCSG standard joint examination  
 Physician’s Global Assessment of Disease Activity (VAS) 
 CHAQ-parent reported 
 Parent’s Assessment of Arthritis Pain (VAS) 
 Parent’s Global Assessment of Overall Well-Being (VAS) 
 Clinically Inactive Disease 
 Clinical remission on medication 
 DMS 
 JADAS 
 FPS-R for study participants ages 5 to 11 years 
 JIA Pain VAS (standard version, ages 12 to 17 years) 
 Fatigue Assessment Scale  
 Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey 
 Concomitant medications and procedures 
 Adverse events 
 IXRS contact (Assignment of all required study medication until next scheduled visit.) 
 CZP plasma concentrations (for study participants enrolled following Protocol 
Amendment 9 only; Weeks 32, 40, and 48 and every 24 weeks thereafter) 
 Anti-CZP antibodies (for study participants enrolled following Protocol Amendment 9 
only; Weeks 32, 40, and 48 and every 24 weeks thereafter)  
 Autoantibodies (ANA and anti-dsDNA antibodies) (Week 48 only) 
 CZP administration (Administration of study medication either by site personnel or 
self/parent/caregiver-administration under supervision of site personnel to ensure properly 
performed.) 
Between scheduled visits (starting at Week 34), CZP will be administered at home by the 
study participant or parent/caregiver or study participants may visit the site for CZP 
administration by staff personnel. 
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8.6 
Unscheduled Visit 
 Vital signs (within approximately 15 minutes prior to dosing and [pulse and blood 
pressure only] approximately 30 minutes after dosing, if dosing is applicable) 
 Concomitant medications and procedures 
 Adverse events 
Other PK and safety assessments should be performed as related to nature of the visit. 
8.6.1 
Unscheduled Visit related to dose change  
If required, study participants will return for an Unscheduled Visit to undergo the dose 
change. Study participants will be monitored at least every 4 weeks over a period of 12 weeks 
after the dose change, either at the regularly scheduled visits or at additional Unscheduled 
Visits. 
The following will be assessed at this visit: 
 Administration of study medication  
 Adverse events 
 Concomitant medications and procedures 
 Vital signs (within approximately 15 minutes prior to dosing and [pulse and blood 
pressure only] approximately 30 minutes after dosing) 
 Hematology/biochemistry 
 CRP 
 PRINTO/PRCSG standard joint examination 
 Physician’s Global Assessment of Disease Activity (VAS) 
 CHAQ-parent reported 
 Parent’s Global Assessment of Overall Well-Being (VAS)  
 IXRS contact, if applicable 
8.7 
Early Discontinuation/End of Treatment Visit 
 Vital signs 
 Height 
 Weight 
 Tanner stages (except growth) 
 Physical examination 
 TB questionnaire (study participant and parent/caregiver) 
 Hematology/biochemistry/urinalysis 
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 Reproductive potential and birth control 
 Pregnancy (urine) test for postmenarcheal females 
 CRP 
 PRINTO/PRCSG standard joint examination 
 Physician’s Global Assessment of Disease Activity (VAS) 
 CHAQ-parent reported 
 Parent’s Assessment of Arthritis Pain (VAS) 
 Parent’s Global Assessment of Overall Well-Being (VAS) 
 Clinically Inactive Disease 
 Clinical remission on medication  
 DMS 
 JADAS 
 FPS-R for study participants ages 5 to 11 years 
 JIA Pain VAS (standard version ages 12 to 17 years) 
 Fatigue Assessment Scale  
 Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey 
 Concomitant medications and procedures 
 Adverse events 
 IXRS contact (to register study participant visit) 
 CZP plasma concentrations (for study participants enrolled following Protocol 
Amendment 9 only  
 Anti-CZP antibodies (for study participants enrolled following Protocol Amendment 9 
only) 
 Autoantibodies (ANA and anti-dsDNA antibodies) 
8.8 
Final Visit 
The final visit is to be completed by all study participants 12 weeks after the final dose of 
CZP. 
 Vital signs  
 Weight 
 Physical examination 
 Hematology/biochemistry/urinalysis 
 Reproductive potential and birth control 
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 Pregnancy (urine) test for postmenarcheal females 
 Concomitant medications and procedures 
 Adverse events 
 IXRS contact (to deactivate the study participant) 
 CZP plasma concentrations (for study participants enrolled following Protocol 
Amendment 9 only) 
 Anti-CZP antibodies (for study participants enrolled following Protocol Amendment 9 
only) 
9 
ASSESSMENT OF PHARMACOKINETICS AND 
IMMUNOLOGICAL VARIABLES 
Blood samples will be collected predose to determine plasma concentrations of CZP and 
anti-CZP antibodies at Baseline (Week 0), Weeks 4, 12, 16, 24, 32, 40, 48, and then every 
24 weeks thereafter; the Early Discontinuation/End of Treatment Visit, and the Final Visit 
12 weeks after the last dose of study medication. For study participants enrolled prior to 
Protocol Amendment 9, samples for CZP plasma concentration and anti-CZP antibodies will 
no longer be collected. In addition, blood samples will be collected 5 to 7 days after dosing at 
Baseline (ie, at Week 1, Visit 3) and Week 16 (ie, return of study participant to clinic site at 
Week 17) to determine postdose plasma concentration.  
All of these blood draws (except for postdose samplings at Week 1 and after Week 16) will 
be performed prior to any study medication administration, where applicable, and all of them 
coincide with the blood collection times for the assessment of hematology and clinical 
chemistry parameters, so that no additional blood draws are required at these visits except at 
Week 1 (Visit 3) and the postdose sampling following Week 16 (Visit 8). Time and date of 
each blood draw will be documented on the CRF. 
Instructions on blood sample collection, processing, storage, and labeling/shipping will be 
provided in the laboratory manual for this study. 
Blood samples to determine plasma concentrations of CZP and anti-CZP antibodies will be 
analyzed by a specialty laboratory. All study participants enrolled following Protocol 
Amendment 9 will have plasma concentrations of CZP and anti-CZP antibodies analyzed 
using an ECLIA method that meets current regulatory standards. In addition, PK and ADA 
samples (for which sufficient volume is available) collected in this study prior to Protocol 
Amendment 9 will be analyzed with the ECLIA method. The collective ECLIA-based PK 
data for this study will form the basis of any future CZP modeling and simulation work. 
These plasma samples may be used additionally for analyses of CZP and its constituent 
moieties using alternative assay methods. The results of the analyses of CZP and its 
constituent moieties from alternative methods may be reported separately. 
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10 
ASSESSMENT OF SAFETY 
10.1 
Adverse events 
10.1.1 
Definition of AE 
An AE is any untoward medical occurrence in a patient or clinical investigation study 
participant administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an IMP, whether or not related to the IMP. 
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 IMP was 
administered but specific study procedures were conducted. This includes all AEs not present 
prior to the initial visit and all medical conditions or AEs which recurred or worsened after 
the initial visit. 
Signs or symptoms of the condition/disease for which the IMP 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 study participant’s history or the period preceding Baseline. 
10.1.2 
Procedures for reporting and recording AEs 
The study participant/caregiver 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 (your child’s) health (since your last 
visit)?” 
In addition, the Investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study to identify potential AEs. 
10.1.3 
Description of AEs 
When recording an AE, the Investigator should report an overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs, where 
possible. If a diagnosis/syndrome is eventually determined, relevant signs and symptom AEs 
should be consolidated under the diagnosis/syndrome rather than continued to be listed 
individually. The CRF and source documents should be consistent. Any discrepancies 
between the study participant’s own words on his/her own records (eg, diary card) 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 instructions. 
10.1.4 
Follow-up on AEs 
An AE should be followed until it has resolved, it has stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the study participant is lost to follow-
up.  
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If an AE is still ongoing at the end of the study for a study participant, follow-up should be 
provided until the AE resolves/reaches a stable level of sequelae, the Investigator no longer 
deems that it is clinically significant, or the study participant is lost to follow-up. If no 
follow-up is provided, the Investigator must provide a justification. Follow-up of any ongoing 
AE is continued until the end of the study for a study participant (Final Visit) or until the 
study participant is lost to follow-up. 
10.1.5 
Rule for repetition of an AE 
An increase in the intensity of an AE (or an ongoing medical condition at the study onset) 
should lead to the repetition of the AE being reported with: 
 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,  
 Change in intensity or severity being recorded. 
10.1.6 
Reporting requirements for events relating to TB 
Reporting requirements for events relating to TB Tuberculosis is a safety topic of interest. 
The safety topics of interest are selected based on findings from the IMP clinical program to 
date, potential risks generally associated with biologic immunomodulators, or findings from 
other medicines with a related mechanism of action. There are no specific AE reporting 
requirements beyond those specified for AEs and SAEs in the protocol; however, special 
monitoring, additional data collection activities, and/or enhanced signal detection activities 
(within UCB) are in place. The reporting requirements for events relating to TB are as 
follows:  
 IGRA test conversions defined as a positive or indeterminate (and confirmed 
indeterminate on repeat) should be reported as AEs. The AE term would need to be 
updated with final diagnosis once available.  
 LTBI must be reported as an AE. Follow-up reports should be completed as per 
protocol requirement until the LTBI resolves.  
 Confirmed active TB is always considered a SAE and must be reported per SAE 
reporting instruction in the study protocol. Follow-up reports should be completed as 
per protocol requirement until TB infection resolves. 
10.1.7 
Pregnancy 
Should a study participant become pregnant after the first intake of IMP, UCB Patient Safety 
should be informed immediately. Study medication must be discontinued as soon as 
pregnancy is known (by positive pregnancy test). Study participants can remain in the study 
under observation and should attend to scheduled visits regularly as their condition allows.  
The Investigator must inform the study participant of information currently known about 
potential risks and about available treatment alternatives.  
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In cases where the partner of a male study participant enrolled in a clinical trial becomes 
pregnant, UCB will ask the Investigator or designee to contact the study participant 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 study participant’s partner (or parent/caregiver if study participant underaged) 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. A pregnancy is considered as an 
SAE in case of contraceptive failure (eg, pill taken everyday at approximately the same time 
each day without having been forgotten or with use of permanent contraceptive devices). 
Those serious events must be additionally reported using the Investigator SAE report form.  
10.1.8 
Suspected transmission of an infectious agent via a medicinal 
product 
For the purposes of reporting, any suspected transmission of an infectious agent via the study 
medication should be considered as an SAE; such cases must be reported immediately, 
recorded in the AE module of the CRF, and followed as any other SAE. Any organism, virus, 
or infectious particle (eg, prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent. 
10.1.9 
Overdose of IMP 
Excessive dosing of IMP (beyond that prescribed in the protocol and including overdose) 
should be recorded in the appropriate CRF module. Since excessive dosing may be 
symptomatic, in that the excessive dosing results in clinical signs and symptoms, or the 
excessive intake may itself be a symptom, any SAE or nonserious AE associated with 
excessive dosing must be followed as any other serious or nonserious AE.  
10.1.10 
Ongoing safety data review and oversight 
This study will be performed using remote data capture (RDC). The Investigator is 
responsible for the prompt reporting of accurate, complete, and legible data in the electronic 
CRFs. Laboratory data will be regularly transferred electronically to the Sponsor for 
incorporation with the Investigator-entered data. 
Adverse event and laboratory data will periodically be reviewed by medically qualified 
personnel at UCB knowledgeable about the disease and treatment. Regular monitoring of all 
safety data collected during CZP clinical studies is performed as described in the Safety 
Signal Detection in the Ongoing Clinical Trials Charter for CZP. The data from this study 
will be reviewed separately, in the context of all CZP data, and in the context of data coming 
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from any other pediatric studies. In addition, a Data and Safety Monitoring Board (DSMB) 
will periodically review emerging safety and efficacy data (see Section 13.7). The DSMB 
will function and meet on a regular basis as per the agreed upon charter.  
The Sponsor Study Physician or medically qualified designee/equivalent will conduct an 
ongoing review of SAEs and perform ongoing SAE reconciliations in collaboration with the 
Patient Safety and Data Management representatives. 
10.2 
Serious adverse events 
10.2.1 
Definition of SAE 
Once it is determined that a study participant 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 study participant and may require medical or surgical intervention to prevent 1 of the 
other outcomes listed in the definition of an SAE: allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias that do not result 
in inpatient hospitalization, pregnancy due to contraceptive failure, or the development of 
drug dependency or drug abuse. 
 Initial inpatient hospitalization or prolongation of hospitalization. 
 A study participant admitted to a hospital, even if released on the same day, meets the 
criterion initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization 
criterion. 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 an SAE (eg, life-threatening adverse experience, important 
medical event). 
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. Preplanned surgery or 
elective surgery must be verified in source document prior to Baseline (eg, timing and type of 
procedure). For example, if a study participant 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 
definition. Please note that, if the pre-existing condition has worsened or manifested in an 
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unusual or uncharacteristic manner, this would then qualify as an AE and, if necessary, the 
seriousness of the event would need to be determined. 
Hospitalization for diagnostic or therapeutic procedures in the absence of any associated AE 
will not be considered as an SAE, except when otherwise required by regulatory authorities. 
Preplanned diagnostic or therapeutic procedures must be verified in source document prior to 
Baseline (eg, timing and type of procedure). If a hospitalization is planned prior to the study 
participant receiving the first dose of IMP (at Week 0), it will not be classified as either an 
AE or SAE. This also applies to a scheduled elective surgery where no AE is present. A 
noncomplicated, preplanned elective surgery will not be considered an AE or SAE even if it 
involves hospitalization. However, if a hospitalization is unplanned or is a result of an AE, 
this will be considered to be an SAE. 
10.2.2 
Procedures for reporting SAEs 
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 Study Contact Information 
section). 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 pharmacovigilance 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 IMP), 
up to 30 days from the end of the study for each study participant, and to also inform 
participating study participants of the need to inform the Investigator of any AE within this 
period. Any SAEs that the Investigator suspects may be associated with the IMP 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 CZP IB. 
10.2.3 
Follow-up of SAEs 
An SAE should be followed until it has resolved, it has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the study participant is lost to follow-
up.  
Information on SAEs obtained after clinical database lock will be captured through the 
Patient Safety database without limitation of time. 
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10.3 
AEs of special interest 
An AESI 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 not fulfill the 
expedited reporting criteria of “serious,” “unexpected,” and “associated with the use of the 
drug.”  
Adverse events of special interest include:  
 Potential Hy’s Law 
 Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for the 
biochemical abnormality (ie, without waiting for any additional etiologic 
investigations to have been concluded). Follow-up information should be reported if 
an alternative etiology is identified during investigation and monitoring of the 
participant. 
 Serious infections, including opportunistic infections  
 Malignancies, including lymphoma  
 Congestive heart failure  
 Demyelinating-like disorders  
 Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leukopenia  
 Serious bleeding events  
 Lupus and lupus-like syndrome  
 Serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrosis, and 
erythema multiforme) 
Adverse events of special interest must be reported immediately by the Investigator (see 
Section 10.4).  
The purpose of the AESI is to identify and capture product specific AEs/reactions requiring 
expedited reporting or close monitoring by 1 or more regulatory authorities or close 
monitoring required by UCB. This tool will help ensure that specific special reporting 
requirements from regulatory authorities and safety topics requiring close monitoring are 
appropriately identified, processed, reported, and monitored. The process also allows for 
detection of safety signals, signal evaluation, and the assessment of changes in the 
benefit-risk ratio of UCB products/compounds, based on all safety and benefit-risk 
information available for the protection of the patient. 
10.4 
Immediate reporting of AEs 
The following AEs must be reported immediately via use of the SAE form (see Study 
Contact Information for contact details): 
 SAE: AE that the Investigator classifies as serious by the aforementioned definitions (see 
Section 10.2.1) regardless of causality 
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 Suspected transmission of an infectious agent via a medicinal product 
 AE of interest (see Section 10.3) 
10.5 
Anticipated serious adverse events 
The following list of Anticipated SAEs has been identified as those events anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure. This original list will remain in effect for the duration of the protocol. 
This list does not change the Investigator’s obligation to report all serious AEs (including 
Anticipated SAEs) as detailed in Section 10.2.2. 
Table 10-1 
Anticipated serious adverse events for JIA population 
Preferred Term 
Juvenile idiopathic arthritis 
10.6 
Laboratory measurements 
Hematology, biochemistry, and urinalysis samples will be collected at Screening, Baseline, 
Weeks 4, 8, 12, 16, 20, 24, 32 and every 8 weeks thereafter (for study participants enrolled 
prior to Protocol Amendment 9, visit frequency changes to every 16 weeks instead of every 
8 weeks following implementation of Protocol Amendment 8), the Early Discontinuation/End 
of Treatment Visit, and the Final Visit 12 weeks after the last dose of study medication. At 
Week 1, only CRP and PK samples will be collected and at Week 2, only CRP samples will 
be collected. In addition, hematology, biochemistry, and CRP samples will be collected at 
Unscheduled Visits for study participants undergoing a dose change (Section 7.2.1 and 
Section 8.6.1).  
Retesting of laboratory assessments within the Screening Period is allowed in case of isolated 
exclusionary laboratory assessments at Screening if, in the Investigator’s opinion, the value is 
not reflective of the study participant’s previous clinical and laboratory pattern (see 
Section 6.3). In addition, retesting within the Screening Period is allowed in case of reporting 
failure of laboratory results (eg, issues with transportation of samples). 
Study participants do not have to fast.  
Laboratory criteria and collection details are provided in the laboratory manual. 
For blood sampling on PK and immunological variables see Section 9. 
Measures to minimize distress and pain have been considered for this study in line with the 
“Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the 
Paediatric Population” (European Medicines Agency, 2008) and the “Guidance for Industry – 
E11 Clinical Investigation of Medicinal Products in the Pediatric Population” (FDA, 2000). 
Unless in the Investigator’s opinion there is a change in the study participant’s status, any 
valid laboratory result obtained at the Screening Visit on hematology, chemistry, and 
urinalysis can be used as the Baseline value, which will avoid the repeated collection of these 
specific samples at Baseline. Only samples for CRP, PK, and immunological variables will 
then be collected at Baseline (Week 0). 
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A qualified central laboratory capable of handling small sample/tube sizes will be used in this 
study. The planned total blood volumes collected at a single time point (visit) will vary 
between 2mL and 9mL. The highest blood sampling frequency will occur during the first 
4 weeks of the study. The maximum total volume collected during this period will be 
approximately 24mL (at the first 4 study visits). 
In addition, treatment of the venipuncture site with an anesthetic cream prior to blood 
sampling is permitted. 
The TB assessment by IGRA testing is required to be performed by the central lab; additional 
blood sampling of approximately 3mL will be required at Screening.  
If the result of the IGRA test is indeterminate, the test may be repeated once. If positive or 
indeterminate on retest, the study participant must not be enrolled (Section 10.7.9.5).  
For study participants from 2 to 4 years of age, TST and IGRA testing will be performed 
(except for study participants with documented BCG vaccination) as described in 
Section 10.7.9.8.2. In countries with high BCG vaccination or high TST positivity, only 
IGRA should be performed (Section 10.7.9.8.2). The TST may be positive due to BCG 
vaccination, however, UCB will not permit enrollment of pediatric study participants 
<5 years old into the study without written approval from a physician with expertise in 
pediatric TB. IGRA testing should be done once a year (approximately every 48 weeks) for 
all study participants.  
The central laboratory will analyze and assess blood and urine samples for the following 
(except dip stick test and urine pregnancy test); other PK assessments may be periodically 
performed as per Section 9: 
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Table 10-2 
Laboratory measurements 
Hematology 
Serum biochemistry 
Urinalysis 
Red blood cells 
Hemoglobin 
Hematocrit 
Platelets 
White blood cells 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total calcium 
Inorganic phosphorus 
Creatinine kinase 
Glucose 
Creatinine 
Uric acid 
Urea 
Total protein 
Albumin 
Alkaline phosphatase 
Gamma glutamyl transferase 
Aspartate aminotransferase 
Alanine aminotransferase 
Lactate dehydrogenase 
Bilirubin 
Total cholesterol 
CRP 
Autoantibodies (ANA and 
anti-dsDNA antibodies) 
pH(a) 
Protein(a) 
Glucose(a)  
Blood(a) 
Microscopy (WBC, RBC, casts, 
crystals, bacteria) (Microscopy 
will be performed only when 
there are abnormalities on 
dipstick)(a) 
 
 
Serum and urine pregnancy 
test(b) 
 
Hepatitis screening(c) 
HBcAb 
HBsAb 
HBsAg 
HCVAb 
HBV DNA, if applicable 
HCV RNA, if applicable 
TB screening(d) 
IGRA,  
TST 
HIV Screening 
HIV antigen or antibody 
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ANA=antinuclear antibody; anti-dsDNA antibodies=double-stranded deoxyribonucleic acid antibody; 
BCG=Bacille Calmette-Guérin; CRP=C-reactive protein; DNA=deoxyribonucleic acid; HBcAb=hepatitis 
B core antibody; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B surface antigen; HBV=hepatitis 
B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IGRA=interferon-gamma release 
assay; RBC=red blood cells; TB=tuberculosis; TST=tuberculin skin test; WBC=white blood cells 
Note: The Screening Visit must be completed at least 4 to 12 working days prior to the Baseline Visit, 
depending on regional requirements and laboratory assessments required for the study participant (refer to 
laboratory manual for country-specific requirements). In case HBV DNA or TB IGRA is to be analyzed, 
the Baseline Visit can be performed at the earliest 12 days after the Screening Visit (6 working days in 
Russia). Study participants can only be enrolled into the study after all laboratory results of the Screening 
Visit have been confirmed.  
a 
Urine dipsticks will be done locally at the site; only abnormalities will be reported. In case of 
abnormalities on dipstick, microscopy will be performed by the central laboratory. 
b 
Serum pregnancy tests will be performed at Screening by the central laboratory (see Section 10.7.7). 
At Baseline, Weeks 8, 16, 24, and every visit thereafter, urine pregnancy tests will be performed 
locally. 
c 
At Screening, laboratory testing includes testing for hepatitis B core antibody, hepatitis B surface 
antibody, hepatitis B surface antigen, hepatitis C virus antibody, and HIV 1/2. Study participants with 
a positive HBV test will not be allowed in the study (except for anti-hepatitis B positive only, in case 
study participant is immune due to well-documented hepatitis B vaccination or isolated false-positive 
anti-HBc test confirmed with a confirmatory test such as hepatitis B virus deoxyribonucleic acid 
[HBV-DNA]). A positive hepatitis C antibody test will be confirmed by a confirmatory test (such as 
HCV RNA) and those with a positive confirmatory test will not be allowed in the study. 
d 
For TB testing refer to Section 10.7.9. IGRA is performed by the central lab. 
10.7 
Other safety measurements 
10.7.1 
Vital signs 
Vital signs will be measured within approximately 15 minutes prior to dosing and in addition 
(pulse and blood pressure only) approximately 30 minutes after dosing with study 
medication. Study participants should be sitting for at least 5 minutes prior and during the 
collection of blood pressure and pulse rate measurements. Vital signs are as follows: 
 Pulse 
 Systolic/diastolic blood pressure measurement 
 Temperature 
Vital signs will be measured at Screening, Baseline, every visit (including all Unscheduled 
Visits) through the Early Discontinuation/End of Treatment Visit, and the Final Visit 
12 weeks after the last dose of study medication. 
10.7.2 
Growth (height and weight) 
Height will be recorded at Screening, Baseline, every 24 weeks thereafter (for study 
participants enrolled prior to Protocol Amendment 9, the height assessment will be performed 
every 48 weeks following Protocol Amendment 8), and the Early Discontinuation/End of 
Treatment Visit. Height will be recorded after the shoes have been removed. Height should 
preferably be measured with a wall-mounted stadiometer.  
At Screening, change in height and weight over the last 6 months and over the last year will 
be collected via parent-/self-report, if not available from medical records. 
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Weight will be recorded after removal of shoes and heavy clothing. Weight will be measured 
at Screening, Baseline, and every visit through the Early Discontinuation/End of Treatment 
Visit, and the Final Visit 12 weeks after the last dose of study medication. 
Results of the weight measurement will be used to determine the study participant’s CZP 
dose as specified in Table 7-1. 
10.7.3 
Tanner stages 
Assessments of study participants’ developmental stages on external genitalia and pubic hair 
(boys) and on breast and pubic hair (girls) will be performed to determine Tanner stages 
(Marshall and Tanner, 1969; Marshall and Tanner, 1970). These assessments will be 
performed at Baseline and every 24 weeks thereafter, and the Early Discontinuation/End of 
Treatment Visit. For study participants enrolled prior to Protocol Amendment 9, Tanner 
stages assessment will be performed every 48 weeks following Protocol Amendment 8, and 
only for those subjects who have not reached Tanner stage V. 
10.7.4 
Physical examination 
Physical examinations (except joint examination) will be performed at Screening, Baseline, 
Week 4, every visit thereafter through the Early Discontinuation/End of Treatment Visit, and 
the Final Visit 12 weeks after the last dose of study medication. Physical examination 
findings will be recorded in the CRF only at Screening. Details of the subsequent physical 
examinations should be recorded in the source documentation. Clinically relevant changes in 
subsequent physical examinations will be recorded as AEs.  
The following body systems will be examined: 
 General appearance 
 Ear, nose, and throat 
 Eyes 
 Hair and skin 
 Respiratory 
 Cardiovascular 
 Gastrointestinal 
 Musculoskeletal 
 Hepatic 
 Neurological  
 Mental status 
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10.7.5 
Demographics, JIA history, prior JIA medication, and general 
medical and procedure history 
Demographic data, JIA history including prior medication, general medical and procedure 
history (including any prior chest radiographs), and concomitant diseases will be recorded by 
the Investigator at the Screening Visit. 
10.7.6 
Reproductive potential and birth control 
Reproductive potential of all study participants will be assessed by clinical questioning at 
Screening, Baseline, and every visit thereafter except at Visits 3 and 4 and at Unscheduled 
Visits. If the study participant is not of reproductive potential, the reason will be recorded (eg, 
prepubescent, pre-menarcheal). If the study participant is of reproductive potential and is 
sexually active, the method of birth control used will be recorded. Sexually active study 
participants (male and female) must use effective contraceptive measures (see Section 6.2, 
Exclusion Criterion 17). 
10.7.7 
Pregnancy testing 
Pregnancy testing for all postmenarcheal female study participants (regardless of sexual 
activity) will consist of serum testing at Screening and urine testing at all other applicable 
visits. For female study participants who start menstruating during the study, urine pregnancy 
testing will be performed starting at the next applicable visit. Pregnancy testing must be 
carried out at Screening, Baseline, and every visit thereafter except at Unscheduled Visits 
(unless deemed necessary by the Investigator). 
10.7.8 
Autoantibody (ANA and anti-dsDNA antibodies) concentrations 
Autoantibodies (ANA and anti-dsDNA antibodies) will be assessed at Baseline (testing for 
anti-dsDNA antibodies only if ANA is positive), Weeks 16 and 48, and the Early 
Discontinuation/End of Treatment Visit. 
All of these blood draws will coincide with the blood collection times for the assessment of 
hematology and clinical chemistry parameters, so that no additional blood draws are required. 
10.7.9 
Assessment and management of TB and TB risk factors 
As TNF inhibitors are known to be associated with significant risk of reactivation of LTBI or 
previously treated active TB, appropriate rigorous precautions are being taken within the 
protocol (see Section 6.2 [Exclusion Criterion 11] and Section 6.4 [Withdrawal Criterion 2]). 
Study participants with known active TB disease, at high risk of acquiring TB infection, or 
with past or current LTBI or current or history of NTMB infection are excluded from the 
study. 
a. Known TB infection whether present or past is defined as: 
 Active TB infection or clinical signs and symptoms strongly suggestive of TB 
(pulmonary or extra pulmonary). 
 History of active TB infection involving any organ system or findings in other organ 
systems consistent with TB infection. 
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 Any evidence by radiography or other imaging modalities consistent with previously 
active TB infection that is not reported in the participant 's medical history. 
b. High risk of acquiring TB infection is defined as: 
 Known close exposure (eg, sleeping in the same room) to another person with active 
TB infection within 3 months prior to Screening. 
 Time spent within 3 months prior to Screening in a healthcare delivery setting or 
institution where individuals infected with TB are housed or where the risk of 
transmission of infection is high. 
c. LTBI is defined as an infection by mycobacteria tuberculosis with: 
 A positive IGRA (or 2 indeterminate IGRAs), AND 
 Chest imaging (or other imaging) negative for TB infection, AND 
 Absence of signs, symptoms (eg, evidence of organ-specific involvement), or physical 
findings suggestive of TB infection. 
d. Pulmonary NTMB infection is defined as a group of lung infections caused by 
mycobacteria different from mycobacterium tuberculosis infections. 
10.7.9.1 
Physical examination 
The investigator should consider all potential sites of infection when assessing for TB during 
the physical examination and other evaluations and based on the study participant’s medical 
or social history. 
The most common primary focus of TB is the lung. Other sites may include gastrointestinal 
system, bones/joints, lymph glands and meninges etc. However, in immune compromised 
patients and/or patients treated with TNF inhibitors, extra-pulmonary manifestations of TB 
are common compared to normal population. 
Some common symptoms that the study participant may present are dependent on the 
primary focus of infection and may include cough, blood in sputum, night sweats, 
lymphadenitis, joint pain/swelling, spinal deformity, headache/confusion, abdominal pain 
(mimicking IBD) etc. Unusual presentations should always be considered. 
10.7.9.2 
IGRA test conversion 
Tuberculosis test conversion is defined as a positive or indeterminate (and confirmed 
indeterminate on repeat) IGRA result for the current test when previous IGRA test results 
were negative. All study participants with positive or indeterminate IGRA test results must 
immediately stop IMP administration. In case of an IGRA test conversion, the study 
participant must be considered as having either a suspected new latent or an active TB 
infection and be promptly referred to an appropriate specialist (eg, pulmonologist, infectious 
disease specialist) for further evaluation. Additional assessments (eg, blood tests or IGRA, 
chest X-rays, or other imaging) should be performed where medically relevant and 
documented. Such conversions should be reported as AEs as described in the protocol. The 
AE term would need to be updated with final diagnosis once available. 
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10.7.9.3 
Latent TB infection 
In case the evaluation by the appropriate specialist diagnoses a new LTBI, the study 
participant must permanently stop IMP and be withdrawn from the study. A TB prophylactic 
therapy in accordance with applicable clinical guidelines might be initiated, if considered 
appropriate. 
Once withdrawn from study treatment, study participants should return for the Early 
Discontinuation Visit and complete all early discontinuation assessments, and complete an 
Final Visit (12 weeks after the last dose of IMP). LTBI must be reported as an AE. Follow-up 
reports should be completed as per protocol requirement until such time as the LTBI resolves. 
10.7.9.4 
Active TB or NTMB infection 
Study participants who develop active TB or NTMB infection during the study must be 
withdrawn from the study. The study participant must be immediately discontinued from 
study medication and an Early Discontinuation Visit must be scheduled as soon as possible, 
but no later than the next scheduled visit. The study participant should be encouraged to keep 
the Final Visit as specified by the protocol. Treatment should be started immediately. 
Note that study participants with history of or active NTMB infection are excluded from the 
study regardless of prior or current therapy for this condition. 
Confirmed active TB is always considered an SAE. UCB’s process requires that these must 
be captured on an SAE report form and provided to the Sponsor in accordance with SAE 
reporting requirements. Follow-up reports should be completed as per protocol requirement 
until such time as the TB infection resolves. 
10.7.9.5 
TB assessment by IGRA or tuberculin skin test (TST) 
During the Screening Period, the TB assessment by IGRA will be performed for all study 
participants (17 years and under). The IGRA (QuantiFERON®-TB GOLD In-Tube test) is the 
protocol-required method of screening for TB. A UCB validated central laboratory shall be 
responsible for interpreting the results of IGRA. The central laboratory must provide UCB 
with all assay values (both measured and calculated) in accordance with the approved test 
label or package insert. The IGRA negative result is as defined by the kit’s manufacturer. If a 
central laboratory is not easily accessible for IGRA, UCB will determine whether the test 
should be performed by a qualified local laboratory. 
If the result of the IGRA test is indeterminate, the test may be repeated once. If positive or 
indeterminate on retest, the study participant may not be enrolled. The retest must be done 
during the protocol-defined Screening window. 
For study participants 6 to 17 years of age, the TST is optional in some regions/locations, 
based on local guidelines or requirements taking into account the prevalence of TB in such 
countries.  
In countries with high bacillus Calmette-Guerin (BCG) vaccination or high TST positivity, it 
is not recommended to do the TST. The TST may be positive due to BCG vaccination. UCB 
will not permit enrollment of pediatric study participants without advice from physician with 
expertise in pediatric TB. 
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A positive TST is defined as an induration of ≥5mm occurring 48 to 72 hours after 
intradermal injection with 5 tuberculin units (TU) of either TST-S or 2TU of TST-RT23. The 
test must be performed and read by a TST qualified health care professional (per local 
guidelines). The exact measurement of the observed induration (in mm) must be documented 
in the study participant’s medical record at the same time that it is read. Documentation must 
include the date and time the test was performed, the testing field (site), and the date and time 
the test was read. 
During the conduct of the study, the TB assessment by IGRA can be repeated at the 
investigator’s discretion. The TST test should not be repeated during the conduct of the study. 
The test results will be reported as positive, negative, or indeterminate and must be reviewed 
by an experienced TB specialist, radiologist, or a pulmonologist. If the assessment by IGRA 
is positive or indeterminate on retest, the study participant must undergo appropriate study-
specified withdrawal procedures. The retest during Screening must be done during the 
protocol-defined Screening window. 
10.7.9.6 
TB assessment by chest x-ray 
Chest radiographic imaging is done at Screening and results must be available at Baseline 
before first drug administration, unless a chest x-ray or CT is available within 2 months prior 
to Screening. The chest x-ray must be clear of signs of TB infection (previous or current) 
before first study medication administration. The chest x-ray should be repeated only if the 
TB test was confirmed positive or any further evidence is suggestive of potential TB infection 
(eg, exposure). Radiographic findings suggestive of inactive TB or active TB may include but 
are not limited to: apical fibrosis, pleural thickening, pulmonary nodules, fibrotic scars, 
calcified granulomas, upper lobe infiltrates, cavitations and pleural effusions, calcified lung 
nodules, calcified hilar lymph nodes, and pericardial calcification. 
The chest imaging must be negative for old or recent TB infection as determined by a 
qualified radiologist and/or pulmonary physician. Any new clinically significant findings post 
Baseline on chest x-ray must be documented in the source documents and the eCRF as an 
AE. 
10.7.9.7 
TB risk factors via the TB questionnaire 
The TB questionnaire “Evaluation of signs and symptoms of tuberculosis” should be 
completed accurately and filed as a critical source document. The questionnaire will assist 
with the identification of study participants who may require therapy for TB. It will be 
completed as outlined in the schedule of assessments (Table 5-1). 
A “Yes” response to any of the questions in the TB questionnaire during the study should 
trigger further assessments to determine if the study participant has either LTBI or active TB 
infection and must be withdrawn from the study (see below for details). As an example, a 
study participant who answers “Yes” at Screening to the question “Has the participant been in 
close (eg, sleeping in the same room) contact with an individual with active TB, or an 
individual who has recently been treated for TB?” should not be allowed in the study pending 
further assessments (including TB specialist consult) to determine if the study participant has 
either LTBI or active TB infection. In case of any doubt, UCB recommends seeking the 
opinion of a TB specialist before starting or continuing study medication intake. 
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10.7.9.8 
TB management 
For inclusion in the study, see Section 6.2 (Exclusion Criteria). 
10.7.9.8.1 
Latent TB, active TB, or other NTMB infection identified during 
study 
During the study, study participants who develop evidence of LTBI, active TB, or NTMB 
infection must immediately stop further administration of study medication and will be 
referred to an appropriate TB specialist (pulmonologist or infectious disease specialist) for 
further evaluation and appropriate clinical management. Study participants must be 
withdrawn and scheduled to return for the Early Discontinuation Visit as soon as possible but 
no later than the next scheduled study visit and complete all Early Discontinuation Visit 
assessments. The study participant should be encouraged to complete the Final Visit 
(12 weeks after the last dose of IMP). 
If infection with NTMB is identified during the study, the same procedure as for active TB 
acquired during the study and compliant TB treatment shall be followed. 
10.7.9.8.2 
Tuberculosis testing during the study for study participants above 
and below 5 years of age 
Upon signing the updated Informed Consent form, all study participants need to undergo TB 
testing as described below. 
Study participants above 5 years of age 
IGRA testing (QuantiFERON) should be done once a year (approximately every 48 weeks) 
for all study participants from 5 to 17 years of age as described in Section 10.7.9.5. 
Study participants below 5 years of age 
At Screening, the TST and IGRA are both mandatory. Both these tests must be negative to be 
eligible for study inclusion (Note that some antihistaminics have the potential to interact with 
the TST response and render it negative). If either test is positive, the study participant should 
be referred to a TB specialist and the study participant must not initiate IMP. If the IGRA 
becomes positive during the study, the IMP administration must be stopped and study 
participants should be referred to TB specialist.  
In countries with high BCG vaccination or high TST positivity, it is not recommended to do 
the TST. The TST may be positive due to BCG vaccination, however UCB will not permit 
enrollment of pediatric study participants <5 years of age into a study without written 
approval from a physician with expertise in pediatric TB.  
IGRA testing (QuantiFERON) should be done once a year (approximately every 48 weeks) 
for all study participants below 5 years of age. There is currently no IGRA adapted to 
pediatrics in terms of blood volume required for the test (ie, no validated test performance 
with a smaller blood volume). Therefore, if a maximum cumulative blood draw volume is 
cited by an IRB/EC for a pediatric clinical study, exceptions may be made for other clinical 
lab assessments in order to accommodate the IGRA volume requirement. 
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11 
ASSESSMENT OF EFFICACY AND HEALTH OUTCOMES 
VARIABLES 
11.1 
PedACR30, PedACR50, PedACR70, and PedACR90 clinical 
response 
The PedACR30, PedACR50, PedACR70, and PedACR90 clinical responses rates 
(Giannini et al, 1997; Lovell et al, 2008) at every visit compared to Baseline (except the Final 
Visit) will be assessed. The assessments are based on a 30%, 50%, 70%, and 90% or greater 
improvement in at least 3 of the 6 core set measures with no more than 1 of the remaining 
worsened by >30%. The 6 core set measures are: 
 Number of joints with active arthritis (joints with swelling not due to deformity or 
inactive synovitis, or joints with limitation of motion with pain, tenderness, or both) 
 Number of joints with limitation of range of motion 
 Physician’s Global Assessment of Disease Activity (VAS) 
 CHAQ completed by parent or caregiver (Appendix 17.1) 
 Parent’s Global Assessment of Overall Well-Being (VAS) (Appendix 17.3) 
 Acute phase reactant (CRP) 
Documentation of the assessment of all 6 core set measures will be submitted to UCB or 
designee for immediate review of completeness at Week 0 (Baseline) and Week 24, while 
the study participant is still on site. 
11.2 
PRINTO/PRCSG standard joint examination 
The following 75 joints are to be examined for swelling, pain on motion (POM), tenderness, 
and limitation of motion (LOM) by the Investigator, another delegated physician, or an 
appropriately qualified medical professional (based on local requirements) who has had 
documented training on how to perform these assessments correctly. Preferably the same 
assessor should evaluate the study participant at each arthritis assessment, as per 
PRINTO/PRCSG guidelines. The individual with this delegated duty must be listed on 
Form 1572. 
 Upper body (6) - bilateral temporomandibular, sternoclavicular, and acromioclavicular 
joints 
 Upper extremity (34) - bilateral shoulders, elbows, wrists, metacarpals (MCP I, II, III, IV, 
and V), proximal interphalangeals (PIP I, II, III, IV, and V) and distal interphalangeals 
(DIP II, III, IV, and V) 
 Lower extremity (30) - bilateral hips, knees, ankles, subtalar, tarsi, metatarsophalangeals 
(MTP I, II, III, IV, and V), and proximal interphalangeals (PIP I, II, III, IV, and V) 
 Spinal (5) – cervical spine, thoracic spine, and lumbar spine, and bilateral sacroiliac joints 
The assessment for LOM is made on 69 joints from the above list. The sternoclavicular, 
acromioclavicular, and sacroiliac joints are excluded. The assessment for swelling is made on 
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66 joints from the above list. The hip, subtalar, cervical spine, thoracic spine, lumbar spine, 
and sacroiliac joints are excluded. Artificial and ankylosed joints are excluded from both 
tenderness and swelling assessments. 
Joint assessment will be based on a 2-point scale as unaffected (Grade 0) and affected 
(Grade 1). 
These assessments are completed at Screening, Baseline, and every visit (including 
Unscheduled Visits that are related to dose change) through the Early Discontinuation/End of 
Treatment Visit. 
11.3 
Number of joints with active arthritis and number of joints 
with limitation of range of motion 
The change in the number of joints with active arthritis and the change in the number of 
joints with limitation of range of motion will be assessed. Joint and joint motion assessments 
will be performed as part of the PRINTO/PRCSG standard joint examination. 
11.4 
Physician’s Global Assessment of Disease Activity (VAS) 
The Investigator will assess the overall status of the study participant with respect to their JIA 
signs and symptoms and functional capacity using a 0 to 100mm VAS where 0 is “very good, 
asymptomatic and no limitation of normal activities” and 100 is “very poor, very severe 
symptoms which are intolerable and inability to carry out all normal activities.” 
The Physician’s Global Assessment of Disease Activity (VAS) will be completed at 
Screening, Baseline, and every visit (including Unscheduled Visits that are related to dose 
change) through the Early Discontinuation/End of Treatment Visit. 
11.5 
Childhood Health Assessment Questionnaire (CHAQ) 
The Childhood Health Assessment Questionnaire (CHAQ) is an adaptation of the Health 
Assessment Questionnaire-Disability Index (HAQ-DI), which is a questionnaire developed to 
assess physical function in adults (Singh et al, 1994). The CHAQ was developed specifically 
as a measure of function for children with juvenile RA and the population evaluated for the 
development of this questionnaire comprised study participants between ages 1 to 19 years 
old with JIA. The CHAQ is a parent/caregiver-reported questionnaire and the recall period is 
“the past week.” 
The disability section of the CHAQ uses 30 questions (5-point Likert scale) to assess 
8 domains of daily living, namely dressing & grooming, arising, eating, walking, hygiene, 
reach, grip, and activities. In addition to the questions on activities of daily living, there are 
14 questions relating to the use of aids or devices, and 8 questions concerning activities in 
which assistance of another person is required. The CHAQ for use in children differs from 
the HAQ-DI in that several new questions have been added such that for each functional area, 
there is at least 1 question that is relevant to children of all ages. Further, to eliminate 
discrepancies introduced by growth and development, parents/caregivers are asked to note 
only those difficulties that are caused by arthritis. The question with the highest score 
determines the score for that functional area. If aids or devices are used or help is needed to 
complete tasks in a certain area, a minimum score of 2 is recorded for the corresponding 
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functional area. The scores for each of the 8 functional areas or domains are averaged to 
calculate the Disability Index which yields a score of 0 representing “no disability” to 3 
representing “very severe disability.” 
A copy of the CHAQ is provided in Appendix 17.1. The CHAQ will be completed by the 
parents/caregivers at Screening, Baseline, and every visit (including Unscheduled Visits that 
are related to dose change) through the Early Discontinuation/End of Treatment Visit. 
Preferably, the same parent/caregiver should complete the questionnaires for each visit. The 
questionnaire will not be collected if the study participant is not living with a parent/caregiver 
at least part-time, ie, if the parent/caregiver is not able to answer the questions appropriately. 
The questionnaire should be checked by site personnel for completeness. 
11.6 
Parent’s Assessment of Arthritis Pain (VAS) 
In the Parent’s Assessment of Arthritis Pain (VAS), the parent/caregiver is asked the 
following question “How much pain do you think your child has had because of his or her 
illness in the past week?” The parent/caregiver should then place a mark on a 100mm 
horizontal line to indicate the severity of the pain. This VAS 100mm line has as anchors 0mm 
representing “No Pain” and 100mm, “Very Severe Pain.” 
The Parent’s Assessment of Arthritis Pain (VAS) is provided in Appendix 17.2. The Pain 
(VAS) will be completed at Screening, Baseline, and every visit through the Early 
Discontinuation/End of Treatment Visit. Preferably, the same parent/caregiver should 
complete the scale for each visit. The scale will not be completed if the study participant is 
not living with a parent/caregiver at least part-time, ie, if the parent/caregiver is not able to 
answer the question appropriately. The scale should be checked by site personnel for 
completeness. 
11.7 
Parent’s Global Assessment of Overall Well-Being (VAS) 
In the Parent’s Global Assessment of Overall Well-Being (VAS), the parent/caregiver is 
asked the following question “Considering all the ways that arthritis affects your child, rate 
how your child is doing on the following scale by placing a mark on the line.” The 
parent/caregiver should then place a mark on a 100mm horizontal line ranging from 0 “Very 
well” to 100 “Very poor.” 
The Parent’s Global Assessment of Overall Well-Being (VAS) is provided in Appendix 17.3. 
The Parent’s Global Assessment of Overall Well-Being (VAS) will be completed at 
Screening, Baseline, and every visit (including Unscheduled Visits that are related to dose 
change) through the Early Discontinuation/End of Treatment Visit. Preferably, the same 
parent/caregiver should complete the scale for each visit. The scale will not be completed if 
the study participant is not living with a parent/caregiver at least part-time, ie, if the 
parent/caregiver is not able to answer the question appropriately. The scale should be checked 
by site personnel for completeness. 
11.8 
C-reactive protein (CRP) 
The acute phase reactant CRP will be analyzed by the central laboratory. Samples will be 
collected at Screening, Baseline, and every visit (including Unscheduled Visits that are 
related to dose change) through the Early Discontinuation/End of Treatment Visit. Values 
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will be used in determining PedACR clinical response, JADAS, CID and CRM, and ratio to 
Baseline in CRP. 
11.9 
JADAS 
The change in the JADAS from Baseline will be assessed. The JADAS-71 is a composite 
disease activity score based on a 71-joint count and includes the measures (normalized as 
needed): Physician’s Global Assessment of Disease Activity (VAS) (0 to 10), the Parent’s 
Global Assessment of Overall Well-Being (VAS) (0 to 10), the active joint count (0 to 71), 
and CRP (0 to 10) (Consolaro et al, 2009; Nordal et al, 2010).  
The JADAS will be completed at Screening, Baseline, and every visit through the Early 
Discontinuation/End of Treatment Visit. 
Values of CRP will be normalized to a 0 to 10 scale as follows: if CRP is expressed in mg/dl, 
any values above 10 are converted to 10. If expressed in mg/L, the value will be first divided 
by 10 and then any values above 10 will be converted to 10. 
Values below the minimum threshold for the method used for CRP determination are 
converted to 0. 
The JADAS is calculated as the linear sum of the scores of the 4 components with a total 
score range of 0 to 101. 
11.10 
Clinically Inactive Disease and clinical remission 
Criteria for Clinically Inactive Disease (CID) are defined as follows (Wallace et al, 2011):  
 No joints with active arthritis* 
 No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to 
JIA 
 No active uveitis as defined by the Standardization of Uveitis Nomenclature Working 
Group** 
 ESR or CRP within normal limits in the laboratory where tested or, if elevated, not 
attributable to JIA 
 Physician’s Global Assessment of Disease Activity score of best possible on the scale 
used (0mm on the 100mm VAS)  
 Duration of morning stiffness of ≤15 minutes 
All criteria must be met. 
* Note: The American College of Rheumatology defines a joint with active arthritis as a joint 
with swelling not due to bony enlargement or, if no swelling is present, limitation of motion 
accompanied by either pain on motion and/or tenderness. An isolated finding of pain on 
motion, tenderness, or limitation of motion on joint examination may be present only if 
explained by either prior damage attributable to arthritis that is now considered inactive or 
nonrheumatologic reasons, such as trauma. 
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** Note: The Standardization of Uveitis Nomenclature Working Group defines inactive 
anterior uveitis as “grade zero cells,” indicating <1 cell in field sizes of 1mm by a 1mm slit 
beam. 
Clinical remission on medication (CRM) is defined as criteria for CID achieved for at least 
6 continuous months (Wallace et al, 2004; Wallace et al, 2009). 
Clinically Inactive Disease will be assessed at every post-Baseline visit except the Final Visit. 
Clinical remission on medication will be assessed at every post-Baseline visit from Week 24 
onwards, except the Final Visit. 
Study participants achieving CRM, ie, after 6 months of continuous CID, may discontinue 
CZP treatment at the Investigator’s discretion following consultation with the Sponsor to 
confirm remission status. Study participants who have discontinued CZP due to achieving 
CRM will be allowed to remain in the study and continue with scheduled study visits. Study 
participants not maintaining persistent CID following achievement of CRM will be allowed 
to resume CZP treatment at any time at the Investigator’s discretion and consultation with the 
Sponsor. If a study participant is on concomitant MTX treatment, the Investigator may decide 
to decrease and ultimately discontinue the MTX dose after complete discontinuation of CZP. 
Study participants not maintaining persistent CID following achievement of CRM and 
resuming treatment will restart the fixed-dose CZP dosing based on their current weight with 
3 loading doses of CZP administered Q2W over 6 weeks, followed by a maintenance dose 
administered Q2W for the duration of the study, with exception of the lowest weight group 
on the reduced dose regimen, who will receive the maintenance dose Q4W.  
11.11 
Duration of morning stiffness (DMS) 
Morning stiffness is defined by the time elapsed between the time of usual awakening (even 
if not in the morning) and the time the study participant is as limber as he/she will be during a 
day involving typical activities. The study participant/caregiver will be asked the following 
question (Kirwan and Reeback, 1986): 
“How long does it take, from the time you (your child) wake up, for you (your child) to 
become as limber as you (your child) will be?” 
For those experiencing relief, the actual hours elapsed should be recorded no matter how 
long. The duration in hours and minutes will be recorded. For those study participants with 
unrelenting stiffness, 24 hours should be recorded. 
Duration of morning stiffness will be assessed at Baseline and at every visit through the Early 
Discontinuation/End of Treatment Visit. 
11.12 
Faces Pain Scale-Revised (FPS-R) 
The Faces Pain Scale-Revised (FPS-R) is a self-reported measure used to assess the intensity 
of children’s pain (Hicks et al, 2001). The original version of the scale consists of 7 faces 
increasing in pain intensity and approximating equal intervals as assessed by children 
(Bieri et al, 1990). Children have to select a level on the scale that matches their own pain. A 
numerical value is associated with the different levels on the scale. The FPS-R was adapted 
from the FPS in order to make scoring possible on the widely accepted 0 to 10 metric. It 
includes 6 faces (instead of 7). This tool has been validated for children aged 5 to 12 years 
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and will be assessed in children ages 5 to 11 years. Study participants enrolled at 5 to 11 
years of age will continue with the FPS-R when reaching 12 years of age. Completion of the 
FPS-R will not be required for study participants enrolled at 2 to 4 years of age if they reach 
5 years of age during the study. 
The FPS-R is provided in Appendix 17.4. The FPS-R will be administered at Baseline and 
then daily during the first week of the study; at Weeks 4, 12, 16, 24, and then every 8 weeks 
thereafter (for study participants enrolled prior to Protocol Amendment 9, visit frequency 
changes to every 16 weeks instead of every 8 weeks following implementation of Protocol 
Amendment 8) through the Early Discontinuation/End of Treatment Visit. The questionnaire 
should be checked by site personnel for completeness. 
11.13 
Patient’s Assessment of Arthritis Pain (JIA Pain VAS) 
In the JIA Pain VAS, study participants aged 12 years or older are asked the following 
question “How much pain have you had because of your illness today (acute version)/in the 
past week (standard version)?” (as applicable). The study participant should then place a 
mark on a 100mm horizontal line to indicate the severity of the pain. This VAS 100mm line 
has as anchors 0mm representing “No Pain” and 100mm, “Very Severe Pain.” 
Both versions of the JIA Pain VAS are provided in Appendix 17.5 and Appendix 17.6. The 
Pain (VAS) will be completed at Baseline (acute and standard versions), daily during the first 
week of treatment (acute version); Weeks 4, 12, 16, 24, and then every 8 weeks thereafter 
(for study participants enrolled prior to Protocol Amendment 9, visit frequency changes to 
every 16 weeks instead of every 8 weeks following implementation of Protocol 
Amendment 8) through the Early Discontinuation/End of Treatment Visit (standard version). 
The scale should be checked by site personnel for completeness. 
11.14 
Fatigue Assessment Scale (NRS) 
The study participant’s level of tiredness (fatigue) will be assessed by the Fatigue Assessment 
Scale (numeric rating scale [NRS]) where the parent/caregiver are asked the following 
question: 
"Please rate your child's fatigue (weariness, tiredness) during the past week on a scale of 
0 to 10" where 0 is "No fatigue" and 10 is "Fatigue as bad as you can imagine." 
The recall period for this instrument is the past week. 
The Fatigue Assessment Scale is provided in Appendix 17.7. The Fatigue Assessment Scale 
will be assessed at Baseline, Weeks 1, 2, 4, 8, and then every 8 weeks thereafter (for study 
participants enrolled prior to Protocol Amendment 9, visit frequency changes to every 16 
weeks instead of every 8 weeks following implementation of Protocol Amendment 8) and the 
Early Discontinuation/End of Treatment Visit. Preferably, the same parent/caregiver should 
complete the scale for each visit. The scale will not be completed if the study participant is 
not living with a parent/caregiver at least part-time, ie, the parent/caregiver is not able to 
answer the question appropriately. The scale should be checked by site personnel for 
completeness. 
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11.15 
Juvenile Arthritis School Attendance and Caregiver Work 
Productivity Survey 
The Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey is a 
parent/caregiver-reported self-administered questionnaire, which captures information related 
to the impact of the disease on the child’s ability to participate in school and 
social/after-school activities and evaluate the impact of disease on the parent or caregiver’s 
productivity at their paid work and in the household. The same parent/caregiver should 
complete the questionnaire at each visit. The recall period, for the questions relating to the 
child’s school attendance and parent/caregiver’s work productivity, is the past 4 weeks. This 
survey collects information related to eg, the child’s attendance to school, number of school 
days missed due to the disease, number of school days impacted due to the disease, level of 
difficulty in performing school activities, the parent or caregiver’s employment status, 
number of days missed from work due to the child’s disease, number of days with work 
productivity reduced by half or more due to child’s disease, days with no household work due 
to child’s disease, days with productivity within household reduced by half or more due to 
child’s disease. For further information please see the instructions provided on the worksheet. 
The Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey 
(parent/caregiver) will be assessed at Baseline, Week 4 and every visit through the Early 
Discontinuation/End of Treatment Visit. The full questionnaire and instructions are provided 
in Appendix 17.8. 
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 
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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 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. 
Some data will be recorded directly in the CRF and will not appear in a source document as 
defined in the Source Data Verification (SDV) form. 
Source documents that are computer-generated and stored electronically do not need to be 
printed if the electronic medical record system at the investigational site is 21CFR Part 11 
compliant. If the system is not 21CFR Part 11 compliant, the source data 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 study participant’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, study participant files, recordings from automated 
instruments, tracings [ECG], x-ray films, laboratory notes).  
The procedures for conducting SDV on computerized study participant records (if the system 
is 21CFR Part 11 compliant) are the same as those for paper records. Source data verification 
is performed by reviewing the electronic record directly. 
All data reported on the CRF should be supported by source documents, unless otherwise 
specified in Section 12.2.1. 
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12.3 
Data handling 
12.3.1 
Case report form completion 
This study will use RDC. The Investigator is responsible for prompt reporting of accurate, 
complete, and legible data in the electronic CRFs and in all required reports. 
Any change or correction to the CRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) must be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the 
electronic 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. The data are entered into the electronic CRFs once and are 
subsequently verified. 
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. 
12.3.3 
Study participant screening and enrollment log/Study participant 
identification code list 
The study participant’s screening and enrollment will be recorded in the study participant 
screening and enrollment log. 
The Investigator will keep a study participant identification code list. This list remains with 
the Investigator and is used for unambiguous identification of each study participant. 
The study participant’s consent and enrollment in the study must be recorded in the study 
participant’s medical record. These data should identify the study and document the dates of 
the study participant’s participation. 
12.4 
Termination of the study 
A futility analysis of the PedACR30 response rate was performed after all active study 
participants on the reduced CZP dose had completed the Week 16 (Visit 8) assessments. If 
less than 50% of the study population enrolled on the reduced CZP dose regimen (Protocol 
Amendment 5) achieved a PedACR30 response at Week 16, the study was to be 
discontinued. The futility analysis confirmed that ≥50% of the study population enrolled on 
the reduced CZP dose regimen achieved a PedACR30 response at Week 16. A further futility 
analysis will not be performed using the additional participants that will be enrolled on the 
original CZP dose regimen following the implementation of Protocol Amendment 9.  
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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. 
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 study participants enrolled have been protected, that enrolled study participants (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). 
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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). Any deviations from the final SAP, as well as changes 
from the protocol, will be detailed in the Clinical Study Report. 
13.1 
Definition of analysis sets 
 The Enrolled Set (ES) will consist of all study participants who have given informed 
consent.  
 The Safety Set (SS) will consist of all study participants in the ES who have received at 
least 1 dose of study medication.  
 The Full Analysis Set (FAS) will consist of all study participants in the SS who have a 
valid Baseline and valid post-Baseline efficacy measurement.  
 The Pharmacokinetic Per-Protocol (PK-PP) Population is a subset of the SS consisting of 
those study participants who took at least 1 dose of study medication, provided 
measurable plasma samples (with recorded sampling time) on at least 1 occasion and who 
had no important protocol deviations affecting the PK parameters, as confirmed during a 
preanalysis review prior to locking the database. This population will be used for the 
PopPK model and for all presentations of plasma concentration and PK data.  
 The Pharmacokinetic-Pharmacodynamic (PK-PD) Population will consist of all study 
participants in the SS who have at least 1 post-Baseline plasma concentration 
measurement and 1 post-Baseline PedACR30 assessment.  
13.2 
General statistical considerations 
The Baseline value is defined as the last nonmissing pretreatment measurement. 
13.2.1 
Data presentation 
For safety and efficacy analyses, study participants will be grouped by their Baseline weight 
strata (10 to <20kg [22 to <44lb], 20 to <40kg [44 to <88lb], and ≥40kg [≥88lb]). Selected 
analyses will also group study participants by their Baseline age group, concomitant MTX 
use, and anti-CZP antibody status. Subgroups defined by CZP dosing regimen will also be 
displayed. Two CZP dosing regimen subgroups will be defined as follows: 
 Original CZP dose regimen: includes all study participants in the SS who began treatment 
in accordance with the original dosing regimen defined for the study (3 loading doses of 
CZP at Weeks 0, 2, and 4 [minimum=100mg Q2W, maximum=400mg Q2W] followed 
by a maintenance dose for the duration of the study [minimum=50mg Q2W, 
maximum=200mg Q2W]). This subgroup includes all study participants who began the 
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study with this CZP dose regimen and received 1 or more doses of this regimen, 
regardless of any subsequent switch to the reduced CZP dose regimen. 
 Reduced CZP dose regimen: includes all study participants in the SS who began 
treatment in accordance with the reduced dosing regimen defined for the study (3 loading 
doses of CZP at Weeks 0, 2, and 4 [minimum=50mg Q2W, maximum=200mg Q2W] 
followed by a maintenance dose for the duration of the study [minimum=50mg Q4W, 
maximum=100mg Q2W]). This subgroup includes all study participants who began the 
study with this CZP dose regimen and received 1 or more doses of this regimen, 
regardless of any subsequent switch to the original CZP dose regimen.  
Summary statistics will consist of frequency tables for categorical variables. For continuous 
variables, descriptive statistics (number of available observations, mean, median, standard 
deviation, minimum and maximum) will be presented. 
For those parameters likely to have a skewed distribution (eg, CRP), geometric means with 
associated coefficients of variation and/or quartiles may be presented. 
13.2.2 
Multicenter studies 
Approximately 55 centers are planned to enroll the original 156 study participants into this 
study. A subset of these centers will be used to enroll the additional 30 study participants 
following Protocol Amendment 9. The enrollment per site is limited to a maximum of 
12 study participants.  
13.2.3 
Coding dictionaries 
Medications will be coded with the World Health Organization Drug Dictionary and AEs will 
be coded according to MedDRA®. In both cases, the version used will be that current to the 
Sponsor at the time of data capture. 
13.3 
Planned safety analyses 
The incidence of serious TEAEs and TEAEs leading to permanent withdrawal of IMP will be 
assessed as primary safety variables in this study. Other safety variables include the incidence 
of TEAEs, TEAEs of interest, TEAEs by relatedness, TEAEs by severity, and TEAEs by 
duration of exposure. The primary summaries of safety will include all study participants in 
the SS, regardless of CZP dose. Safety variables will be summarized overall and separately 
for the 2 CZP dose regimens (original CZP dose regimen, reduced CZP dose regimen).  
Safety summaries will include presentations of AEs, extent of exposure, laboratory values 
(hematology and biochemistry), vital signs, concomitant medications and procedures, and 
autoantibody (ANA and anti-dsDNA antibodies) concentrations. Urinalysis results will be 
listed. Tanner stages will be presented by category. Growth as measured by height and weight 
will be assessed in relation to a comparative population and this may include an assessment 
of any change after treatment with CZP. 
For AEs, the exposure-adjusted incidence rate (EAIR) will also be calculated. For EAIR, the 
numerator will be the total number of study participants experiencing a particular AE. The 
denominator will be study participant-years, ie, the total summation of individual study 
participant-years at risk up to the first occurrence of the given AE for study participants with 
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that AE, plus the total study participant-years at risk for those study participants not 
experiencing that AE.  
For the original CZP dose regimen subgroup, in addition to the overall presentation of AEs, 
AEs will be summarized separately for the periods of exposure to original CZP dose regimen 
and the reduced CZP dose regimen, in addition to exposure for study participants that 
switched from the reduced CZP dose regimen to the original CZP dose regimen following 
Protocol Amendment 9. Additionally, the frequency and percentage of AEs reported during 
the first 16 weeks of study medication exposure will be summarized separately for the 2 CZP 
dose regimens (original CZP dose regimen, reduced CZP dose regimen). This analysis will be 
repeated, excluding any study participants who switched from the original to the reduced 
CZP dose regimen prior to Week 16. Selected safety summaries will be presented overall and 
by Baseline weight strata, as well as by age (2 to 5 years, 6 to 11 years, and 12 to 17 years), 
by concomitant MTX use, and by anti-CZP antibody status.  
13.4 
Planned PK, PD, and immunological variable analysis 
Certolizumab pegol plasma concentrations levels at Week 16 and Week 48 will be assessed 
as primary variables in this study. Other PK and immunological variables include CZP 
plasma concentrations at other study timepoints and anti-CZP antibody levels throughout the 
study.  
Plasma CZP concentrations will be used to build a PopPK model with the nonlinear mixed-
effect modeling (NONMEM) software. The model will be parameterized in terms of 
clearance, volume of distribution, and absorption rate constant. Details of the PopPK 
modeling procedures will be described in a separate data analysis plan. The pediatric PopPK 
model will be combined with PD data (PedACR) and if the data allow, an exposure response 
relationship will be derived. These modeling analyses and results will be reported separately. 
All study participants enrolled following Protocol Amendment 9 will have plasma CZP 
concentrations and anti-CZP antibodies analyzed using the ECLIA method. In addition, PK 
and ADA samples (for which sufficient volume is available) collected in this study prior to 
Protocol Amendment 9 will be analyzed with the ECLIA method.  
Data from the ECLIA method will constitute the study's main PK and anti-CZP antibody 
evaluations. As such, PK and anti-CZP antibody data generated with the original ELISA 
method will be reported as Listings. Plasma CZP concentration data generated by the ECLIA 
method will be tabulated and summarized (geometric mean, arithmetic mean, minimum, 
maximum, standard deviation and % coefficient of variation) by study dose regimen (original 
CZP dose regimen or reduced CZP dose regimen) for each PK sampling visit. Plasma 
concentration time curves will be plotted, along with respective individual anti-CZP antibody 
titers where available, separately for study participants who began treatment according to the 
original CZP dose regimen or the reduced CZP dose regimen, overall, and by Baseline age 
stratum. Subgroup analyses will include study participants enrolled with Protocol 
Amendment 9 and those treated up to the Week 16 timepoint under the original maintenance 
dosing regimen. Where available, individual ECLIA-based anti-CZP antibody data will be 
tabulated by study visit and Baseline age stratum (all study participants, 2 to 5 years, 6 to 
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11 years, and 12 to 17 years). In addition, safety and efficacy profiles by antibody titers (or 
titer categories) may be investigated.  
In addition, the effect of concomitant use of MTX versus monotherapy on CZP plasma 
concentration and incidence of anti-CZP antibodies will be evaluated. 
13.5 
Planned efficacy and health outcomes analyses 
Summary statistics will be presented for efficacy and health outcomes variables using the 
FAS.  
All efficacy and health outcomes variables results will be presented overall and separately for 
the 2 CZP dose regimens (original CZP dose regimen, reduced CZP dose regimen). 
The following efficacy variables are defined as secondary variables in this study: 
 PedACR30, PedACR50, PedACR70, and PedACR90 response rates at Week 16 as 
compared to Baseline. 
The following efficacy variables are defined as other variables: 
 PedACR30, PedACR50, PedACR70, and PedACR90 response rates at every visit except 
Week 16 and Final Visit as compared to Baseline. 
For PedACR30, PedACR50, PedACR70, and PedACR90, results will be presented overall 
and by Baseline weight strata, as well as by age (2 to 5 years, 6 to 11 years, and 12 to 
17 years), by concomitant MTX use, and by anti-CZP antibody status.  
 Change from Baseline in number of joints with active arthritis at every visit except Final 
Visit. 
 Change from Baseline in number of joints with limitation of range of motion at every 
visit except Final Visit. 
 Change from Baseline in Physician’s Global Assessment of Disease Activity (VAS) at 
every visit except Final Visit. 
 Change from Baseline in CHAQ at every visit except Final Visit. 
 Change from Baseline in Parent's Assessment of Arthritis Pain (VAS) at every visit 
except Final Visit. 
 Change from Baseline in Parent’s Global Assessment of Overall Well-Being (VAS) at 
every visit except Final Visit. 
 Ratio to Baseline in CRP at every visit except Final Visit. 
 Change from Baseline in JADAS at every visit except Final Visit. The JADAS is a 
composite disease activity score including the Physician’s Global Assessment of Disease 
Activity, the Parent’s Global Assessment of Overall Well-Being, the active joint count, 
and CRP. 
 Percentage of study participants with Clinically Inactive Disease (CID), as defined in 
Section 11.10, at every post-Baseline visit except Final Visit. 
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 Percentage of study participants with clinical remission on medication (CRM), as defined 
in Section 11.10, at every post-Baseline visit from Week 24 onwards except Final Visit. 
 Time (in days) to CID. 
 Time (in days) to CRM. 
 Change from Baseline in DMS at every visit except Final Visit. 
 Change from Baseline on FPS-R (child-reported, for study participants ages 5 to 11 
years), daily during the first 7 days of treatment; Weeks 4, 12, 16, 24, and then every 
8 weeks thereafter (for study participants enrolled prior to Protocol Amendment 9, visit 
frequency changes to every 16 weeks instead of every 8 weeks following implementation 
of Protocol Amendment 8) through the Early Discontinuation/End of Treatment Visit.  
 Change from Baseline in JIA Pain VAS, daily during the first week of the study (acute 
and standard versions); Weeks 4, 12, 16, 24, and then every 8 weeks thereafter (for study 
participants enrolled prior to Protocol Amendment 9, visit frequency changes to every 16 
weeks instead of every 8 weeks following implementation of Protocol Amendment 8) 
through the Early Discontinuation/End of Treatment Visit (standard version) for study 
participants ages 12 to 17 years. 
 Change from Baseline in Fatigue Assessment Scale at every visit except Weeks 12 and 
20, and Final Visit. 
 Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey responses 
at Baseline, Week 4, and every visit thereafter except Final Visit. 
13.6 
Handling of dropouts or missing data 
For all binary efficacy endpoints assessing response, study participants who withdraw early 
will be considered as non-responders from that time point onwards. The exception is efficacy 
data for study participants who withdraw after Week 56: Per Protocol Amendment 7, these 
will not be imputed (as nonresponse or missing) and will be analyzed as observed. 
For continuous efficacy endpoints, missing assessments will be imputed using the last 
observation carried forward (LOCF) approach. These summaries will be supported by 
observed case (OC) analyses. Per Protocol Amendment 7, missing assessments after Week 56 
will no longer be imputed and will be analyzed as observed. 
Data collected after the taking of rescue medication will be treated as missing for continuous 
efficacy endpoints and non-response for binary efficacy endpoints in all analyses except 
where specifically stated otherwise. See Section 7.8.2 for a list of medications which would 
result in data at only the next scheduled visit (and not all subsequent visits) being treated as 
missing/non-response. These data will then be imputed as for any other missing data. The 
exception is any rescue medication use that is initiated after Week 56: Per Protocol 
Amendment 7, efficacy data after any rescue medication use initiated after Week 56 will not 
be imputed (as nonresponse or missing) and will be analyzed as observed. 
Missing or partial dates for safety evaluations will be imputed and full details of these 
algorithms will be presented in the SAP. 
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As discussed in Section 13.2, Baseline is defined as the last nonmissing pretreatment 
measurement, therefore if available, data from the Screening visit will be used as Baseline 
values, if these data are missing at Week 0. 
No further imputations of any other missing data are planned (eg, efficacy data missing at 
random [MAR]). 
13.7 
Interim analysis and data monitoring 
A futility analysis of the PedACR30 response rate was performed after all active study 
participants enrolled on the reduced CZP dose had completed the Week 16 (Visit 8) 
assessments. If less than 50% of the study population enrolled on the reduced CZP dose 
regimen (Protocol Amendment 5) achieved a PedACR30 response at Week 16, the study was 
to be discontinued. The futility analysis confirmed that ≥50% of the study population enrolled 
on the reduced CZP dose regimen achieved a PedACR30 response at Week 16. Given the 
descriptive nature of the data presentations, there were no statistical implications of this 
interim analysis. A further futility analysis will not be performed using the additional study 
participants that will be enrolled on the original CZP dose regimen following the 
implementation of Protocol Amendment 9.  
In addition to the futility analysis, several interim analyses were planned, including interim 
analyses of PK data, and full interim analyses of PK, immunogenicity, safety, and efficacy 
endpoints, as described below. 
Interim analyses of PK data 
Per original protocol, if the pediatric plasma concentrations demonstrate that the geometric 
mean and median concentrations are below the adult 5th percentile or above the 95th 
percentile, the PK data will be used to re-evaluate the weight-based dose adjustment 
algorithm for pediatric study participants. Interim CZP plasma concentration data available at 
the time of Protocol Amendment 3 indicated that no change to the dosing algorithm was 
required. The protocol stated that if future interim analyses, which may include PopPK, 
indicate that plasma concentrations of JIA study participants are outside of the exposure 
range observed in previous adult RA studies, a revised pediatric dose algorithm will be 
derived. Any change in dose regimen will require a protocol amendment prior to 
implementation. 
An interim analysis of PK data conducted following Protocol Amendment 3 compared CZP 
plasma concentration data from this study with CZP plasma concentrations observed 
previously in adult study participants with RA. Interim analysis of CZP plasma 
concentrations was started when 6 study participants in 1 of the age groups completed 
Week 12 (Visit 7). Comparisons were made between the Week 12 geometric mean and 
median values for the pediatric and adult study participants, as well as between the individual 
pediatric data and the adult 5th and 95th percentile and minimum and maximum observed 
values. 
Based on results of this interim PopPK analysis (also described in Section 5.1), the dosing 
regimen was changed with Protocol Amendments 4 and 5, and the doses to be administered 
were reduced by 50% for all weight groups. This change was intended to achieve plasma 
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concentrations similar to the effective concentrations observed in previous studies in adult 
study participants with RA.  
Interim analyses of PK, immunogenicity, safety, and efficacy endpoints 
An interim analysis of PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants that were enrolled and treated prior to implementation of 
Protocol Amendment 9 had completed the Week 24 (Visit 10) assessments, and the results 
were reported separately. An interim analysis, including all enrolled participants, for all PK, 
immunogenicity, safety, and efficacy endpoints will be performed after all active study 
participants, including those enrolled following the implementation of Protocol 
Amendment 9, have completed the Week 24 (Visit 10) assessments. 
Further interim analyses may be performed at the Sponsor’s discretion as required. 
A DSMB will periodically review emerging safety and efficacy data. The DSMB members 
will be independent of the Sponsor and Investigators. The DSMB members will be informed 
by the Patient Safety representative (or designee) of all SAEs at the time of expedited 
reporting and will periodically review emerging safety data (eg, SAEs, AEs, safety laboratory 
data) and efficacy data, as applicable, during the course of the study. Based on the safety 
data, the DSMB can recommend modifying/stopping the study. 
13.8 
Determination of sample size 
Based upon the ICH guideline for the assessment of safety, it is planned to enroll a sufficient 
number of study participants to this study to have a minimum of 100 with at least 12 months 
continuous exposure to CZP. Assuming a dropout rate of approximately 20%, it was 
originally determined that 125 study participants would need to be enrolled. At the time of 
Protocol Amendment 5, 78 study participants had been enrolled according to the original 
CZP dose regimen, and it was planned to enroll a further 78 study participants on the reduced 
CZP dose regimen, so that a comparable number of study participants on the reduced CZP 
dose regimens could be analyzed. Thus, the total number of study participants planned to be 
enrolled was increased to 156 study participants. Assuming a Screening failure rate of 25%, it 
is planned to screen 195 study participants in total. 
With Protocol Amendment 9, an additional 30 study participants will be enrolled on the 
original dose regimen with the aim to enroll at least 5 study participants in each weight range 
of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and ≥40kg (≥88lb). 
Prior to the start of study conduct, simulations using the adult population PK model in 
pediatric study participants with JIA suggested that the planned sample size of 125 study 
participants was adequate for PK assessment purposes. Individual apparent clearance (CL/F) 
and volume of distribution (V/F) were simulated for a total of 125 study participants (using 
the same approach presented in C87079 report addendum 08 Oct 2008 performed for 
190 study participants). In all age groups, the standard errors of both PK parameters, CL/F 
and V/F, relative to their mean were substantially <20%, with values ranging from 5.5 to 
7.0% for CL/F and from 4.6 to 7.5% for V/F. A tabular summary of the results is presented 
below. 
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Table 13-1 
PK simulation results for 125-study participant study sample size 
Parameter 
Age group (years) 
Mean 
Standard error 
Standard error/ 
Mean (%) 
CL/F 
4 to 8 
0.253 
0.015 
6.0 
 
9 to 12 
0.356 
0.025 
7.0 
 
13 to 17 
0.432 
0.024 
5.5 
V/F 
4 to 8 
2.90 
0.134 
4.6 
 
9 to 12 
4.80 
0.358 
7.5 
 
13 to 17 
6.80 
0.334 
4.9 
CL/F=apparent clearance; PK=pharmacokinetic; V/F=apparent volume of distribution 
Data from all 186 study participants will be included in the final PopPK analysis, and 
therefore should allow CL/F and V/F to be determined with sufficient precision. 
14 
ETHICS AND REGULATORY REQUIREMENTS 
14.1 
Informed consent 
Adequate information will be provided to the study participant and his/her parent(s)/legally 
acceptable representative(s) in both oral and written form and consent will be obtained in 
writing prior to performance of any study specific procedure. The content and process of 
obtaining informed consent will be in accordance with all applicable regulatory and IRB/IEC 
requirements. 
All IRBs which oversee US research must be registered with the FDA. 
UCB will provide a sample informed consent form, child assent form, and study participant 
information sheet. The final consent form must be approved by the IRB/IEC and should 
contain the applicable ICH-GCP elements in a language readily understood by the study 
participant (ie, lay terminology). 
If the informed consent 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. 
For the US sites a Health Insurance Portability and Accountability Act (HIPAA) agreement 
will be provided if required by the IRB or institution. 
The Investigator or designee should fully inform the study participant about all pertinent 
aspects of the study including the fact that the protocol has been granted the approval of the 
IRB/IEC and local regulatory authorities if required. 
Study participants and their parent(s)/legally acceptable representative(s) will be informed of 
the purpose of the study in unambiguous language they easily understand. Their participation 
is voluntary and they can at any time decide to stop their participation without any influence 
on their future care or treatment. The study participants and their parent(s)/legally acceptable 
representative(s) must be informed about the main procedures used to guarantee their 
anonymity, especially during the analysis of their personal data. Study participants and their 
parent(s)/legally acceptable representative(s) should be able to ask any questions about the 
study and to receive relevant answers. 
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After having received extensive information about the purpose and risks of the study and 
having had enough time to consider participation in the study, the study participant’s 
parent(s)/ legally acceptable representative(s) or legal guardian must give their written 
consent by signing and dating the Informed Consent Form. This form will also be signed and 
dated by the person who obtained the informed consent and then retained by the Investigator. 
If applicable, a child assent form may be used. This form will also be dated and signed by the 
study participant and by the person who obtained the child assent and then retained by the 
Investigator. Obtaining of consent (and child assent, where applicable) will be confirmed in 
the study participant’s medical records. The study participant’s parent(s)/legally acceptable 
representative(s) will receive a copy of the signed and dated consent form (and child assent, 
where applicable) and the original will be filed in the Investigator’s Study File. 
The study participants and their parent(s)/legally acceptable representative(s) may withdraw 
their consent to participate in the study at any time. A study participant is considered as 
enrolled in the study when his/her parent(s)/legally acceptable representative(s) has signed 
the informed consent form (and child assent, where applicable). A CRF must not be started, 
nor may any study specific procedure be performed for a given study participant, without 
having obtained his/her parent’s or legally acceptable representative’s written consent to 
participate in the study. 
If any new information that could influence the study participant’s decision to stay in the 
study becomes available, this information will be transmitted to the study participant’s 
parent(s)/legally acceptable representative(s) without delay. In addition, the informed consent 
form (and child assent form where applicable) must be amended accordingly or a separate 
consent form (and child assent form where applicable) be created and submitted to the 
IRB/IEC for approval prior to being implemented for reconsent (and child assent) of all 
ongoing study participants in the study and for use in obtaining consent from all 
parent(s)/legally acceptable representative(s) of study participants (and child assent) who 
enter the study from that point forward. 
Adequate information will be provided to the study participant and his/her parent(s)/legally 
acceptable representative(s) in both oral and written form and consent (and child assent) will 
be obtained in writing prior to performance of any study specific procedure. The content and 
process of obtaining informed consent (and child assent) will be in accordance with all 
applicable regulatory and IRB/IEC requirements. 
14.2 
Study participant identification cards 
Upon signing the informed consent form and child assent form (as applicable), the study 
participant or legal representative will be provided with a study participant identification card 
in the language of the study participant. The Investigator will fill in the name of the study and 
medical emergency contact information. The Investigator will instruct the study 
participant/legal representative to keep the card with them at all times. 
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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, IB, Investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other study participant-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 study participants or others, and any 
protocol deviations, to eliminate immediate hazards to study participants. 
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 study 
participants. 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 study 
participant 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. 
14.4 
Study participant privacy 
UCB staff (or designee) will affirm and uphold the study participant’s confidentiality. 
Throughout this study, all data forwarded to UCB (or designee) will be identified only by the 
study participant number assigned at Screening. 
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 study participant’s primary medical records that directly concerns this study 
(including, but not limited to, laboratory test result reports, ECG reports, admission/discharge 
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summaries for hospital admissions occurring during a study participant’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 
Bieri D, Reeve RA, Champion GD, Addicoat L, Ziegler JB. The Faces Pain Scale for the 
self-assessment of the severity of pain experienced children: development, initial validation, 
and preliminary investigation for ratio scale properties. Pain. 1990;41:139-50. 
Centers for Disease Control and Prevention. http:www.cdc.gov/TB/topic/testing/default.htm. 
Accessed 03 Sep 2012. 
Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S, Filocamo G et al. 
Development and validation of a composite disease activity score for juvenile idiopathic 
arthritis. Arthritis Rheum. 2009;61:658-66. 
European Medicines Agency. Ethical Considerations for Clinical Trials on Medicinal 
Products Conducted with the Paediatric Population.2008. 
http://ec.europa.eu/health/files/eudralex/vol-10/ethical_considerations_en.pdf. Accessed 
13 Jul 2011. 
FDA Guidance for Industry – Bioanalytical Method Validation. 2018. 
FDA. Guidance for Industry – E11 Clinical Investigation of Medicinal Products in the 
Pediatric Population. 2000. 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129477.pdf. Accessed 
13 Jul 2011. 
Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition 
of improvement in juvenile arthritis. Arthritis Rheum. 1997;40:1202-9. 
Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain 
Scale-Revised: toward a common metric in pediatric pain measurement. Pain. 
2001;93(2):173-83. 
International League of Associations for Rheumatology Classification of Juvenile Idiopathic 
Arthritis: Second Revision, Edmonton. J Rheumatol. 2004;31(2):390-2. 
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Kirwan JR, Reeback TS. Stanford Health Assessment modified to assess disability in British 
patients with rheumatoid arthritis. Br J Rheumatol. 1986;25:206–9. 
Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, et al. Etanercept 
in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology 
Collaborative Study Group. N Engl J Med. 2000 Mar 16;342(11):763-9. 
Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, et al. Adalimumab with or 
without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359:810-20.  
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. 
Nigrovic PA, White PH. Care of the adult with juvenile rheumatoid arthritis. Arthritis 
Rheum. 2006;55:208-16. 
Nordal E, Zak M, Berntson L, Aalto K, Peltoniemi S, Nielsen S, et al. Validation of the 
Juvenile Arthritis Disease Activity Score (JADAS) based on C-reactive protein in a 
population-based Nordic cohort of juvenile idiopathic arthritis. Pediatric Rheumatology 
European Society Congress, Valencia, Spain. 2010: Poster abstract; p.164. 
Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369:767-78. 
Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in children with 
juvenile rheumatoid arthritis. Arthritis Rheum. 1994;37:1761-9. 
Tocilizumab (RoActemra®), Summary of Product Characteristics. Roche Registration 
Limited, United Kingdom. July 2010. 
Vastert SJ, Kuis W, Grom AA. Systemic JIA: New Developments in the Understanding of 
the Pathophysiology and Therapy. Best Pract Res Clin Rheumatol. 
2009 October;23(5):655-64. 
Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology 
provisional criteria for defining clinical inactive disease in select categories of juvenile 
idiopathic arthritis. Arthritis Care Res. 2011;63:929-36. 
Wallace CA, Giannini EH, Ruperto N. Optimization of the provisional criteria for clinically 
inactive disease for select categories of juvenile idiopathic arthritis. Arthritis Rheum. 
2009;60(10 Suppl):749-50. 
Wallace CA, Ruperto N, Giannini EH. Preliminary criteria for clinical remission for select 
categories of juvenile idiopathic arthritis. J Rheum. 2004;31:2290-4. 
Zitelli B, McIntire S, Nowalk A. Zitelli and Davis’ Atlas of pediatric physical diagnosis, 6th 
edition. Chapter 7: Rheumatology, Section: Juvenile Idiopathic Arthritis. Elsevier Health 
Sciences, 2012, 264. 
 
 
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17 
APPENDICES 
Scales in the appendix are intended for information only and are not to be copied for use in 
data collection. The actual CRF page may differ in format or presentation from what is 
contained in the protocol appendix. 
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17.1 
Childhood Health Assessment Questionnaire (CHAQ) 
1 
CHILDHOOD HEALTH ASSESSMENT QUESTIONNAIRE 
2 
 
 
 
 
 
 
 
 
In this section we are interested in learning how your child's illness affects his/her ability to function in daily life. Please feel free 
to add any comments on the back of this page. In the following questions, please check the one response which best describes your 
child's usual activities (averaged over an entire day) OVER THE PAST WEEK. ONLY NOTE THOSE DIFFICULTIES OR 
LIMITATIONS WHICH ARE DUE TO ILLNESS. If most children at your child's age are not expected to do a certain activity, 
please mark it as "Not Applicable". For example, if your child has difficulty in doing a certain activity or is unable to do it 
because he/she is too young but not because he/she is RESTRICTED BY ILLNESS, please mark it as "NOT Applicable". 
 
  
 
 
 
 
 
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© Singh G:  Arthritis Rheum 1994; 37:1764-9.  For information and permission to use, please 
contact gsingh@stanford.edu 
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17.2 
Parent’s Assessment of Arthritis Pain (VAS) 
 
17.3 
Parent’s Global Assessment of Overall Well-Being (VAS) 
 
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17.4 
Faces Pain Scale-Revised 
 
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17.5 
Patient’s Assessment of Arthritis Pain 
(JIA Pain VAS, acute version) 
 
17.6 
Patient’s Assessment of Arthritis Pain 
(JIA Pain VAS, standard version) 
 
17.7 
Fatigue Assessment Scale (NRS) 
 
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17.8 
Juvenile Arthritis School Attendance and Caregiver Work 
Productivity Survey  
 
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17.9 
TB questionnaire 
 
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17.10 
Liver Safety – Suggested Actions and Follow-up Assessments 
17.10.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.4, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as AEs and reported to the study site and sponsor within 24 hours of learning of 
their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 10.3), and, if applicable, also reported as an 
SAE (see Section 10.2). 
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 17‒1 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 17.10.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 17.10.1.4). 
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
Table 17‒1 summarizes the approach to investigate PDILI. 
 
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Table 17‒1: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptoms a of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULN b 
NA 
Hepatology consult.c 
Medical Monitor 
must be notified 
within 24 hours 
(eg, by laboratory 
alert) and participant 
discussed with 
Medical Monitor 
ASAP. 
Immediate, 
permanent IMP 
discontinuation. 
Essential: Must 
have repeat liver 
chemistry values 
and additional 
testing completed 
ASAP (see 
Section 17.10.1.3
); recommended 
to occur at the 
site with HCP. 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
values.d 
≥8xULN 
NA 
NA 
≥3xULN 
NA 
Yes 
Immediate, 
temporary or 
permanent, IMP 
discontinuation. 
≥3xULN 
(and ≥2x 
baseline) 
and 
<5xULN 
<2xULN 
No 
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for IMP continuation 
is met. 
Further investigation 
– immediate IMP 
discontinuation not 
required (see 
Section 17.10.1.2). 
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator). 
≥5xULN 
(and ≥2x 
baseline) 
<2xULN 
No 
Discussion with 
Medical Monitor 
required. 
Immediate, 
permanent IMP 
discontinuation. 
Essential: Every 
attempt must be 
made to have 
repeat liver 
chemistry values 
and additional 
testing completed 
within 48 hours 
at the site with 
HCP (see 
Section 17.10.1.3
). 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
values.d 
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ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal 
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause). 
b If the participant also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
c Details provided in Section 17.10.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d Unless an alternative monitoring schedule is agreed by the investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
 
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17.10.1.1 
Consultation with Medical Monitor and local hepatologist 
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the participant must be discussed with the Medical 
Monitor as soon as possible. If required, the participant must also be discussed with the local 
hepatologist. The local hepatologist is the expert usually consulted by the treating physician 
for assessment and management of potential hepatic disease. This would usually be a 
hepatologist, but may be a gastroenterologist. If determined necessary, this discussion should 
be followed by a full hepatology assessment (see Section 17.10.1.3) and SAE report (if 
applicable). 
17.10.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring. 
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) 
to immediate and permanent discontinuation (see Section 6.4 and Table 17‒1 for details). 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any 
medically required concomitant medication known to be hepatotoxic to a suitable alternative. 
17.10.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events 
when there is a reasonable possibility that they may have been caused by the IMP are detailed 
in Table 17‒2 (laboratory measurements) and Table 17‒3 (additional information). Results of 
the laboratory measurements and information collected are to be submitted to the sponsor on 
the corresponding eCRFs. If the medical history of the participant indicates a requirement for 
other assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid 
results, a concurrent sample should also be sent to the central laboratory whenever possible. 
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The following measurements are to be assessed: 
Table 17‒2: PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain heterophile 
antibody or monospot testing) 
Immunology 
Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation 
Additional 
Prothrombin time/INR a 
Serum pregnancy test 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; 
LDH=lactate dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; 
RNA=ribonucleic acid; ULN=upper limit of normal 
a Measured only for participants with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause). 
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The following additional information is to be collected: 
Table 17‒3: PDILI information to be collected 
New or updated information 
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included. 
Pertinent medical history, including the following: 
 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”) 
 
Adverse reactions to drugs 
 
Allergies 
 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency) 
 
Recent travel 
 
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash) 
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Alcohol and illicit drug use 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Any postmortem/pathology reports 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury 
17.10.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 17‒1. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to baseline. Determination of stabilization is at the discretion of the investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
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17.11 
Protocol Amendment 1 
The version of the protocol dated 14 Jan 2010 was submitted to FDA on 28 Jan 2010. This 
version has not been submitted to any other regulatory authorities, IRBs/IECs, or 
Investigators. Therefore the integrated protocol contains only the rationale for the amendment 
and a general summary of changes. The detailed changes to the protocol dated 14 Jan 2010 
are available upon request. 
Rationale for the amendment 
The primary purpose of this substantial protocol amendment is to revise the protocol in line 
with change requests from health authorities following discussions on the CZP pediatric 
arthritis development program.  
In addition, a list of anticipated SAEs for CZP in the JIA population was added based on the 
FDA Final Rule on safety reporting for IND studies. 
Further key revisions include updates of eligibility criteria, update of the protocol to current 
terminology used in the rheumatology community and to current company standards, and 
clarification of assessments and concomitant medications. In addition, administrative and 
editorial changes were made to update study personnel, rearrange the schedule of study 
assessments to group related assessments, and correct typographical errors. 
Modifications and changes 
Global changes 
The following changes were made throughout the protocol: 
 The Sponsor name has been changed from “SCHWARZ BIOSCIENCES GmbH – A 
Member of the UCB Group of Companies” to “UCB BIOSCIENCES GmbH.” 
 The assessments of vital signs and laboratory parameters previously included in the 
primary safety variable have been redefined as “other” safety variables. The primary 
safety variable is the incidence of AEs.  
 The assessment of the effectiveness of CZP on the clinical response in children and 
adolescents with moderate to severe polyarticular-course JIA was added as a secondary 
objective. 
 In line with the change above, a few efficacy variables formerly listed as “exploratory” 
have been redefined as “secondary” (PedACR30, PedACR50, PedACR70, and 
PedACR90 response rates at Week 16) or “other” variables (all other efficacy variables). 
 An additional study objective has been added to reflect the “other” variables. 
 The study population was further defined to include study participants with polyarticular-
course JIA except systemic JIA. In addition, the term “polyarticular-course JIA” for the 
studied indication replaces “polyarticular JIA.” 
 The study population was further defined to include a minimum number of study 
participants in each body weight and age class, to include a minimum number of study 
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participants with ERA, and to include a minimum number of study participants who 
receive CZP as monotherapy.  
 The exclusion criteria have been reordered to group arthritis-related criteria and medical 
history-related criteria.  
 Text describing planned interim analyses has been updated to reflect full interim analyses 
at Week 16 and Week 56, instead of Week 24. 
 A study stopping rule has been added, stating that the study will be discontinued if less 
than 50% of the study population achieves PedACR30 response at Week 16. 
 For the comparison of PK data with previously observed plasma concentrations from 
adult study participants with RA, at least 20 study participants instead of 15 study 
participants (minimum of 6 instead of 4 study participants in each age group) are required 
to have completed Week 12 (Visit 7). 
 The protocol has been updated with current terminology used in the rheumatology 
community with regard to “Clinically Inactive Disease (CID)” and “clinical remission.”  
 “Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey” replaces 
“productivity measure.”  
 The Patient’s Assessment of Arthritis Pain questionnaire (“How much pain have you had 
because of your illness today/in the past week?”) has been separated into an acute 
version, which will be used daily during the first week of treatment (“How much pain 
have you had because of your illness today?”) and a standard version (“How much pain 
have you had because of your illness in the past week?”). 
 The following assessments have been removed throughout the protocol: erythrocyte 
sedimentation rate, respiration rate, thyroid function, and rheumatoid factor. 
 “Tanner stage (pubertal maturity only)” has been changed to “Tanner stages (except 
growth)” for clarity. 
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17.12 
Protocol Amendment 2 
Rationale for the amendment 
The primary purpose of this administrative amendment is to reflect a change in the 
participating countries, including removal of Western Europe. RA0043 will not be included 
in the European Paediatric Investigational Plan and will therefore not be conducted in 
Western Europe. 
In addition, study personnel and the phone contact information for SAE reporting were 
updated.  
The format and style of the document was changed to comply with UCB’s new document 
authoring software; these changes are not specifically noted. 
Modifications and changes 
Specific changes 
This section displays the modifications in this amendment compared with the previous 
version of the protocol dated 26 Aug 2011. The changes are displayed in the order of 
appearance. 
Change #1 
Under SPONSOR DECLARATION, the name of the Clinical Program Director: 
 
Has been changed to: 
 
Change #2 
Under STUDY CONTACT INFORMATION, the name and contact details of the Clinical 
Program Director: 
Clinical Program Director  
Name: 
 
Address: 
1950 Lake Park Drive 
Smyrna, GA 30080 
USA 
Phone: 
 
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Have been changed to: 
Clinical Program Director  
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
 
Change #3 
Under SERIOUS ADVERSE EVENT REPORTING, the phone contact information for SAE 
reporting (24h) and safety related issues: 
 Phone 
Europe and Rest of the World: +32 2 386 24 68 
USA & Canada: +1 678 799 4007 
Has been changed to: 
 Phone 
Europe, USA & Canada, and Rest of the World: +32 2 386 24 68 
Change #4 
Section 5.1.3 Anticipated regions and countries: 
The regions planned for participation in this study are North America and Western Europe, 
with possible extension to other regions. 
Has been changed to: 
The regions planned for participation in this study are North and South America and Russia, 
with possible extension to other regions. 
Change #5 
Section 5.4.1 Study design, the last sentence of the first paragraph has been removed: 
In addition, the study is proposed to fulfill the requirements for a pediatric investigation plan 
in compliance with the European pediatric regulation, with the objective to develop and make 
CZP available in the pediatric JIA population in the EU. 
 
 
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17.13 
Protocol Amendment 3 
Rationale for the amendment 
The primary purpose of this substantial amendment is to update the exclusion criteria and 
guidelines related to TB detection and monitoring in order to comply with the revised UCB 
TB Task Force policy applied to all UCB-sponsored studies that include study participants 
with immunological diseases, who are at risk of developing or reactivation of TB infection, 
which might be associated with the class of anti-TNF blockers including the investigational 
drug. These instructions are evidence-based and reflect the updated recommendations of 
various national guidelines (eg, CDC diagnosis of latent TB infection, 
http://www.cdc.gov/TB/topic/testing/default.htm). This guideline includes the preference of 
use of PPD testing over IGRA in children below the age of 5 years. With the implementation 
of Protocol Amendment 3, PPD testing will be mandatory for study participants from 2 to 4 
years of age in this study, unless the study participant has received a BCG vaccination, and 
IGRA testing will be required for study participants from 5 to 17 years of age.  
In addition, the assessment of vital signs (especially the measurement of blood pressure) was 
adapted to the current UCB standard of safety assessment for CZP studies, in order to follow 
a consistent process in the collection of safety data across the UCB development program, 
and lactate dehydrogenase was added to complete the panel of laboratory parameters. 
A DSMB will be implemented to conform with the standards for pediatric clinical studies. 
The DSMB will review emerging safety data from the study and will replace the 
study-specific Safety Review Committee. Activities will be defined in the DSMB charter. 
Furthermore, this substantial amendment introduces a full interim analysis at Week 24 
involving a complete data analysis for the inclusion in the marketing application for the JIA 
indication. At the same time, the planned analysis at Week 16 has been reduced to an analysis 
of the PedACR30 response rate required to confirm adequate response of the study 
population to CZP treatment and to confirm continuation of RA0043.  
Key revisions also include modifications of the following eligibility criteria: 
 Eligibility criteria related to the diagnosis of JIA (inclusion criterion 6) have been revised 
for clarity. 
 Use of DMARDS and MTX (inclusion criteria 8 and 9) has been revised for clarity. 
 TB exclusion criteria (exclusion criterion 11 and withdrawal criteria 3 and 4) have been 
updated to comply with the revised UCB policy. 
 Exclusion criterion 13 (hepatitis screening panel) has been revised for clarity. 
 Follow-up period for pregnancy and contraception (exclusion criteria 16 and 17) has been 
adapted to allow for compliance with local requirements. 
 An exclusion criterion for infections (exclusion criterion 25) has been added. 
In addition, the Per Protocol Set was deleted given that efficacy variables are secondary in 
this study, and an additional PK-PD Population was defined. 
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Further revisions were made to clarify study-related procedures (eg, the process of analyzing 
CZP plasma concentrations in the first cohort of study participants and the completion of 
parent-reported questionnaires), to clarify the CZP assay methodology, and to correct errors 
in the previous protocol version (eg, in relation to the components of the PedACR). In 
addition, the definition of the Physician’s Global Assessment criterion for CID and CRM was 
changed to conform with the most current standard as defined by Wallace et al (2011).  
The sentence that the pediatric PopPK model may be combined with PD data (PedACR) for 
an exposure response relationship has been moved from the variables section into the section 
on the assessment of pharmacokinetics and immunological variables as it represents an 
analysis rather than a variable. 
References to the findings of the interim analysis of plasma concentration data from the 
clinical study of CZP in children and adolescents with Crohn’s disease (C87035) have been 
removed from the protocol because of the differences between C87035 and the present study 
(ie, differences in dose interval and potential for impact of disease characteristics on 
clearance), and in consideration of the more relevant plan for an interim analysis of plasma 
concentration data from the present study in children and adolescents with JIA, as described 
in this protocol. 
The reference to the JADAS has been changed from “JADAS-75” to “JADAS” and it has 
been clarified that for the purpose of this study, 71 joints will be included in the analysis in 
line with the PRINTO/PRCSG joint assessment used in this study. 
In addition, administrative and editorial changes have been made, eg, to update study 
personnel and correct typographical errors. 
Modifications and changes 
Global changes 
The following changes have been made throughout the protocol: 
 All procedures related to TB detection and monitoring have been updated in order to 
comply with the revised UCB TB Task Force policy and company-wide 
recommendations that are based on international guidelines. This applies to eligibility 
criteria, withdrawal criteria, and timing and descriptions of related assessments 
throughout the protocol. In the tabular schedule of study assessments and the description 
of study procedures by visit, TB-related assessments have been grouped for clarity. 
 References to the findings of an interim analysis of plasma concentration data from 
C87035 in children and adolescents with Crohn’s disease have been removed throughout 
the protocol. 
 “Study participant and parent/caregiver” has been added throughout the “Study 
procedures by visit” section for the TB questionnaire. This global change is not listed 
under the specific changes. 
 The following terminology changes have been made throughout the protocol; these global 
changes are not listed under the specific changes:  
 “QuantiFERON” has been replaced by “IGRA” in line with the updated TB policy. 
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 The reference to the JADAS has been changed from “JADAS-75” to “JADAS” 
throughout the protocol. 
 “IVRS phone call” has been changed to “IXRS contact” to account for the use of an 
interactive voice/web response system.  
 References to Global Clinical Safety and Pharmacovigilance (GCSP) have been 
changed to “Drug Safety.”  
Specific changes 
This section displays the modifications in this amendment compared with the previous 
version of the protocol dated 02 Jul 2012. The changes are displayed in the order of 
appearance. 
Change #1 
On the SPONSOR DECLARATION page, the name of the Clinical Trial Biostatistician: 
 
Has been changed to: 
 
Change #2 
On the SPONSOR DECLARATION page, the name of the Clinical Program Director: 
 
Has been changed to: 
 
Change #3 
Under STUDY CONTACT INFORMATION, the name and contact details of the Clinical 
Program Director: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
 
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Have been changed to: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
Change #4 
Under STUDY CONTACT INFORMATION, the name and contact details of the Clinical 
Trial Biostatistician: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
Have been changed to: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
Change #5 
Under STUDY CONTACT INFORMATION, the name of the Medical Monitor Europe: 
Name: 
Phone: 
Fax: 
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Has been changed to: 
Name: 
Phone: 
Fax: 
Change #6 
Under SERIOUS ADVERSE EVENT REPORTING, the contact details: 
Serious Adverse Event reporting (24h) and safety related issues 
 Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA: +1 800 880 6949 
Canada: +1 877 582 8842 
 Phone 
Europe, USA & Canada, and Rest of the World: +32 2 386 24 68 
Have been changed to: 
Serious adverse event reporting (24h)  
 Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA: +1 800 880 6949 
Canada: +1 877 582 8842 
 E-mail 
Global: DS_ICT@ucb.com  
Change #7 
LIST OF ABBREVIATIONS, the following abbreviations have been added: 
CDC 
DSMB 
IBD 
IGRA 
Centers for Disease Control and Prevention 
Data and Safety Monitoring Board 
inflammatory bowel disease 
interferon-gamma release assay 
IXRS  
interactive voice/web response system 
LTB 
NTMB 
PK-PD 
SDV 
latent tuberculosis 
nontuberculous mycobacteria 
Pharmacokinetic-Pharmacodynamic 
source data verification 
Change #8 
LIST OF ABBREVIATIONS, the following abbreviations have been removed: 
GCSP 
Global Clinical Safety and Pharmacovigilance 
IVRS 
interactive voice response system 
PPS 
Per Protocol Set 
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Change #9 
Section 1 Summary, third paragraph, the second sentence: 
Study participants must have had polyarticular-course JIA for at least 6 months prior to 
Baseline. 
Has been changed to: 
Study participants must have had onset of signs and symptoms consistent with polyarticular-
course JIA and initiation of JIA treatment for at least 6 months prior to Baseline. 
Change #10 
Section 1 Summary, the following has been added below the fifth paragraph: 
An interim analysis of the American College of Rheumatology Pediatric 30% (PedACR30) 
response rate will be performed after all active study participants have completed the Week 
16 (Visit 8) assessments. The study will be discontinued if less than 50% of the study 
population achieves a PedACR30 response at Week 16. 
Change #11 
Section 1 Summary, the seventh paragraph: 
Full interim analyses will be performed after all active study participants have completed the 
Week 16 (Visit 8) assessments and after all active study participants have completed the 
Week 56 (Visit 14) assessments. 
Has been changed to: 
Full interim analyses will be performed after all active study participants have completed the 
Week 24 (Visit 10) assessments, as well as after all active study participants have completed 
the Week 56 (Visit 14) assessments. The study will continue until the approval of the 
marketing application for the polyarticular-course JIA indication in the study participant’s 
country or region, or until discontinuation of the study based on the Week 16 analysis of 
response, or until further notice from UCB. 
Change #12 
Section 1 Summary, the following sentence has been moved from the seventh paragraph to 
the new text below the fifth paragraph: 
The study will be discontinued if less than 50% of the study population achieves at least an 
American College of Rheumatology 30% (PedACR30) response rate at Week 16. 
Change #13 
Section 1 Summary, the eighth paragraph: 
Certolizumab pegol will be administered as a fixed dose based on weight every 2 weeks 
(Q2W) throughout the study consisting of 3 loading doses at Weeks 0, 2, and 4 
(minimum=100mg, maximum=400mg) followed by a treatment dose (minimum=50mg, 
maximum=200mg). Once at least 20 study participants (minimum 6 study participants in 
each age group: 2 to 5 years, 6 to 11 years, and 12 to 17 years) have completed Week 12 
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(Visit 7), PK data will be compared with plasma concentrations observed previously in 
studies conducted in adult study participants with rheumatoid arthritis (RA). Interim data 
from an ongoing clinical study in children and adolescents with Crohn’s disease (ages 6 to 17 
years) confirm that the weight-based dose adjustment for pediatric study participants with 
Crohn’s disease leads to similar plasma concentrations as observed previously in adult study 
participants with Crohn’s disease. However, if plasma levels of JIA study participants are not 
consistent with those observed in previous adult RA studies, the dosing algorithm may be 
changed via a protocol amendment. 
Has been changed to: 
Certolizumab pegol will be administered as a fixed dose based on weight every 2 weeks 
(Q2W) throughout the study consisting of 3 loading doses at Weeks 0, 2, and 4 
(minimum=100mg, maximum=400mg) followed by a treatment dose (minimum=50mg, 
maximum=200mg). Interim analysis of PK data will compare plasma concentration data from 
this study with CZP plasma concentrations observed previously in adult study participants 
with rheumatoid arthritis (RA). This CZP plasma concentration analysis will be done on an 
ongoing basis throughout the study, starting when 6 study participants in 1 of the age groups 
have completed Week 12 (Visit 7). Interim CZP plasma concentration data available at the 
time of Protocol Amendment 3 indicate that no change to the dosing algorithm is required. If 
future analyses indicate that plasma levels of JIA study participants are outside of the 
exposure range observed in previous adult RA studies, the dosing algorithm may be changed 
via a protocol amendment. 
Change #14 
Section 1 Summary, last paragraph, the second sentence:  
Other exploratory efficacy and health outcomes variables include: … 
Has been changed to: 
Other efficacy and health outcomes variables include: … 
Change #15 
Section 1 Summary, last paragraph, the following variable has been removed:  
Shifts by visit of CRP from Baseline 
Change #16 
Section 1 Summary, last paragraph, the following variable:  
Number of study participants meeting criteria of Clinically Inactive Disease (CID) and 
clinical remission on medication (CRM) 
Has been changed to: 
Percentage of study participants meeting criteria of Clinically Inactive Disease (CID) and 
clinical remission on medication (CRM) 
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Change #17 
Section 2 Introduction, the first sentence: 
Certolizumab pegol (CDP870, CZP, Cimzia®) is approved in the United States of America 
(USA), the European Union, and a number of other countries worldwide for the treatment of 
moderate to severe active RA in adults.  
Has been changed to: 
Certolizumab pegol (CDP870, CZP, Cimzia®) is approved in the United States of America 
(USA), the European Union, and a number of other countries worldwide for the treatment of 
moderately to severely active RA in adults. 
Change #18 
Section 2 Introduction, 13th paragraph, the first sentence: 
In a placebo-controlled clinical study of study participants with RA, no difference was 
detected in antibody response to vaccine between CZP and placebo treatment groups when 
the pneumococcal polysaccharide vaccine and influenza vaccine were administered 
concurrently with CZP. 
Has been changed to: 
In a placebo-controlled clinical study of study participants with RA, no meaningful difference 
was detected in antibody response to vaccine between CZP and placebo treatment groups 
when the pneumococcal polysaccharide vaccine and influenza vaccine were administered 
concurrently with CZP. 
Change #19 
Section 4.3 Other variables, the following has been removed at the beginning of the section: 
Other pharmacodynamic (PD) variables are: 
 The pediatric PopPK model will be combined with PD data (PedACR) and if the data 
allow, an exposure response relationship will be derived. 
Change #20 
Section 4.3 Other variables, under “Other efficacy and health outcomes variables,” the ninth 
bullet has been removed: 
 Shifts by visit of CRP from Baseline. 
Change #21 
Section 5.1 Study description, the fourth and fifth paragraphs: 
Full interim analyses will be performed: 
 After all active study participants have completed the Week 16 (Visit 8) assessments 
 After all active study participants have completed the Week 56 (Visit 14) assessments 
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If less than 50% of the study population achieves at least PedACR30 response at Week 16, 
the study will be discontinued. 
Have been changed to: 
An interim analysis of PedACR30 response rates will be performed after all active study 
participants have completed the Week 16 (Visit 8) assessments. If less than 50% of the study 
population achieves a PedACR30 response at Week 16, the study will be discontinued. 
Full interim analyses will be performed: 
 After all active study participants have completed the Week 24 (Visit 10) assessments  
 After all active study participants have completed the Week 56 (Visit 14) assessments 
Change #22 
Section 5.1 Study description, the last 3 paragraphs: 
Once at least 20 study participants (minimum 6 study participants in each age group: 2 to 5 
years, 6 to 11 years, and 12 to 17 years) have completed Week 12 (Visit 7), PK data will be 
compared with plasma concentrations observed previously in adult study participants with 
RA. 
This CZP plasma concentration analysis may be done in 2 or 3 stages if at least 20 study 
participants in total complete Week 12 (Visit 7) before 6 study participants in 1 or both of the 
other age groups have completed. The plasma concentration analysis would be performed on 
the available completed study participants in the first stage. The analysis would then be 
performed on the other age groups once the required minimum number of 6 study participants 
have completed Week 12 (Visit 7). 
The therapeutic plasma concentration of CZP in children and adolescents is expected to be 
similar to that required for the adult population (see Section 5.4.2). If plasma concentrations 
are not consistent with those observed in previous studies with adults, the dosing algorithm 
may be changed via a protocol amendment. This study will continue during the PK analysis. 
All study participants assessed in this analysis will continue treatment after Week 12 (Visit 
7). 
Have been changed to: 
Interim analysis of PK data will compare CZP plasma concentration data from this study with 
plasma concentrations observed previously in adult study participants with RA. This plasma 
concentration analysis will be done on an ongoing basis throughout the study, starting when 
6 study participants in 1 of the age groups have completed Week 12 (Visit 7).  
The therapeutic plasma concentration of CZP in children and adolescents is expected to be 
similar to that required for the adult population (see Section 5.4.2). Interim CZP plasma 
concentration data available at the time of Protocol Amendment 3 indicate that no change to 
the dosing algorithm is required. If future analyses indicate that plasma concentrations are 
outside of the exposure range observed in previous studies with adults, the dosing algorithm 
may be changed via a protocol amendment. This study will continue during the PK analysis. 
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All study participants assessed in this analysis will continue treatment after Week 12 (Visit 
7). 
Change #23 
Section 5.1.1 Study duration by study participant, the last line: 
Planned Last Study participant, First Visit – 2Q 2013 
Has been changed to: 
Planned Last Study participant, First Visit – 3Q/4Q 2013 
Change #24 
Section 5.1.2 Planned number of study participants and sites, the first sentence:  
Approximately 167 study participants will be screened at about 70 centers in order to enroll 
125 study participants in this study. 
Has been changed to: 
Approximately 167 study participants will be screened at about 55 centers in order to enroll 
125 study participants in this study. 
Change #25 
Section 5.2 Schedule of study assessments, Table 5-1, Week 17 with footnote “u” has been 
added in the second header row, sixth column: 
Study period 
Screening 
Baseline 
 
 
 
 
 
 
 
Week 
-4 to 0(a) 
0 
1 
2 
4, 8, 12, 16, 
(17(u)), 20, 
24 
32 and every  
8 weeks 
thereafter 
Unsch. 
Visit(b) 
Early Disc/  
End of 
Treatment 
Final  
Visit(c) 
Change #26 
Section 5.2 Schedule of study assessments, Table 5-1, the row for “TB questionnaire” has 
been moved below the row for “TB screening.” 
Change #27 
Section 5.2 Schedule of study assessments, Table 5-1, the row “TB screening”: 
Study period 
Screening 
Baseline 
 
 
 
 
 
 
 
Week 
-4 to 0(a) 
0 
1 
2 
4, 8, 12, 
16, 20, 24 
32 and every  
8 weeks 
thereafter 
Unsch. 
Visit(b) 
Early Disc/  
End of 
Treatment 
Final  
Visit(c
) 
Visit (+/-3 days)(a) 
1 
2 
3 
4 
5 to 10 
11 onwards 
 
 
FV 
TB screening(n)  
X 
 
 
 
 
X(o) 
 
 
 
 Has been changed to: 
Study period 
Screening 
Baseline 
 
 
 
 
 
 
 
Week 
-4 to 0(a) 
0 
1 
2 
4, 8, 12, 
16, 17u, 
20, 24 
32 and every  
8 weeks 
thereafter 
Unsch. 
Visit(b) 
Early Disc/  
End of 
Treatment 
Final  
Visit(c
) 
Visit (+/-3 days)(a) 
1 
2 
3 
4 
5 to 10 
11 onwards 
 
 
FV 
TB screening(n) and chest x-ray(o) 
X 
 
 
 
 
 
 
 
 
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Change #28 
Section 5.2 Schedule of study assessments, footnote “a” in Table 5-1: 
a 
Screening Visit must be completed at least 4 days prior to the Baseline Visit. For all other visits, the Visit 
window is ±3 days relative to Baseline. 
Has been changed to: 
a 
Screening Visit must be completed at least 4 to 12 working days prior to the Baseline Visit, depending on 
regional requirements and laboratory assessments required for the study participant (please refer to Section 
10.6 and the laboratory manual). For all other visits, the Visit window is ±3 days relative to Baseline.  
Change #29 
Section 5.2 Schedule of study assessments, footnote “d” in Table 5-1: 
d 
Pulse, systolic/diastolic blood pressure, and temperature to be measured within approximately 15 minutes 
prior to dosing. 
Has been changed to: 
d 
Pulse, systolic/diastolic blood pressure, and temperature to be measured within approximately 15 minutes 
prior to dosing and in addition (pulse and blood pressure only) approximately 30 minutes after dosing.  
Change #30 
Section 5.2 Schedule of study assessments, footnotes “i,” “j,” and “k” in Table 5-1: 
i 
TB questionnaire to be completed at Weeks 12 and 24, every 16 weeks thereafter, and Early 
Discontinuation/End of Treatment.  
j 
Analyses will be performed by a central laboratory. Study participants do not have to be fasting.  
k 
At Screening, laboratory testing includes testing for HBcAb, HBsAb, HBsAg, and HCVAb. In addition, 
HBV DNA is required for study participants with only positive HBcAb (negative HBsAg and HBsAb) or 
with only positive HBsAg. Rescreening on 1 additional occasion within the Screening Period is allowed 
after consultation with the Medical Monitor in case of isolated exclusionary laboratory results, if, in the 
Investigator’s opinion, the value is not reflective of the study participant’s previous clinical and laboratory 
pattern. In addition, retesting within the Screening Period is allowed after consultation with the Medical 
Monitor in case of reporting failure of laboratory results (eg, issues with transportation of samples). 
Have been changed to: 
i 
TB questionnaire to be completed at Weeks 12 and 24, every 16 weeks thereafter, and Early 
Discontinuation/End of Treatment. If the Investigator suspects reactivation of TB or active TB, TB testing 
and/or a chest x-ray should be performed. 
j 
Analyses will be performed by a central laboratory, except urine dipsticks, which will be done locally at the 
site. Study participants do not have to be fasting. 
k 
At Screening, laboratory testing includes testing for HBcAb, HBsAb, HBsAg, and HCVAb. In addition, 
HBV DNA is required for study participants with only positive HBcAb (negative HBsAg and HBsAb) or 
with only positive HBsAg. Retesting on 1 additional occasion within the Screening Period is allowed in 
case of isolated exclusionary laboratory results, if, in the Investigator’s opinion, the value is not reflective 
of the study participant’s previous clinical and laboratory pattern. In addition, retesting within the Screening 
Period is allowed in case of reporting failure of laboratory results (eg, issues with transportation of 
samples). 
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Change #31 
Section 5.2 Schedule of study assessments, footnotes “m,” “n,” and “o” in Table 5-1: 
m 
Pregnancy testing for postmenarcheal female study participants. Serum testing by a central laboratory at 
Screening and urine testing at Baseline, Weeks 8, 16, 24, and every visit thereafter. 
n 
Performed ≤3 months within Screening. PPD tests should be read by a trained health care worker between 
48 and 72 hours after injection. QuantiFERON testing is required to be performed by the central lab if the 
study participant has a documented history of severe positive PPD reaction or a documented history of 
Bacille Calmette-Guérin (BCG) vaccination. 
o 
TB screening to be done at Week 48 and yearly (every 48 weeks) thereafter. 
Have been changed to: 
m 
Pregnancy testing for postmenarcheal female study participants. Serum testing by a central laboratory at 
Screening and urine testing locally at the site at Baseline, Weeks 8, 16, 24, and every visit thereafter. 
n 
TB screening if not performed within 3 months of Screening: Interferon-gamma release assay (IGRA) 
testing (QuantiFERON®) is required to be performed by the central lab for all study participants from 5 to 
17 years of age. PPD testing is mandatory for study participants from 2 to 4 years of age in this study unless 
written documentation of BCG vaccination is available (refer to Section 6.2 [exclusion criterion 11] and 
Section 10.7.9).  
o 
A chest radiograph (anterior-posterior view at minimum, but preferably anterior-posterior and lateral) must 
be taken if the study participant has a positive IGRA/PPD testing at Screening or, if written documentation 
of BCG vaccination is available for study participants ages 2 to 4 years, a TB questionnaire indicating an 
increased study participant’s risk of exposure or infection with TB. If a study participant has had a recent 
radiograph of the chest within approximately 3 months prior to Screening, it may be used in lieu of the 
protocol-required radiograph. All chest imaging must be read by a qualified radiologist/pulmonary 
physician who is specifically required to look for evidence of active TB or inactive TB. Refer to 
Section 10.7.9.2.1 for further information on chest x-rays.  
Change #32 
Section 5.2 Schedule of study assessments, footnote “u” in Table 5-1: 
u 
CZP plasma level and anti-CZP antibodies to be measured at Weeks 4, 12, 16, and 24. A postdose CZP 
plasma sample will be collected at approximately 5 to 7 days following the Week 16 Visit (ie, requires an 
additional clinic site visit at Week 17). 
Has been changed to: 
u 
CZP plasma level and anti-CZP antibodies to be measured at Weeks 4, 12, 16, and 24. A postdose CZP 
plasma sample will be collected at approximately 5 to 7 days following the Week 16 Visit (ie, requires an 
additional clinic site visit for blood collection at Week 17). 
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Change #33 
Section 5.3 Schematic diagram:  
 
Has been changed to: 
 
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Change #34 
Section 5.4.2 Dose selection, the last sentence has been removed: 
Interim data from the ongoing clinical study in children and adolescents with Crohn’s disease 
(ages 6 to 17 years) confirm that the weight-based dose adjustment for pediatric study 
participants with Crohn’s disease leads to similar plasma concentrations as observed 
previously in adult study participants with Crohn’s disease. 
Change #35 
Section 6.1 Inclusion criteria, inclusion criterion 6: 
6. Study participants must have had a diagnosis of JIA (according to the International League 
of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis, 2001) for 
at least 6 months prior to Baseline (Visit 2). Eligible JIA categories include: polyarthritis 
rheumatoid factor-positive, polyarthritis rheumatoid factor-negative, extended 
oligoarthritis, juvenile psoriatic arthritis, and ERA.  
Has been changed to: 
6. Study participants must have had onset of signs and symptoms consistent with a diagnosis 
of JIA (according to the International League of Associations for Rheumatology 
Classification of Juvenile Idiopathic Arthritis, 2001) and initiation of JIA treatment for at 
least 6 months prior to Baseline (Visit 2). Eligible JIA categories include: polyarthritis 
rheumatoid factor-positive, polyarthritis rheumatoid factor-negative, extended 
oligoarthritis, juvenile psoriatic arthritis, and ERA.  
Change #36 
Section 6.1 Inclusion criteria, inclusion criterion 8: 
8. Study participants must have had an inadequate response to, or intolerance to, at least 1 
DMARD (nonbiologic and biologic). 
Has been changed to: 
8. Study participants must have had an inadequate response to, or intolerance to, at least 1 
DMARD (nonbiologic or biologic). For example, study participant had prior inadequate 
response to MTX (based on the Investigator’s clinical judgment). 
Change #37 
Section 6.1 Inclusion criteria, inclusion criterion 9: 
9. If the study participant is using MTX, then the dose must have been stable for at least 1 
month before Screening at ≥10 to ≤15mg/m2 per week. If the study participant is not using 
MTX, then the treatment must have been previously withdrawn for documented reasons of 
intolerability or inadequate response. 
Has been changed to: 
9. If the study participant is using MTX, then the study participant must have been on MTX 
for a minimum of 3 months at Screening. In addition, the dose must have been stable for at 
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least 1 month before Screening at ≥10 to ≤15mg/m2 per week. If the study participant is 
not using MTX, then the treatment must have been previously withdrawn for documented 
reasons of intolerability or inadequate response. 
Change #38 
Section 6.2 Exclusion criteria, exclusion criterion 6, the exclusion criterion for biologic 
DMARDs infliximab and abatacept in Table 6-1 Prohibited medications at entry (Baseline): 
Use of infliximab or abatacept within 84 days prior to the Baseline arthritis assessment. 
Has been changed to: 
Use of infliximab or abatacept within 60 days prior to the Baseline arthritis assessment. 
Change #39 
Section 6.2 Exclusion criteria, exclusion criterion 11: 
11. Known TB disease, high risk of acquiring TB infection, or latent TB infection: 
a. 
Known TB disease of either Study participant or Caregiver 
 Currently active TB disease or clinical signs and symptoms suspicious for TB. 
 Prior history of active TB disease involving any organ system (clinically 
documented). 
 Chest radiograph evidence of past active TB disease (not clinically 
documented), which could include apical lung fibrosis, pleural thickening, 
calcified lung nodules, calcified hilar lymph nodes, pericardial calcification. 
a. High risk of acquiring TB infection 
 Known exposure of Study participant or Caregiver to another person with 
active TB disease <3 months prior to Screening. 
 High risk of future exposure of Study participant or Caregiver to another person 
with active TB disease (eg, time spent in an institutional setting). 
b. Latent TB infection - Study participants who don’t meet criteria “a=known TB 
disease” or “b=high risk of acquiring TB infection” but do meet any of the 
following, regardless of prior TB treatment: 
 Currently purified protein derivative (PPD) positive (+) (test must be performed 
≤3 months prior to Screening). 
OR 
 An alternative to the PPD skin test must be used if study participants meet the 
following criteria: 
◦ 
Study participants with documented history of severe positive PPD 
reaction, eg, necrosis, blistering, anaphylactic shock, or ulcerations (test 
performed >3 months prior to Screening), or  
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◦ 
Study participants with previous documented history of Bacille Calmette-
Guérin (BCG) vaccination.  
 
If any one of these 2 conditions is met, study participants must have a 
QuantiFERON® test conducted at Screening. If the result of the QuantiFERON 
is indeterminate, the test may be repeated once; if positive or indeterminate on 
retest, the study participant is excluded. The retest must be conducted in the 
allowable Screening window. 
◦ 
Study participants with QuantiFERON (performed ≤3 months prior to 
Screening) positive or indeterminate are excluded. 
 Exception from exclusion 11c is permitted only if treatment for latent TB infection is 
initiated or has been initiated at least 1 month prior to study medication administration 
and treatment is still ongoing at the time of study entry. 
 A positive PPD is defined as ≥5mm of induration 48 to 72 hours after intradermal 
injection of 5TU of PPD-S or 2TU of PPD-RT23 regardless of the study participant’s 
history of BCG vaccination. 
 Reports of PPD results not taken at Screening but (performed ≤3 months prior to 
Baseline and) reported from elsewhere must be documented with exact induration 
measurement and date. 
 Treatment for latent TB infection includes eg, isonicotinic acid hydrazide/isoniazid 
(INH) therapy for 9 months (with vitamin B6); another latent TB infection treatment 
regimen should be considered if the study participant is living in or has emigrated 
recently from a country with a high endemic rate of INH-resistant or multi-drug-
resistant TB. 
Has been changed to: 
11. Study participants with known TB infection, at high risk of acquiring TB infection, or 
latent TB (LTB) infection are excluded: 
a. Known TB infection whether present or past is defined as:  
 Active TB infection or clinical signs and symptoms suspicious for TB 
(pulmonary or extra-pulmonary) 
 History of active TB infection involving any organ system or findings in other 
organ systems consistent with TB infection  
 Any evidence by radiography or other imaging modalities consistent with 
previously active TB infection that is not reported in the study participant’s 
medical history 
b. High risk of acquiring TB infection is defined as: 
 Known exposure of Study participant or Caregiver to another person with 
active TB infection within the 3 months prior to Screening 
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 Time spent in a healthcare delivery setting or institution where individuals 
infected with TB are housed and where the risk of transmission of infection to 
Study participant or Caregiver is high 
c. Latent TB infection (unless appropriate prophylaxis is initiated prior to study 
treatment according to Section 10.7.9.1.1 and continued to completion of 
prophylaxis) is defined as: 
Absence of signs, symptoms (ie, evidence of organ-specific involvement), or 
physical findings suggestive of TB infection with a positive interferon-gamma 
release assay (IGRA [QuantiFERON]) test (or 2 indeterminate IGRA test results) 
or positive PPD (where the PPD skin test is approved for use by UCB; mandatory 
for ages 2 to 4 years in this study) or, if written documentation of Bacille 
Calmette-Guérin (BCG) vaccination is available for study participants ages 2 to 
4 years, a TB questionnaire indicating an increased study participant’s risk of 
exposure or infection with TB, and a chest x-ray (or other imaging) without 
evidence of TB infection.  
Note: If available, respiratory or other specimens must also be smear and culture 
negative for TB (Centers of Disease Control and Prevention [CDC] diagnosis of 
LTB infection, http://www.cdc.gov/TB/topic/testing/default.htm). 
Refer to Section 10.7.9 for additional information on TB definition and clinical signs, 
diagnosis, documentation, and treatment. 
Study participants with a history of or active infection with nontuberculous mycobacteria 
(NTMB) are excluded from this study. 
Change #40 
Section 6.2 Exclusion criteria, exclusion criterion 12: 
12. Study participant has a current sign or symptom which may indicate infection (eg, fever, 
cough), a history of chronic or recurrent infections (more than 3 episodes requiring 
antibiotics/antivirals during the 12 months prior to Screening [Visit 1]), had a recent 
(within the 6 months prior to Screening [Visit 1]) serious or life-threatening infection 
(including herpes zoster), or is at a high risk of infection in the Investigator’s opinion (eg, 
study participants with leg ulcers, indwelling urinary catheter, and persistent or recurrent 
chest infections or permanently bed-ridden or wheelchair bound). 
Has been changed to: 
12. Study participant has a current sign or symptom which may indicate infection (eg, fever, 
cough), a history of chronic or recurrent infections within the same organ system (more 
than 3 episodes requiring antibiotics/antivirals during the 12 months prior to Screening 
[Visit 1]), had a recent (within the 6 months prior to Screening [Visit 1]) serious or 
life-threatening infection (including herpes zoster), or is at a high risk of infection in the 
Investigator’s opinion (eg, study participants with leg ulcers, indwelling urinary catheter, 
and persistent or recurrent chest infections or permanently bed-ridden or wheelchair 
bound). 
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Change #41 
Section 6.2 Exclusion criteria, exclusion criterion 13: 
13. Study participant with known concurrent viral hepatitis or known positivity to hepatitis B 
surface antigen (HBsAg) or hepatitis C virus (HCV) antibody or known human 
immunodeficiency virus (HIV) infection. 
Has been changed to: 
13. Study participant with known concurrent viral hepatitis or known positivity for hepatitis 
B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody or known human 
immunodeficiency virus (HIV) infection. At Screening, a hepatitis panel result which 
indicates immunity due to hepatitis B vaccination is not considered an exclusion criterion. 
Change #42 
Section 6.2 Exclusion criteria, exclusion criterion 16: 
16. Study participant is breast-feeding, pregnant or plans to become pregnant during the study 
or within 12 weeks following the last dose of study medication. Female study participants 
of childbearing potential (ie, postmenarcheal) must have a negative result at Screening 
and Baseline (Visits 1 and 2) pregnancy tests to be eligible for study entry. 
Has been changed to: 
16. Study participant is breast-feeding, pregnant or plans to become pregnant during the study 
or within 12 weeks following the last dose of study medication (or longer if required by 
local regulations). Female study participants of childbearing potential (ie, 
postmenarcheal) must have a negative result at Screening and Baseline (Visits 1 and 2) 
pregnancy tests to be eligible for study entry. 
Change #43 
Section 6.2 Exclusion criteria, exclusion criterion 17: 
17. Study participant is a sexually active female of childbearing potential (ie, 
postmenarcheal) and is not practicing or will not agree to practice an effective means of 
birth control. For postmenarcheal female study participants not currently sexually active, 
the study participant and parent or legal representative should agree that the study 
participant will employ an effective means of birth control should the study participant 
become sexually active. Acceptable methods of birth control are: 
oral/parenteral/implantable hormonal contraceptives (stable at least 2 months prior to 
Screening (Visit 1) if initiated prior to entering the study) or a combination of barrier and 
spermicide. Study participants must agree to use adequate contraception during the study 
and for 12 weeks after their last dose of study medication. Male study participants who 
are sexually active must agree to ensure they or their female partner(s) uses adequate 
contraception during the study and for 12 weeks after the study participant receives their 
last dose of study medication. (Sexually active means engaging in sexual intercourse, 
regardless of frequency). 
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Has been changed to: 
17. Study participant is a sexually active female of childbearing potential (ie, 
postmenarcheal) and is not practicing or will not agree to practice an effective means of 
birth control. For postmenarcheal female study participants not currently sexually active, 
the study participant and parent or legal representative should agree that the study 
participant will employ an effective means of birth control should the study participant 
become sexually active. Acceptable methods of birth control are: 
oral/parenteral/implantable hormonal contraceptives (stable at least 2 months prior to 
Screening (Visit 1) if initiated prior to entering the study) or a combination of barrier and 
spermicide. Study participants must agree to use adequate contraception during the study 
and for 12 weeks after their last dose of study medication (or longer if required by local 
regulations). Male study participants who are sexually active must agree to ensure they or 
their female partner(s) uses adequate contraception during the study and for 12 weeks 
after the study participant receives their last dose of study medication (or longer if 
required by local regulations). (Sexually active means engaging in sexual intercourse, 
regardless of frequency). 
Change #44 
Section 6.2 Exclusion criteria, exclusion criterion 24: 
24. Study participant is wheelchair-bound. 
Has been changed to: 
24. Study participant is wheelchair-bound at the time of enrollment. 
Change #45 
Section 6.2 Exclusion criteria, a new exclusion criterion 25 has been added: 
25. Study participant with a history of or active systemic/respiratory infection due to fungal, 
parasitic, or mycotic pathogens including but not limited to histoplasmosis, coccidiosis, 
paracoccidiosis, pneumocystis, blastomyces, and aspergillus.  
Radiographic evidence suggestive of any of these infections is sufficient grounds for 
exclusion. 
Change #46 
Section 6.3 Rescreening: 
6.3 
Rescreening 
Rescreening is allowed after consultation with the Medical Monitor as per the following: 
 Study participants with isolated exclusionary laboratory assessments at Screening may 
have this laboratory assessment repeated once if, in the Investigator’s opinion, the value 
is not reflective of the study participant’s previous clinical and laboratory pattern. 
Retesting must be completed within the stated Screening Period. If the repeat values are 
within the acceptable ranges of the study and the study participant remains eligible during 
the Baseline Visit (Week 0), the study participant may be dosed. 
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 Study participants who failed Screening (eg, due to transient out-of-range safety 
laboratory values or in the Investigator’s judgment mild acute illness, eg, a cold) may be 
rescreened after complete recovery of the mild acute illness and/or normalization of the 
out-of-range safety laboratory values. 
Has been changed to: 
6.3 
Retesting and rescreening 
Retesting of laboratory assessments within the Screening Period is allowed as per the 
following: 
 Study participants with isolated exclusionary laboratory assessments at Screening may 
have this laboratory assessment repeated once if, in the Investigator’s opinion, the value 
is not reflective of the study participant’s previous clinical and laboratory pattern. 
Retesting must be completed within the stated Screening Period. If the repeat values are 
within the acceptable ranges of the study and the study participant remains eligible during 
the Baseline Visit (Week 0), the study participant may be dosed. 
Rescreening is only allowed after consultation with the Medical Monitor as per the following: 
 Study participants who failed Screening (eg, due to transient out-of-range safety 
laboratory values or in the Investigator’s judgment mild acute illness, eg, a cold) may be 
rescreened after complete recovery of the mild acute illness and/or normalization of the 
out-of-range safety laboratory values. 
 Study participants with LTB infection, indicated by positive PPD skin test or positive 
IGRA test result (or TB questionnaire indicating an increased risk of exposure or infection 
with TB for study participants ages 2 to 4 years with documented BCG vaccination) and a 
chest imaging without evidence of TB infection at Screening, may be rescreened after 
initiation of treatment for latent TB. Prior to first study medication administration, TB 
treatment must have been ongoing for at least 4 weeks before enrollment will be allowed 
and after approval of the Medical Monitor. Treatment for TB must be continued until 
completion of 9 months of therapy (refer to Section 10.7.9).  
 Rescreening might be allowed more than once but not in case of repeated occurrence of 
the same illness. All Screening assessments must be repeated as applicable in case of 
Rescreening. The maximum duration of the Rescreening Period is 28 days or 4 weeks. 
Rescreening must only be scheduled after an appropriate time period after the initial 
Screening Visit allowing for repetition of blood collection (depending on local 
requirements for maximum blood volumes; depending on study participant weight). 
 All study participants who failed to be enrolled within the Screening Period of 28 days 
must be registered as Screen Failure in the interactive voice/web response system (IXRS). 
Study participants approved to be rescreened must be registered with a new study 
participant number. 
Change #47 
Section 6.4 Withdrawal criteria, the third withdrawal criterion: 
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3. Study participant develops confirmed latent or active TB once enrolled or discontinues 
treatment for latent TB prematurely or is noncompliant with anti-TB therapy in the 
Investigator’s or Sponsor’s opinion must discontinue further use of study medication and 
be immediately withdrawn from study participation (see Section 10.7.9). 
Has been changed to: 
3. Study participant who develops confirmed reactivation of latent or active TB or NTMB 
infection during the study (including, but not limited to, conversion demonstrated by 
IGRA or PPD or other diagnostic means, eg, TB questionnaire, during the course of the 
study) must be withdrawn.  
Change #48 
Section 6.4 Withdrawal criteria, a new withdrawal criterion has been added below withdrawal 
criterion 3, and subsequent criteria have been renumbered: 
4. Study participant who prematurely discontinues treatment for LTB, or, in the opinion of 
the Investigator or Sponsor, is noncompliant with anti-TB therapy must be withdrawn. 
Change #49 
Section 7.2 Treatments to be administered, fourth paragraph, the last sentence: 
In addition, study participants will have the option to either switch to home-based CZP 
injection or switch back to administration at the study site at anytime during the study. 
Has been changed to: 
In addition, if needed, home dosing can be performed by qualified health care professionals 
according to the written instructions for the correct sc injection technique provided by the site 
staff. Study participants will have the option to either switch to home-based CZP injection or 
switch back to administration at the study site at anytime during the study. 
Change #50 
Section 7.2 Treatments to be administered, the fifth paragraph: 
The method of injection (ie, qualified site personnel-injection at study site; injection by the 
study participant/caregiver at the study site or at home) and the site of injection (abdomen, 
thigh) will be recorded in the CRF at each visit. 
Has been changed to: 
The method of injection (ie, qualified site personnel-injection at study site; injection by the 
study participant/caregiver or qualified health care professional at the study site or at home) 
and the site of injection (abdomen, thigh) will be recorded in the CRF at each visit. 
Change #51 
Section 7.4 Labeling, second paragraph, the third sentence: 
The tear-off section will be removed and attached to the CRF at the time of study medication 
administration to the study participant and the main section will remain affixed to the 
individual container. 
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Has been changed to: 
The tear-off section will be removed and attached to the source document at the time of study 
medication administration to the study participant and the main section will remain affixed to 
the individual container. 
Change #52 
Section 7.8.1 Permitted concomitant treatments (medications and therapies), the first bullet: 
 MTX, if being used:  
 Must have been stable for at least 1 month before Screening (Visit 1) at ≥10 to 
≤15mg/m2 per week.  
 The maximum dose allowed during the study is 15mg/m2 per week.  
 Prior to Week 16, route of administration must not change. After Week 16, the route 
of administration may be changed. 
 During the study, the MTX dose may be decreased, but not discontinued (except for 
documented reasons of intolerance or toxicity, or in association with study 
participants achieving CRM and after CZP was discontinued). 
 After discontinuation, MTX treatment can be restarted. 
Has been changed to: 
 MTX, if being used:  
 Must have been stable for at least 1 month before Screening (Visit 1) at ≥10 to 
≤15mg/m2 per week.  
 During the study, an increase is allowed only after Week 16 and to a maximum dose 
of 15mg/m2 per week.  
 Prior to Week 16, route of administration must not change. After Week 16, the route 
of administration may be changed. 
 During the study, the MTX dose may be decreased, but not discontinued. 
Methotrexate may be discontinued only for documented reasons of intolerance or 
toxicity, or in study participants who achieve CRM and only after discontinuation of 
CZP. 
 Study participants who do not achieve persistent CRM status can reinitiate therapy 
with MTX.  
Change #53 
Section 7.8.1 Permitted concomitant treatments (medications and therapies), the fifth bullet: 
 Corticosteroids:  
 At study entry, the dose should have been stable for at least 7 days prior to the 
Baseline joint examination at a maximum dose of 10mg or 0.2mg/kg prednisone (or 
equivalent) per day, whichever is the smaller dose. 
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 During the study, the dose of oral corticosteroids may be decreased but not initiated or 
increased above 10mg or 0.2mg/kg prednisone (or equivalent) per day, whichever is 
the smaller dose. The dose must be stable in the 7 days prior to a joint examination. 
 Intra-articular (ia) corticosteroids may be administered no more frequently than every 
4 months and no more than up to 3 times in 1 year and only into up to 3 joints at a 
single time point. 
 If 1 or more joints have been injected (limited to 3 joints at a single time point), 
this/these joint(s) must be excluded from the PRINTO/PRCSG standard joint 
examination. 
 Intravenous (iv) corticosteroid use is permitted only for stress dosing for the purposes 
of surgery. 
Has been changed to: 
 Corticosteroids:  
 At study entry, the dose should have been stable for at least 7 days prior to the 
Baseline joint examination at a maximum dose of 10mg or 0.2mg/kg prednisone (or 
equivalent) per day, whichever is the smaller dose. 
 During the study, the dose of oral corticosteroids may be decreased but not initiated or 
increased above 10mg or 0.2mg/kg prednisone (or equivalent) per day, whichever is 
the smaller dose. The dose must be stable in the 7 days prior to a joint examination. 
 Initiation of topical corticosteroids is allowed for treatment of uveitis if developed 
during the course of the study. 
 Intra-articular (ia) corticosteroids may be administered no more frequently than every 
4 months and no more than up to 3 times in 1 year and only into up to 2 joints at a 
single time point. 
 Any joint injected with ia corticosteroids will be excluded from the efficacy analysis 
for a period of 3 months. 
 Intravenous (iv) corticosteroid use is permitted only for stress dosing for the purposes 
of surgery. 
Change #54 
Section 7.8.2 Rescue medication, the fourth and fifth paragraphs: 
The following medications are defined as rescue medication in the first 16 weeks of this 
study: 
 Initiation of MTX (if not being used at study entry), or increase of MTX above Baseline. 
 Initiation of oral corticosteroids, or increase of oral corticosteroids above Baseline.  
 Injection of intra-articular (ia) corticosteroids into more than 3 joints at a single time 
point. 
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 Injection of intra-articular (ia) corticosteroids into the same joint more frequently than 
3 times in a 12-month period.  
 Intravenous (iv) corticosteroids (any dose), if not used for stress dosing for the purposes 
of surgery. 
 Intramuscular (im) corticosteroids. 
The following medications are defined as rescue medication for the remainder of the study: 
 Initiation of MTX (if not being used at study entry), and increase of MTX above 15mg/m2 
per week at any time. 
 Initiation of oral corticosteroids, or increase to >10mg or 0.2mg/kg (whichever is the 
smaller dose).  
 Injection of intra-articular (ia) corticosteroids into more than 3 joints at a single time 
point. 
 Injection of intra-articular (ia) corticosteroids into the same joint more frequently than 
3 times in a 12-month period.  
 Intravenous (iv) corticosteroids (any dose), if not used for stress dosing for the purposes 
of surgery. 
 Intramuscular corticosteroids (im). 
Have been changed to: 
The following medications are defined as rescue medication in the first 16 weeks of this 
study: 
 Initiation of MTX (if not being used at study entry), or increase of MTX above Baseline. 
 Initiation of oral corticosteroids, or increase above Baseline.  
The following medications are defined as rescue medication after Week 16: 
 Initiation of MTX (if not being used at study entry), and increase of MTX above 15mg/m2 
per week at any time. 
 Initiation of oral corticosteroids, or increase to >10mg or 0.2mg/kg prednisone (or 
equivalent) per day, whichever is the smaller dose. 
The following medications are defined as rescue medication when given at any time during 
the study: 
 Injection of intra-articular (ia) corticosteroids into more than 2 joints at a single time 
point. 
 Injection of intra-articular (ia) corticosteroids into the same joint more frequently than 
3 times in a 12-month period.  
 Intravenous (iv) corticosteroids (any dose), if not used for stress dosing for the purposes 
of surgery. 
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 Intramuscular (im) corticosteroids. 
Change #55 
Section 7.9 Enrollment and numbering of study participants, the second sentence: 
The IVRS will provide the Investigator with the unique study participant number assigned to 
each study participant.  
Has been changed to: 
The Investigator will enter the unique study participant number assigned to each study 
participant, based on a predefined range of study participant numbers assigned to the 
Investigator’s site.  
Change #56 
Section 8.1 Visit 1 (Week -4 to 0) Screening, the tenth bullet has been moved below the 
bullet “TB screening”: 
 TB questionnaire 
Change #57 
Section 8.1 Visit 1 (Week -4 to 0) Screening, a new bullet has been added above the 15th 
bullet “TB screening”: 
 Chest x-ray (only for study participants with positive IGRA or PPD testing)** 
Change #58 
Section 8.1 Visit 1 (Week -4 to 0) Screening, the 15th bullet: 
 TB screening if not performed within 3 months of Screening: PPD skin test (or 
QuantiFERON required to be performed by the central lab if the study participant has a 
documented history of severe positive PPD reaction or a documented history of BCG 
vaccination) 
Has been changed to: 
 TB screening if not performed within 3 months of Screening: PPD skin test for study 
participants from 2 to 4 years of age (unless written documentation for BCG vaccination 
is available) or IGRA (to be performed by the central lab) for study participants from 5 to 
17 years of age)** 
Change #59 
Section 8.1 Visit 1 (Week -4 to 0) Screening, the last bullet: 
 IVRS phone call (to receive study participant number assignments) 
Has been changed to: 
 IXRS contact (to register study participant with unique study participant number) 
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Change #60 
Section 8.1 Visit 1 (Week -4 to 0) Screening, the note at the end of the section: 
*Change in height and weight over the last 6 months and over the last year will be collected 
via parent-/self-report, if available from medical records. 
Has been changed to: 
*Change in height and weight over the last 6 months and over the last year will be collected 
via parent-/self-report, if not available from medical records. 
Change #61 
Section 8.1 Visit 1 (Week -4 to 0) Screening, a new note has been added at the end of the 
section for chest x-ray, TB screening, and TB questionnaire: 
**For details of TB screening and testing, see Section 10.7.9. 
Change #62 
Section 8.2 Visit 2 (Week 0) Baseline, the 19th and 20th bullets: 
 FPS-R for study participants ages 5 to 11 years (at Baseline and daily assessment during 
the first 7 days of treatment) 
 JIA Pain VAS for study participants ages 12 to 17 years; acute and standard versions 
(both at Baseline and daily assessment of the acute version during the first 7 days of 
treatment)  
Has been changed to: 
 FPS-R for study participants ages 5 to 11 years (at Baseline and daily assessment on Day 
1 to Day 7) 
 JIA Pain VAS for study participants ages 12 to 17 years; acute and standard versions 
(both at Baseline and daily assessment of the acute version on Day 1 to Day 7)  
Change #63 
Section 8.2 Visit 2 (Week 0) Baseline, the paragraph at the end of the section: 
Documentation of the assessment of all 6 core set measures of PedACR response 
(PRINTO/PRCSG standard joint examination, Physician’s Global Assessment of Disease 
Activity [VAS], CHAQ-parent reported, Parent’s Assessment of Arthritis Pain [VAS], 
Parent’s Global Assessment of Overall Well-Being [VAS] and DMS) will be submitted to 
UCB or designee for immediate review of completeness, while the study participant is 
still on site. 
Has been changed to: 
Documentation of the assessment of all 6 core set measures of PedACR response 
(PRINTO/PRCSG standard joint examination, Physician’s Global Assessment of Disease 
Activity [VAS], CHAQ-parent reported, Parent’s Assessment of Arthritis Pain [VAS], 
Parent’s Global Assessment of Overall Well-Being [VAS] and CRP) will be submitted to 
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UCB or designee for immediate review of completeness, while the study participant is 
still on site. 
Change #64 
Section 8.3 Visits 3 and 4 (Weeks 1 and 2), the ninth bullet: 
 Collection of JIA Pain VAS or FPS-R completed during the first 7 days of treatment  
Has been changed to: 
 Collection of JIA Pain VAS or FPS-R completed on Day 1 to Day 7 
Change #65 
Section 8.4 Visits 5 to 10 (Weeks 4, 8, 12, 16, 20, and 24), the paragraph at the end of the 
section: 
Documentation of the Week 16 assessment of all 6 core set measures of PedACR response 
(PRINTO/PRCSG standard joint examination, Physician’s Global Assessment of Disease 
Activity [VAS], CHAQ-parent reported, Parent’s Assessment of Arthritis Pain [VAS], 
Parent’s Global Assessment of Overall Well-Being [VAS] and DMS) will be submitted to 
UCB or designee for immediate review of completeness, while the study participant is 
still on site. 
Has been changed to: 
Documentation of the Week 16 and Week 24 assessment of all 6 core set measures of 
PedACR response (PRINTO/PRCSG standard joint examination, Physician’s Global 
Assessment of Disease Activity [VAS], CHAQ-parent reported, Parent’s Assessment of 
Arthritis Pain [VAS], Parent’s Global Assessment of Overall Well-Being [VAS] and CRP) 
will be submitted to UCB or designee for immediate review of completeness, while the 
study participant is still on site. 
Change #66 
Section 8.5 Visits 11 and continuing (Week 32 and every 8 weeks thereafter), the eleventh 
bullet has been removed: 
 TB screening is to be repeated every 48 weeks in those study participants with a negative 
TB test at their most recent assessment. A PPD skin test must be performed. 
(QuantiFERON required to be performed by the central lab if the study participant has a 
documented history of severe positive PPD reaction or a documented history of BCG 
vaccination) (Week 48 and every 48 weeks thereafter). 
Change #67 
Section 8.5 Visits 11 and continuing (Week 32 and every 8 weeks thereafter), the paragraph 
at the end of the section: 
Documentation of the Week 56 assessment of all 6 core set measures of PedACR response 
(PRINTO/PRCSG standard joint examination, Physician’s Global Assessment of Disease 
Activity [VAS], CHAQ-parent reported, Parent’s Assessment of Arthritis Pain [VAS], 
Parent’s Global Assessment of Overall Well-Being [VAS] and DMS) will be submitted to 
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UCB or designee for immediate review of completeness, while the study participant is 
still on site. 
Has been changed to: 
Documentation of the Week 56 assessment of all 6 core set measures of PedACR response 
(PRINTO/PRCSG standard joint examination, Physician’s Global Assessment of Disease 
Activity [VAS], CHAQ-parent reported, Parent’s Assessment of Arthritis Pain [VAS], 
Parent’s Global Assessment of Overall Well-Being [VAS] and CRP) will be submitted to 
UCB or designee for immediate review of completeness, while the study participant is 
still on site. 
Change #68 
Section 9 Assessment of pharmacokinetics and immunological variables, the third, fourth, 
and fifth paragraphs: 
Once at least 20 study participants (minimum 6 study participants in each age group: 2 to 5 
years, 6 to 11 years, and 12 to 17 years) have completed Week 12 (Visit 7), PK data will be 
compared with plasma concentrations observed previously in adult study participants with 
RA.  
This CZP plasma concentration analysis may be done in 2 or 3 stages if at least 20 study 
participants in total complete Week 12 (Visit 7) before 6 study participants in 1 or both of the 
other age groups have completed. The plasma concentration analysis would be performed on 
the available completed study participants in the first stage. The analysis would then be 
performed on the other age groups once the required minimum number of 6 study participants 
have completed Week 12 (Visit 7). 
If plasma concentrations are not consistent with those observed in previous studies with 
adults, the dosing algorithm may be changed via a protocol amendment. This study will 
continue during the PK analysis. All study participants assessed in this analysis will continue 
treatment after Week 12 (Visit 7). 
Have been changed to: 
Plasma concentration data for CZP from this study will be compared with plasma 
concentrations observed previously in adult study participants with RA, as described in 
Section 13.7. This plasma concentration analysis will be done on an ongoing basis throughout 
the study, starting when 6 study participants in 1 of the age groups have completed Week 12 
(Visit 7). 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicate that no change to the dosing algorithm is required. If future analyses indicate that 
plasma concentrations are outside of the exposure range of those observed in previous studies 
with adults, the dosing algorithm may be changed via a protocol amendment, and if necessary 
additional interim analyses including PopPK, may be performed. This study will continue 
during the PK analysis. All study participants assessed in this analysis will continue treatment 
after Week 12 (Visit 7). 
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Change #69 
Section 9 Assessment of pharmacokinetics and immunological variables, the following 
sentence has been added below the fourth paragraph: 
The final pediatric PopPK model will be combined with PD data (PedACR) and if the data 
allow, an exposure-response relationship will be derived. 
Change #70 
Section 9 Assessment of pharmacokinetics and immunological variables, the following has 
been added at the end of the section: 
These plasma samples may be used additionally for analyses of CZP and its constituent 
moieties using alternative assay methods. The results of the analyses of CZP and its 
constituent moieties from alternative methods may be reported separately. 
Change #71 
Section 10.1.8 Ongoing safety data review and oversight, second paragraph, the fourth and 
fifth sentences: 
In addition, there will be a study-specific Safety Review Committee consisting of the UCB 
study physician, the UCB study GCSP representative, and an external pediatric 
rheumatologist experienced in the field and clinical studies in pediatrics and familiar with 
safety issues in this population. A charter will be developed to address the logistics of such a 
committee. 
Has been changed to: 
In addition, a Data and Safety Monitoring Board (DSMB) will periodically review all 
emerging safety data (see Section 13.7). The DSMB will function and meet on a regular basis 
as per the agreed upon charter. 
Change #72 
Section 10.1.8 Ongoing safety data review and oversight, the last sentence: 
The Sponsor 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. 
Has been changed to: 
The Sponsor Study Physician or medically qualified designee/equivalent will conduct an 
ongoing review of SAEs and perform ongoing SAE reconciliations in collaboration with the 
Drug Safety and Data Management representatives. 
Change #73 
Section 10.3 AEs of special interest: 
10.3 AEs of special interest 
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An AE of special interest is any AE which a regulatory authority has mandated to be reported 
on an expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to 
the administration of a UCB product/compound. 
 Adverse events of special interest must be reported immediately by the Investigator (see 
Section 10.4). The following are AEs of special interest for this study:  
 Serious infections, including opportunistic infections  
 Malignancies, including lymphoma  
 Congestive heart failure  
 Demyelinating-like disorders  
 Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leukopenia  
 Serious bleeding events  
 Lupus and lupus-like illness  
 Serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrosis, and 
erythema multiforme) 
The purpose of the AE of special interest list is to identify and capture product specific 
AEs/reactions requiring expedited reporting or close monitoring by 1 or more regulatory 
authorities or close monitoring required by UCB. This tool will help ensure that specific 
special reporting requirements from regulatory authorities and safety topics requiring close 
monitoring are appropriately identified, processed, reported, and monitored. The process also 
allows for detection of safety signals, signal evaluation, and the assessment of changes in the 
benefit-risk ratio of UCB products/compounds, based on all safety and benefit-risk 
information available for the protection of the patient. 
Has been changed to: 
10.3 AEs of interest 
An AE of 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 not 
fulfill the expedited reporting criteria of “serious,” “unexpected,” and “associated with the 
use of the drug.”  
Adverse events of interest include:  
 Serious infections, including opportunistic infections  
 Malignancies, including lymphoma  
 Congestive heart failure  
 Demyelinating-like disorders  
 Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leukopenia  
 Serious bleeding events  
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 Lupus and lupus-like syndrome  
 Serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrosis, and 
erythema multiforme) 
Adverse events of interest must be reported immediately by the Investigator (see 
Section 10.4).  
The purpose of the AE of interest list is to identify and capture product specific AEs/reactions 
requiring expedited reporting or close monitoring by 1 or more regulatory authorities or close 
monitoring required by UCB. This tool will help ensure that specific special reporting 
requirements from regulatory authorities and safety topics requiring close monitoring are 
appropriately identified, processed, reported, and monitored. The process also allows for 
detection of safety signals, signal evaluation, and the assessment of changes in the 
benefit-risk ratio of UCB products/compounds, based on all safety and benefit-risk 
information available for the protection of the patient. 
Change #74 
Section 10.4 Immediate reporting of AEs, the third bullet: 
 AE of special interest (see Section 10.3) 
Has been changed to: 
 AE of interest (see Section 10.3) 
Change #75 
Section 10.6 Laboratory measurements, the first and second paragraphs: 
Hematology, biochemistry, urinalysis samples will be collected at Screening, Baseline, 
Weeks 4, 8, 12, 16, 20, 24, 32, every 8 weeks thereafter, the Early Discontinuation/End of 
Treatment Visit, and the Final Visit 12 weeks after the last dose of study medication. At 
Weeks 1 and 2, CRP samples will be collected only.  
Retesting within the Screening Period is allowed after consultation with the Medical Monitor 
in case of reporting failure of laboratory results (eg, issues with transportation of samples). 
Have been changed to: 
Hematology, biochemistry, and urinalysis samples will be collected at Screening, Baseline, 
Weeks 4, 8, 12, 16, 20, 24, 32, every 8 weeks thereafter, the Early Discontinuation/End of 
Treatment Visit, and the Final Visit 12 weeks after the last dose of study medication. At 
Week 1, only CRP and PK samples will be collected and at Week 2, only CRP samples will 
be collected.  
Retesting of laboratory assessments within the Screening Period is allowed in case of isolated 
exclusionary laboratory assessments at Screening if, in the Investigator’s opinion, the value is 
not reflective of the study participant’s previous clinical and laboratory pattern (see Section 
6.3). In addition, retesting within the Screening Period is allowed in case of reporting failure 
of laboratory results (eg, issues with transportation of samples). 
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Change #76 
Section 10.6 Laboratory measurements, the following sentence has been added at the end of 
the sixth paragraph: 
Only samples for CRP, PK, and immunological variables will then be collected at Baseline 
(Week 0). 
Change #77 
Section 10.6 Laboratory measurements, seventh paragraph, the second sentence: 
The planned total blood volumes collected at a single time point (visit) will not exceed 
approximately 8mL. 
Has been changed to: 
The planned total blood volumes collected at a single time point (visit) will vary between 
2mL and 9mL. 
Change #78 
Section 10.6 Laboratory measurements, the eighth to tenth paragraphs: 
In addition, treatment of the veinpuncture site with an anesthetic cream prior to dosing is 
permitted. 
If QuantiFERON testing is required to be performed by the central lab (for study participants 
with documented history of severe positive PPD reaction or previous documented history of 
BCG vaccination, see Section 6.2) additional blood sampling of approximately 3ml will be 
required at Screening. 
If the result of the QuantiFERON is indeterminate, the test may be repeated once. The retest 
must be conducted in the allowable Screening window. Study participants with 
QuantiFERON (performed ≤3 months prior to Screening) positive or indeterminate are 
excluded. 
Have been changed to: 
In addition, treatment of the venipuncture site with an anesthetic cream prior to blood 
sampling is permitted. 
If IGRA testing is required to be performed by the central lab (for all study participants from 
5 to 17 years of age, see Section 6.2) additional blood sampling of approximately 3mL will 
be required at Screening.  
If the result of the IGRA is indeterminate, the test may be repeated once. The retest must be 
conducted in the allowable Screening window. Study participants with IGRA (performed ≤3 
months prior to Screening) positive or indeterminate and a chest x-ray confirmative of TB 
infection are excluded (see Section 10.7.9.2).  
For study participants from 2 to 4 years of age, PPD testing will be performed locally (except 
for study participants with documented BCG vaccination) as described in Section 10.7.9.2.3. 
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Change #79 
Section 10.6 Laboratory measurements, the sentence above the table and Table 10-2 
Laboratory measurements: 
The central laboratory will analyze and assess blood and urine samples for the following 
(except urine pregnancy test): 
Table 10-2 
Laboratory measurements 
Hematology 
Serum biochemistry 
Urinalysis 
Red blood cells 
Hemoglobin 
Hematocrit 
Platelets 
White blood cells 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total calcium 
Inorganic phosphorus 
Creatinine kinase 
Glucose 
Creatinine 
Uric acid 
Urea 
Total protein 
Albumin 
Alkaline phosphatase 
Gamma glutamyl tranferase 
Aspartate aminotransferase 
Alanine aminotransferase 
Bilirubin 
Total cholesterol 
CRP 
Autoantibodies (ANA and 
anti-dsDNA antibodies)  
pH 
Protein 
Glucose  
Blood 
Microscopy (WBC, RBC, casts, 
crystals, bacteria) (Microscopy 
will be performed only when 
there are abnormalities on 
dipstick) 
Serum pregnancy test(a) 
 
Hepatitis screening(b) 
HBcAb 
HBsAb 
HBsAg 
HCVAb 
HBV DNA, if applicable 
TB screening(c) 
QuantiFERON 
ANA=antinuclear antibody; anti-dsDNA antibodies=double-stranded deoxyribonucleic acid antibody; 
CRP=C-reactive protein; HBcAb=hepatitis B core antibody; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis 
B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; RBC=red blood cells; WBC=white blood cells  
a 
Serum pregnancy tests will be performed at Screening by the central laboratory (see Section 10.7.7). At 
Baseline, Weeks 8, 16, 24, and every visit thereafter, urine pregnancy tests will be performed locally. 
b 
Study participants will be tested for hepatitis at Screening. HBV DNA is required for study participants with 
only positive HBcAb (negative HBsAg and HBsAb) or only positive HBsAg 
c 
Only study participants with documented history of severe positive PPD reaction or previous documented 
history of BCG vaccination, see Section 6.2.  
Note: Other pharmacokinetic assessments may be periodically performed as per Section 9. 
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Have been changed to: 
The central laboratory will analyze and assess blood and urine samples for the following 
(except dip stick test and urine pregnancy test); other PK assessments may be periodically 
performed as per Section 9: 
Table 10-2 
Laboratory measurements 
Hematology 
Serum biochemistry 
Urinalysis 
Red blood cells 
Hemoglobin 
Hematocrit 
Platelets 
White blood cells 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total calcium 
Inorganic phosphorus 
Creatinine kinase 
Glucose 
Creatinine 
Uric acid 
Urea 
Total protein 
Albumin 
Alkaline phosphatase 
Gamma glutamyl transferase 
Aspartate aminotransferase 
Alanine aminotransferase 
Lactate dehydrogenase 
Bilirubin 
Total cholesterol 
CRP 
Autoantibodies (ANA and 
anti-dsDNA antibodies)  
pH(a) 
Protein(a) 
Glucose(a)  
Blood(a) 
Microscopy (WBC, RBC, casts, 
crystals, bacteria) (Microscopy 
will be performed only when 
there are abnormalities on 
dipstick)(a) 
Serum and urine pregnancy 
test(b) 
 
Hepatitis screening(c) 
HBcAb 
HBsAb 
HBsAg 
HCVAb 
HBV DNA, if applicable 
TB screening(d) 
IGRA (ages 5-17 years ),  
PPD (ages 2-4 years) 
ANA=antinuclear antibody; anti-dsDNA antibodies=double-stranded deoxyribonucleic acid antibody; BCG=Bacille 
Calmette-Guérin; CRP=C-reactive protein; DNA=deoxyribonucleic acid; HBcAb=hepatitis B core antibody; 
HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C 
virus; IGRA=interferon-gamma release assay; RBC=red blood cells; TB=tuberculosis; WBC=white blood cells 
Note: The Screening Visit must be completed at least 4 to 12 working days prior to the Baseline Visit, depending on 
regional requirements and laboratory assessments required for the study participant (refer to laboratory manual for 
country-specific requirements). In case HBV DNA or TB IGRA is to be analyzed, the Baseline Visit can be 
performed at the earliest 12 days after the Screening Visit (6 working days in Russia). Study participants can only be 
enrolled into the study after all laboratory results of the Screening Visit have been confirmed. 
a 
Urine dipsticks will be done locally at the site; only abnormalities will be reported. In case of abnormalities on 
dipstick, microscopy will be performed by the central laboratory. 
b 
Serum pregnancy tests will be performed at Screening by the central laboratory (see Section 10.7.7). At 
Baseline, Weeks 8, 16, 24, and every visit thereafter, urine pregnancy tests will be performed locally. 
c 
Study participants will be tested for hepatitis at Screening. HBV DNA is required for study participants with 
only positive HBcAb (negative HBsAg and HBsAb) or only positive HBsAg. A hepatitis panel result which 
indicates immunity due to hepatitis B vaccination is not considered an exclusion criterion. 
d 
IGRA testing is required at Screening for all study participants aged 5 to 17 years; PPD testing is required for 
all study participants aged 2 to 4 years (except for study participants with documented BCG vaccination).  
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Change #80 
Section 10.7.1 Vital signs, the first sentence: 
Vital signs will be measured within approximately 15 minutes prior to dosing with study 
medication.  
Has been changed to: 
Vital signs will be measured within approximately 15 minutes prior to dosing and in addition 
(pulse and blood pressure only) approximately 30 minutes after dosing with study 
medication. 
Change #81 
Section 10.7.9 Assessment and management of TB and TB risk factors: 
10.7.9.1  
Assessment and management of TB and TB risk factors 
As TNF-antagonists are known to be associated with significant risk of reactivation of latent 
TB, appropriate rigorous precautions are being taken within the protocol to address this. For 
inclusion in the study, see Section 6.2 (Exclusion Criterion 11). 
Study participants who develop evidence of latent or active TB during the study must 
immediately discontinue further administration of study medication. Once withdrawn from 
study treatment, study participants should return for the Early Discontinuation Visit, 
complete all Early Discontinuation assessments, and complete a Final Visit 12 weeks after 
the last dose of study medication. 
10.7.9.1  
Tuberculosis assessments 
10.7.9.1.1 
Tuberculin purified protein derivative (PPD) skin test 
A Mantoux tuberculin skin test must be performed preferably at the Screening Visit but at 
least within 3 months prior to Screening 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. 
If the skin test is positive, induration will be seen at and around the place of injection or 
puncture. The size (diameter) of the induration is measured and recorded. The results of the 
test are assessed in accordance to the criteria set in Section 6.2 (Exclusion Criterion 11). 
10.7.9.1.2 
Administration of the Mantoux tuberculin skin test 
The intradermal injection of a measured amount of tuberculin is the standard method of 
detecting infection with Mycobacterium tuberculosis. One-tenth milliliter of PPD (ie, 5TU 
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), 27G needle and a tuberculin 
syringe. The tuberculin should be injected by a qualified health care worker just 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 
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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. The study study participant 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. 
If a study participant fails to return within 72 hours and has a negative skin test, tuberculin 
testing should be repeated. If a positive PPD is read after 72 hours, the study participant will 
be considered to be TB positive. Study participants should never be allowed to read their own 
tuberculin skin tests.  
The 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. Erythema should not be 
measured. The presence or absence of induration 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 for those tests classified as negative (ie, 0mm).  
An induration of 5mm or greater 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, ie, an induration of 5mm or greater, 
in response to the tuberculin skin test is reserved for immunocompromised study participants. 
This definition is to be applied here to maximize the likelihood of detecting latent TB. 
T-cell interferon gamma release assays  
A QuantiFERON®-TB GOLD must be done at the Screening Visit in those study participants 
with a documented history of severe positive PPD reaction or a documented history of BCG 
vaccination. Mantoux tuberculin skin testing must be done on all other study participants. 
10.7.9.1.3 
Tuberculosis questionnaire 
The questionnaire “Evaluation of signs and symptoms of tuberculosis” (see Appendix 17.9) 
should be used as a source document. The questionnaire will be completed at Screening, 
Baseline, Weeks 12 and 24, every 16 weeks thereafter, and at the Early Discontinuation/End 
of Treatment Visit. The questionnaire will be completed by the Investigator or designee twice 
at each visit, once for the study participant and once for the caregiver and appropriately 
identified (ie, labeled study participant or caregiver). The questionnaire will assist with the 
identification of study participants who may require therapy for TB. A study 
participant/caregiver who answers “Yes” to the question “Has the study participant/caregiver 
been in close contact with an individual with active TB, or an individual who has recently 
been treated for TB?” at Screening is excluded. A “Yes” response to any of the other 
questions within the questionnaire at Screening should trigger further careful assessment to 
determine if study participant has latent or active TB (see Exclusion Criterion 11, Section 
6.2). A “Yes” response to any of the questions during the study should trigger further careful 
assessment to determine if the study participant has TB (regardless if latent or active) and has 
to be withdrawn from the study. 
Responses to the questions and the Investigator’s assessment of the study participant’s status 
and any action taken must be recorded in the source documents. 
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10.7.9.2  
Tuberculosis management 
For inclusion in the study, see Section 6.2 (Exclusion Criterion 11). 
It is the Sponsor’s requirement that all study participants who are on latent TB treatment at 
Baseline must comply with the full therapy course (see Section 6.2, Exclusion Criterion 11). 
Study participants who discontinue treatment for latent TB prematurely or who are 
noncompliant with anti-TB therapy in the Investigator’s or Sponsor’s opinion must 
discontinue further use of study medication and be immediately withdrawn from study 
participation. Once withdrawn from study treatment, study participants should return for the 
Early Discontinuation Visit to complete all early withdrawal assessments, and complete the 
Final Visit 12 weeks after the last dose of study medication. 
Study participants that develop evidence of latent or active TB once enrolled in the study and 
receiving IMP must immediately discontinue further administration of study medication until 
diagnosis is confirmed. If latent or active TB is confirmed, the study participant also must be 
withdrawn immediately from the study. The study participant must return for the Early 
Discontinuation Visit to complete all early withdrawal assessments, and complete the Final 
Visit 12 weeks after the last dose of study medication. Confirmed active TB (ie, positive 
culture or acid-fast bacilli smear) is an SAE which 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. Confirmed latent TB should be recorded both as an AE and 
the reason for discontinuation from the study. 
Follow-up information of suspected and confirmed TB cases 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 data, and TB diagnostic procedures used to 
follow-up and confirm recovery of TB. 
Has been changed to: 
10.7.9  
 
Tuberculosis guidance, testing, and screening 
10.7.9.1  
Guidance  
TNFα-inhibitors are known to be associated with an increased risk of TB and therefore, 
precautions are taken within the protocol to mitigate this risk. Study participants who develop 
signs or symptoms that may indicate latent TB infection or active TB during the Treatment 
Period must immediately discontinue further administration of IMP. Additional actions 
required are provided below. The Investigator should consider all potential sites of infection 
when assessing for TB during the study participant’s history and the physical examination, 
and other evaluations. Sites commonly infected by TB include: the lungs, larynx, lymph 
glands, pleura, gastrointestinal system, genito-urinary tract (including renal), bones and 
joints, meninges, peritoneum, pericardium, and skin. This is not an exhaustive list and 
unusual presentations and areas of involvement should always be considered. Common 
symptoms that the study participant may present with include cough, blood in sputum, night 
sweats, lymphadenitis, joint pain/swelling, spinal deformity, headache/confusion, abdominal 
pain mimicking inflammatory bowel disease (IBD), frequent or painful urination, scrotal 
mass in men and pelvic inflammatory disease in women as well as other symptoms, or 
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nonspecific symptoms. This is not an exhaustive list and unusual presentations should always 
be considered.  
Note that study participants with a history of NTMB or active NTMB infection are excluded 
from the study regardless of prior or current therapy.  
10.7.9.1.1 
Latent tuberculosis infection  
Per exclusion criterion 11c, LTB infection is defined as a positive TB test (IGRA or PPD) 
and chest imaging without positive findings for TB along with the absence of signs, 
symptoms, or physical findings suggestive of TB infection. If available, smears and cultures 
of secretions or tissues should also be negative. At Screening, study participants who have 
recently (defined as no more than 12 months prior to Screening) completed a full course of 
prophylaxis for LTB infection may be considered for study participation. Study participants 
who have received prophylactic therapy for LTB infection for at least 4 weeks prior to 
enrollment (initiation of CZP treatment at Baseline) and are committed to completing the full 
course of therapy, may be considered for study participation. The Investigator must provide 
documentation of duration, and start and stop date of such therapy and method of therapy (eg, 
self-administration or directly observed therapy). This evidence of treatment should be 
recorded contemporaneously with the treatment date and should be filed in the source 
document. The Investigator must assess that the study participant’s likelihood of completing 
the therapy is high and duly record their opinion in the study participant’s record prior to 
enrolling the study participant. The Investigator must discuss each case with the Study 
Physician or Medical Monitor prior to allowing the study participant to be screened (in event 
the LTB infection was discovered prior to study participant screening) or enrolled (if LTB 
infection was identified at Screening). 
Study participants with LTB infection, indicated by positive PPD skin test or positive IGRA 
test result (or TB questionnaire indicating an increased study participant’s risk of exposure or 
infection with TB for study participants ages 2 to 4 years with documented BCG vaccination) 
and a chest imaging without evidence of TB infection at Screening, may be rescreened after 
initiation of treatment for latent TB and after approval of the Medical Monitor. Prior to first 
study medication administration TB treatment must have been ongoing for at least 4 weeks 
before enrollment will be allowed. Treatment for TB must be continued until completion of 
9 months of therapy. 
Prophylaxis may include isonicotinic acid hydrazide/isoniazid [INH] therapy (with vitamin 
B6) for 9 months or any other locally approved therapy or combination regimen/therapy 
appropriate for immunosuppressed study participants. For study participants living in or 
recently emigrated (within 5 years prior to initiation of Screening) from a country or region 
with a high endemic rate of INH resistant or multidrug resistant TB, an approved 
combination therapy must be followed that is both approved for the region in which the 
infection was likely to have originated and targeted to the study participant’s specific TB 
infection. If there is disagreement between the local guidelines and the UCB standards, the 
more stringent guidance will apply and should be considered appropriate for the study 
participant’s specific TB infection.  
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Study participants with LTB infection must not undergo repeat PPD testing. The IGRA test 
should be used for any protocol-mandated TB screening, except for study participants who 
are 2 to 4 years of age and for whom the PPD test is the mandatory test in this study, unless 
written documentation of a BCG vaccination is available. 
LTB infection and active TB identified during study  
During the study, study participants who develop evidence of LTB infection or active TB 
must immediately discontinue further administration of IMP, be scheduled for the Early 
Discontinuation Visit and Final Visit, and referred to a TB specialist for evaluation. Evidence 
of LTB infection is defined as study participant’s IGRA test converts to positive or 
indeterminate (and confirmed indeterminate on repeat), or PPD converts to positive (this only 
applies for regions or sites where UCB has determined PPD may be used for screening and 
follow-up), or the study participant’s questionnaire or history and physical examination 
indicates that TB infection or exposure may have occurred. Evidence of active TB includes, 
in addition to the aforementioned tests, signs and symptoms of organ involvement. In either 
situation, the study participant should be carefully assessed by a TB specialist for active TB 
(see Section 10.7.9.1). Study participants diagnosed with active TB or LTB infection should 
receive appropriate TB or prophylaxis therapy respectively per local and UCB guidelines as 
described above. Any presumptive diagnosis or diagnosis of LTB infection or active TB is a 
reportable event; refer to Section 10.2.2 for details. The Investigator is to complete and 
submit the TB follow-up form provided.  
The study participant should be transferred to the care of their physician and managed 
according to the best available standard of care. Study participants identified as having 
converted to LTB infection or active TB during the study must be scheduled to return for the 
Early Discontinuation Visit as soon as possible but no later than the next scheduled study 
visit. The study participant should be encouraged to keep the Final Visit as specified by the 
protocol. 
If infection with NTMB is identified during the study, the same procedure as for active TB 
acquired during the study must be followed. 
10.7.9.2  
TB screening and testing  
10.7.9.2.1 
Chest x-ray  
A chest radiograph (anterior-posterior view at minimum, but preferably anterior-posterior and 
lateral) must be taken for study participants with a positive or repeatedly indeterminate IGRA 
or PPD testing or TB questionnaire indicating an increased study participant’s risk of 
exposure or infection with TB (study participants 2 to 4 years of age with a written 
documentation of BCG vaccination) at Screening. If a study participant has had a recent 
radiograph of the chest within approximately 3 months prior to Screening, it may be used in 
lieu of the protocol-required radiograph. All chest imaging must be read by a qualified 
radiologist/pulmonary physician who is specifically required to look for evidence of active 
TB or inactive TB.  
Radiographic findings suggestive of inactive TB or active TB may include but are not limited 
to: apical fibrosis, pleural thickening, pulmonary nodules, fibrotic scars, calcified 
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granulomas, upper lobe infiltrates, cavitations and pleural effusions, calcified lung nodules, 
calcified hilar lymph nodes, and pericardial calcification.  
The chest x-ray (or, if done, Computed Axial Tomography of the Chest) must be negative for 
TB infection as determined by a qualified radiologist/pulmonary physician. All chest imaging 
(particularly x-rays) should be available for review by the Investigator before enrollment of 
the study participant. 
10.7.9.2.2 
Interferon-gamma release assay (IGRA test)  
The IGRA (QuantiFERON®-TB GOLD In-Tube test) is the protocol-required method of 
screening for TB in study participants from 5 to 17 years of age and will be performed at the 
central laboratory. The IGRA and PPD skin test may not be performed at the same time and a 
positive or indeterminate outcome in 1 test may not be overruled by a negative result in the 
other. If the result of the IGRA test is indeterminate, the test may be repeated once. If positive 
or indeterminate on retest, the study participant may not be enrolled without further 
evaluation and treatment, as well as discussion by the Investigator with the Study Physician 
or Medical Monitor. The retest must be done during the protocol-defined Screening window. 
10.7.9.2.3 
Tuberculin Purified Protein Derivative (PPD skin test)  
In study participants from 2 to 4 years of age (except for study participants 2 to 4 years of age 
with a written documentation of BCG vaccination), the PPD skin test must be administered 
during Screening or within the 3 months prior to Screening in accordance with the 
instructions below.  
PPD skin test administration guidance:  
The PPD skin test should be administered by a qualified health care professional. The 
injection is made intradermally into the inner surface of the forearm using a 27-gauge needle 
and tuberculin syringe using one-tenth milliliter of PPD (5TU PPD-S or 2TU of PPD-RT 23). 
If necessary, a site on the anterior thigh may be used. The site on the forearm used for 
administration should be free of lesions and away from superficial veins. 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 attempt was improperly administered, 
another attempt may be made using a new site that is at least 3cm away from the original. 
The site used for the second test should be recorded in the source documents. The study 
participant should be instructed to refrain from scratching the site and to avoid covering the 
area with a bandage.  
The PPD skin test must be interpreted by a trained health care professional between 48 and 
72 hours after administration. The reading should be done in a good light, with the forearm 
slightly flexed at the elbow. The presence or absence of induration, as determined by 
inspection and by palpation is the basis for interpreting the result. The diameter of induration 
is measured transversely to the long axis of the forearm and recorded in millimeters. 
Erythema should not be measured. An induration greater than or equal to 5mm is considered 
positive for the purposes of this study; regardless of study participant’s history of vaccination 
with BCG. Study participants are not permitted to read their own PPD skin tests. If a study 
participant fails to return within 72 hours and has a negative skin test, the PPD skin test must 
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be repeated. Documentation must include a record of the date, time, and site of the test, and 
the date and time the test was read with exact induration measurement. 
The PPD skin test should not be applied to study participants with the following history: 
 History of severe positive PPD reaction, or 
 History of a positive PPD skin test 
 History of BCG vaccination regardless of time since vaccination 
 History of positive IGRA test (or 2 indeterminate IGRA tests)  
10.7.9.3 TB questionnaire (evaluation of signs and symptoms associated with 
TB and guidelines for evaluating exposure risk)  
A questionnaire “Evaluation of Signs and Symptoms of Tuberculosis” will be provided as a 
source document (see Appendix 17.9). The questionnaire will assist study sites with the 
identification of study participants that may require prophylactic therapy for TB as well as 
suspect new cases of active TB. In this study, the TB questionnaire will be completed for 
study participant and parent/caregiver at the following visits: Screening, Baseline, Weeks 12 
and 24, every 16 weeks thereafter, and at the Early Discontinuation/End of Treatment Visit.  
Responses of “yes” to any of the items on the questionnaire may indicate that a study 
participant’s risk of exposure or infection with TB has increased. This should prompt the 
Investigator to further examine the circumstances and consider initiating investigations 
necessary to rule out infection with TB. Depending on the outcome of the investigations, the 
Investigator will determine if prophylaxis or treatment for TB is required. Any presumptive 
diagnosis or diagnosis of LTB infection or active TB is a reportable event; refer to Section 
10.2.2 for details. The Investigator is to complete and submit the TB follow-up form 
provided. 
Change #82 
Section 11.1 PedACR30, PedACR50, PedACR70, and PedACR90 clinical response, the 
fourth bullet: 
 CHAQ completed by parent or caregiver (including the Parent's Assessment of Arthritis 
Pain [VAS]) (Appendices 17.1 and 17.2) 
Has been changed to: 
 CHAQ completed by parent or caregiver (Appendix 17.1) 
Change #83 
Section 11.1 PedACR30, PedACR50, PedACR70, and PedACR90 clinical response, the 
bolded sentence at the end of the section: 
Documentation of the assessment of all 6 core set measures will be submitted to UCB or 
designee for immediate review of completeness at Week 0 (Baseline), Week 16, and 
Week 56, while the study participant is still on site. 
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Has been changed to: 
Documentation of the assessment of all 6 core set measures will be submitted to UCB or 
designee for immediate review of completeness at Week 0 (Baseline), Week 16, Week 24, 
and Week 56, while the study participant is still on site. 
Change #84 
Section 11.2 PRINTO/PRCSG standard joint examination, second paragraph, the second 
sentence: 
The assessment for swelling is made on 67 joints from the above list. 
Has been changed to: 
The assessment for swelling is made on 66 joints from the above list. 
Change #85 
Section 11.5 Childhood Health Assessment Questionnaire (CHAQ), third paragraph, the third 
sentence: 
The same parent/caregiver should complete the questionnaires for each visit. 
Has been changed to: 
Preferably, the same parent/caregiver should complete the questionnaires for each visit. The 
questionnaire will not be collected if the study participant is not living with a parent/caregiver 
at least part-time, ie, if the parent/caregiver is not able to answer the questions appropriately.  
Change #86 
Section 11.6 Parent’s Assessment of Arthritis Pain (VAS), second paragraph, the third 
sentence: 
The same parent/caregiver should complete the scale for each visit. 
Has been changed to: 
Preferably, the same parent/caregiver should complete the scale for each visit. The scale will 
not be completed if the study participant is not living with a parent/caregiver at least part-
time, ie, if the parent/caregiver is not able to answer the question appropriately.  
Change #87 
Section 11.7 Parent’s Global Assessment of Overall Well-Being (VAS), second paragraph, 
the third sentence: 
The same parent/caregiver should complete the scale for each visit. 
Has been changed to: 
Preferably, the same parent/caregiver should complete the scale for each visit. The scale will 
not be completed if the study participant is not living with a parent/caregiver at least part-
time, ie, if the parent/caregiver is not able to answer the question appropriately.  
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Change #88 
Section 11.9 Juvenile Arthritis Disease Activity Score 75-joint (JADAS-75), the heading and 
the first paragraph: 
11.9 Juvenile Arthritis Disease Activity Score 75-joint (JADAS-75) 
The change in the JADAS-75 from Baseline will be assessed. The JADAS-75 is a composite 
disease activity score based on a 75-joint count and includes the measures (normalized as 
needed): Physician’s Global Assessment of Disease Activity (VAS) (0 to 10), the Parent’s 
Global Assessment of Overall Well-Being (VAS) (0 to 10), the active joint count (0 to 75), 
and CRP (0 to 10) (Consolaro et al, 2009; Nordal et al, 2010).  
Have been changed to: 
11.9 JADAS 
The change in the JADAS from Baseline will be assessed. The JADAS-71 is a composite 
disease activity score based on a 71-joint count and includes the measures (normalized as 
needed): Physician’s Global Assessment of Disease Activity (VAS) (0 to 10), the Parent’s 
Global Assessment of Overall Well-Being (VAS) (0 to 10), the active joint count (0 to 71), 
and CRP (0 to 10) (Consolaro et al, 2009; Nordal et al, 2010).  
Change #89 
Section 11.10 Clinically Inactive Disease and clinical remission, first paragraph, the fifth 
bullet: 
 Physician’s Global Assessment of Disease Activity score of ≤5mm on a 100mm VAS 
Has been changed to: 
 Physician’s Global Assessment of Disease Activity score of best possible on the scale 
used (0mm on the 100mm VAS) 
Change #90 
Section 11.11 Duration of morning stiffness (DMS), the second sentence: 
The study participant/caregiver will be asked the following question (Kirwan, JR and 
Reeback TS, 1986): 
Has been changed to: 
The study participant/caregiver will be asked the following question (Kirwan and Reeback, 
1986): 
Change #91 
Section 11.12 Faces Pain Scale-Revised (FPS-R), the following has been added at the end of 
the first paragraph: 
Study participants enrolled at 5 to 11 years of age will continue with the FPS-R when 
reaching 12 years of age. Completion of the FPS-R will not be required for study participants 
enrolled at 2 to 4 years of age if they reach 5 years of age during the study. 
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Change #92 
Section 11.13 Patient’s Assessment of Arthritis Pain (JIA Pain VAS), the first sentence: 
In the JIA Pain VAS, study participants ages 12 to 17 years are asked the following question 
“How much pain have you had because of your illness today (acute version)/in the past week 
(standard version)?” (as applicable). 
Has been changed to: 
In the JIA Pain VAS, study participants aged 12 years or older are asked the following 
question “How much pain have you had because of your illness today (acute version)/in the 
past week (standard version)?” (as applicable). 
Change #93 
Section 11.14 Fatigue Assessment Scale (NRS), fourth paragraph, the third and fourth 
sentences: 
The same parent/caregiver should complete the questionnaires for each visit. The 
questionnaire should be checked by site personnel for completeness. 
Have been changed to: 
Preferably, the same parent/caregiver should complete the scale for each visit. The scale will 
not be completed if the study participant is not living with a parent/caregiver at least part-
time, ie, the parent/caregiver is not able to answer the question appropriately. The scale 
should be checked by site personnel for completeness. 
Change #94 
Section 11.15 Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey, 
the following sentence has been added at the end of the first paragraph: 
For further information please see the instructions provided on the worksheet. 
Change #95 
Section 12.2.1 Definition of source data, fourth paragraph, the first sentence: 
Source documents that are computer-generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports).  
Has been changed to: 
Source documents that are computer-generated and stored electronically do not need to be 
printed if the electronic medical record system at the investigational site is 21CFR Part 11 
compliant. If the system is not 21CFR Part 11 compliant, the source data must be printed for 
review by the monitor (eg, ECG reports).  
Change #96 
Section 12.2.2 Source data verification, the following has been added below the first 
paragraph: 
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The procedures for conducting SDV on computerized study participant records (if the system 
is 21CFR Part 11 compliant) are the same as those for paper records. Source data verification 
is performed by reviewing the electronic record directly. 
Change #97 
Section 12.4 Termination of the study, the first sentence: 
If, in the results of the first interim analysis, less than 50% of the study population achieves at 
least a PedACR30 response at Week 16, the study will be discontinued. 
Has been changed to: 
If, in the results of the first interim analysis, less than 50% of the study population achieves a 
PedACR30 response at Week 16, the study will be discontinued. 
Change #98 
Section 13.1 Definition of analysis sets, the following set has been removed: 
 The Per-Protocol Set (PPS) will consist of study participants in the FAS who have 
completed a prespecified minimal exposure to the treatment regimen without any 
important protocol deviations that may influence the validity of the efficacy data.  
Change #99 
Section 13.1 Definition of analysis sets, the following set has been added: 
 The Pharmacokinetic-Pharmacodynamic (PK-PD) Population will consist of all study 
participants in the SS who have at least 1 post-Baseline plasma concentration 
measurement and 1 post-Baseline PedACR30 assessment. 
Change #100 
Section 13.2.1 Data presentation, the following sentence has been added at the beginning of 
the paragraph: 
For safety and efficacy analyses, study participants will be grouped by their Baseline weight 
strata (10 to <20kg [22 to <44lb], 20 to <40kg [44 to <88lb], and ≥40kg [≥88lb]). Selected 
analyses will also group study participants by their Baseline age group, concomitant MTX 
use, and anti-CZP antibody status. 
Change #101 
Section 13.2.2 Multicenter studies, the first sentence: 
Approximately 70 centers are planned to enroll 125 study participants into this study.  
Has been changed to: 
Approximately 55 centers are planned to enroll 125 study participants into this study.  
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Change #102 
Section 13.3 Planned safety analyses, the third paragraph: 
Selected safety summaries will be presented overall as well as by age (2 to 5 years, 6 to 
11 years, and 12 to 17 years) and weight strata (10 to <20kg [22 to <44lb], 20 to <40kg [44 to 
<88lb], and ≥40kg [≥88lb]) and study participants with or without concomitant MTX use. 
Safety summaries will be based upon the SS (study participants who were enrolled and took 
at least 1 dose of study medication). 
Has been changed to: 
Selected safety summaries will be presented overall and by Baseline weight strata, as well as 
by age (2 to 5 years, 6 to 11 years, and 12 to 17 years), by concomitant MTX use, and by 
anti-CZP antibody status. Safety summaries will be based upon the SS (study participants 
who were enrolled and took at least 1 dose of study medication). 
Change #103 
Section 13.5 Planned efficacy and health outcomes analyses, the fourth paragraph: 
For PedACR30, PedACR50, PedACR70, and PedACR90, results will be presented overall as 
well as by age (2 to 4 years, 5 to 11 years, and 12 to 17 years) and weight strata (10 to <20kg 
[22 to <44lb], 20 to <40kg [44 to <88lb], and ≥40kg [≥88lb]) and study participants with or 
without concomitant MTX use. 
Has been changed to: 
For PedACR30, PedACR50, PedACR70, and PedACR90, results will be presented overall 
and by Baseline weight strata, as well as by age (2 to 5 years, 6 to 11 years, and 12 to 
17 years), by concomitant MTX use, and by anti-CZP antibody status.  
Change #104 
Section 13.5 Planned efficacy and health outcomes analyses, the eighth bullet below the 
fourth paragraph has been removed: 
 Shifts by visit of CRP from Baseline. 
Change #105 
Section 13.6 Handling of dropouts or missing data, the third paragraph, the first and second 
sentences: 
Data collected after the taking of rescue medication will be treated as missing/non-response 
in all analyses except where specifically stated otherwise. See Section 7.8.2 for a list of 
medications which, if commenced after Week 16, would result in data at only the next 
scheduled visit (and not all subsequent visits) being treated as missing/non-response. 
Has been changed to: 
Data collected after the taking of rescue medication will be treated as missing for continuous 
efficacy endpoints and non-response for binary efficacy endpoints in all analyses except 
where specifically stated otherwise. See Section 7.8.2 for a list of medications which would 
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result in data at only the next scheduled visit (and not all subsequent visits) being treated as 
missing/non-response. 
Change #106 
Section 13.7 Planned interim analysis and data monitoring: 
Following completion of Week 12 (Visit 7) by at least 20 study participants (minimum 
6 study participants in each age group: 2 to 5 years, 6 to 11 years, and 12 to 17 years), PK 
data will be reviewed by age stratum and compared with plasma concentrations observed 
previously in adult study participants with RA. The plasma concentration analysis may be 
done in 2 or 3 stages if at least 20 study participants in total complete Week 12 (Visit 7) 
before 6 study participants in 1 or both of the other age groups have completed (see Section 
5.1). 
Comparisons will be made between the geometric mean and median values for the pediatric 
and adult study participants, as well as between the individual pediatric data and the adult 5th 
and 95th percentile and minimum and maximum observed values. 
If the pediatric plasma concentrations demonstrate that the geometric mean and median 
concentrations are below the adult 5th percentile or above the 95th percentile, the PK data will 
be used to re-evaluate the weight-based dose adjustment algorithm for pediatric study 
participants. If necessary, a revised pediatric dose algorithm will be derived. Any change in 
dose regimen will require a protocol amendment prior to implementation. 
Population PK or PK/PD analyses will not be performed separately on this initial 15-study 
participant cohort but later on the entire population. 
After the last study participant has reached the Week 16 Visit (Visit 8, including collection of 
the Week 16 postdose blood samples), the database will be cut and a full interim analysis will 
be performed based upon 16 weeks of exposure for each individual (or all data for those cases 
who withdrew before this timepoint). This will be used to determine whether the study will 
continue or not. Given the descriptive nature of the data presentations, there are no statistical 
implications of this interim analysis. 
A second full interim analysis will be performed upon 56 weeks of exposure (Visit 14) and 
will be used for the initial submission of results for regulatory purposes. 
Further interim analyses may be performed at the Sponsor’s discretion as required. 
Has been changed to: 
Interim analysis of PK data will compare CZP plasma concentration data from this study with 
CZP plasma concentrations observed previously in adult study participants with RA. This 
plasma concentration analysis will be done on an ongoing basis throughout the study, starting 
when 6 study participants in 1 of the age groups have completed Week 12 (Visit 7).  
Comparisons will be made between the Week 12 geometric mean and median values for the 
pediatric and adult study participants, as well as between the individual pediatric data and the 
adult 5th and 95th percentile and minimum and maximum observed values. 
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If the pediatric plasma concentrations demonstrate that the geometric mean and median 
concentrations are below the adult 5th percentile or above the 95th percentile, the PK data will 
be used to re-evaluate the weight-based dose adjustment algorithm for pediatric study 
participants. Interim CZP plasma concentration data available at the time of Protocol 
Amendment 3 indicate that no change to the dosing algorithm is required. If future interim 
analyses, which may include PopPK, indicate that plasma levels of JIA study participants are 
outside of the exposure range observed in previous adult RA studies, a revised pediatric dose 
algorithm will be derived. Any change in dose regimen will require a protocol amendment 
prior to implementation. 
After all active study participants have completed the Week 16 (Visit 8) assessments, an 
interim analysis of PedACR30 response rates will be performed and the study will be 
discontinued if less than 50% of the study population achieves a PedACR30 response at 
Week 16. Given the descriptive nature of the data presentations, there are no statistical 
implications of this interim analysis. 
After the last study participant has reached the Week 24 Visit (Visit 10), the database will be 
cut and a full interim analysis of all safety and efficacy endpoints will be performed based 
upon 24 weeks of exposure for each individual (or all data for those cases who withdrew 
before this timepoint).  
A second full interim analysis of all safety and efficacy endpoints will be performed based 
upon 56 weeks of exposure (Visit 14). 
Further interim analyses may be performed at the Sponsor’s discretion as required. 
A DSMB will periodically review all emerging safety data. The DSMB members will be 
independent of the Sponsor and Investigators. The DSMB members will be informed by the 
Drug Safety representative (or designee) of all SAEs at the time of expedited reporting and 
will review periodically all emerging safety data (eg, SAEs, AEs, safety laboratory data). 
Based on the safety data, the DSMB can recommend modifying/stopping the study. 
Change #107 
Section 16 References, the following reference has been added: 
Centers for Disease Control and Prevention. http:www.cdc.gov/TB/topic/testing/default.htm. 
Accessed 03 Sep 2012. 
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17.14 
Protocol Amendment 4 
Rationale for the amendment 
The primary purpose of this substantial amendment is to implement a change in the dosing 
algorithm for children and adolescents currently enrolled in RA0043. A thorough review of 
all SAEs and AEs by the Safety Review Committee was performed and there were no 
unexpected safety findings. An interim PopPK analysis of CZP plasma concentration data 
from 35 study participants with post-Baseline samples in RA0043 was performed in 
combination with PK data from studies in Western (mainly Caucasian) adult study 
participants with RA and in Japanese adult study participants with RA. The interim PopPK 
analysis and subsequent simulations indicated that in all weight groups (10 to <20kg, 20 to 
<40kg, and ≥40kg), a higher exposure in terms of the maximum plasma concentration (Cmax) 
and the area under the curve (AUC) is likely to be observed in the population of children and 
adolescents with the current dosing algorithm. This difference is not due to body mass/weight 
differences alone, and therefore an additional adjustment to the dosing algorithm to account 
for these unexplained differences is necessary in order to maintain children and adolescents 
within the adult exposure ranges. The clinical relevance in terms of efficacy or safety is 
currently unknown. 
Based on the results of the interim PopPK analysis, new enrollment into RA0043 will be 
suspended, effective 17 Jul 2013, and the dose for study participants already enrolled in 
RA0043 will be reduced with Protocol Amendment 4. An overall dose reduction for pediatric 
study participants of 50% of the dose currently used in RA0043 is proposed to provide a 
pragmatic dosing regimen that will yield a closer match to the adult plasma concentration 
range achieved in adults with the approved label for RA (CZP 400mg at Weeks 0, 2, and 4 
followed by CZP 200mg Q2W thereafter).  
A summary table of the proposed revised dosing recommendations for loading and treatment 
doses in RA0043 based on the PopPK model simulations is provided below. 
Table 17‒1 Proposed revised dosing recommendation based on PopPK 
model simulations 
Weight range 
Loading dose  
(Weeks 0, 2, and 4) 
Treatment dose 
(Week 6 and onwards) 
10 to <20kg (22 to <44lb) 
50mg Q2W 
50mg Q4W 
20 to <40kg (44 to <88lb) 
100mg Q2W 
50mg Q2W 
≥40kg (≥88lb) 
200mg Q2W 
100mg Q2W 
PopPK=population pharmacokinetic; Q2W=every 2 weeks; Q4W=every 4 weeks 
The reduced loading dose will only apply to study participants already enrolled in RA0043 
who do not achieve persistent CID and resume CZP treatment after implementation of 
Protocol Amendment 4. 
A dose reduction of 50% can be implemented immediately by using the existing IMP without 
causing a study delay to acquire new drug supply. Following the change of dose, the ≥40kg 
(≥88lb) weight group will use the 0.5ml PFS (CZP 100mg) for treatment doses, while the 20 
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to <40kg (44 to <88lb) weight group will use the 0.25ml PFS (CZP 50mg) for treatment 
doses. As a PFS containing 25mg is not available, the lowest body weight category (10 to 
<20kg [22 to <44lb]) will use the 0.25ml PFS (CZP 50mg) administered with a 4-week dose 
interval. 
Additional assessments of CZP plasma concentration after the change in dose have been 
added to the tabular schedule of study assessments to ensure that the 50% dose reduction will 
result in plasma concentrations within the target range of those observed in adults. Additional 
Unscheduled Visits have been implemented, as required, in order to closely monitor the study 
participants over a period of 12 weeks after the dose change.   
In addition, changes have been made to clarify study-related procedures, and administrative 
and editorial changes have been made to update study personnel, update terminology, and 
correct errors. 
Modifications and changes 
Global changes 
The following changes have been made throughout the protocol: 
 The description of the dose regimen has been changed throughout the protocol to reflect 
the reduction of the treatment dose for study participants in the 3 weight categories.  
 Additional PK samples after the dose change have been added throughout the protocol. 
 The term “level” has been changed to “concentration” throughout the protocol for CZP 
plasma concentrations and antibody concentrations. This global change is not listed under 
the specific changes. 
 The timing of predose and postdose vital sign assessments has been added throughout 
Section 8 for clarification, where applicable. This global change is not listed under the 
specific changes. 
 The following clarification has been added in the description of timepoints for efficacy 
assessments in Section 11: “(including Unscheduled Visits that are related to the dose 
change implemented with Protocol Amendment 4).” This global change is not listed 
under the specific changes. 
Specific changes 
This section displays the modifications in this amendment compared with the previous 
version of the protocol dated 06 May 2013. The changes are displayed in the order of 
appearance. 
Change #1 
On the SPONSOR DECLARATION page, the name of the Clinical Program Director: 
 
Has been changed to: 
 
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Change #2 
Under STUDY CONTACT INFORMATION, the name and contact details of the Clinical 
Program Director: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
 
Have been changed to: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
 
Change #3 
LIST OF ABBREVIATIONS, the following abbreviation: 
Q2W 
every 2 weeks 
Has been changed to: 
Q2W, Q4W 
every 2 weeks, every 4 weeks 
Change #4 
Section 1 Summary, eighth paragraph, the first sentence: 
Certolizumab pegol will be administered as a fixed dose based on weight every 2 weeks 
(Q2W) throughout the study consisting of 3 loading doses at Weeks 0, 2, and 4 
(minimum=100mg, maximum=400mg) followed by a treatment dose (minimum=50mg, 
maximum=200mg). 
Has been changed to: 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 (minimum=50mg every 2 weeks 
[Q2W], maximum=200mg Q2W) followed by a treatment dose (minimum=50mg every 
4 weeks [Q4W], maximum=100mg Q2W). With the implementation of Protocol 
Amendment 4, the reduced loading dose applies only for already enrolled study participants 
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who resume CZP treatment after nonpersistent Clinically Inactive Disease (CID). Prior to 
implementation of Protocol Amendment 4, the minimum and maximum loading doses in the 
study were CZP 100mg Q2W and CZP 400mg Q2W, respectively, and the minimum and 
maximum treatment doses were CZP 50mg Q2W and CZP 200mg Q2W, respectively. 
Change #5 
Section 1 Summary, eighth paragraph, the sixth and seventh sentences: 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicate that no change to the dosing algorithm is required. If future analyses indicate that 
plasma levels of JIA study participants are outside of the exposure range observed in previous 
adult RA studies, the dosing algorithm may be changed via a protocol amendment.  
Has been changed to: 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicated that no change to the dosing algorithm was required. The protocol stated that if 
future analyses indicate that plasma concentrations of JIA study participants are outside of 
the exposure range observed in previous adult RA studies, the dosing algorithm may be 
changed via a protocol amendment.  
Change #6 
Section 1 Summary, the following has been added below the eighth paragraph: 
Results of an interim population pharmacokinetic (PopPK) analysis suggest that while 
observed CZP plasma concentrations have remained in the adult range, they have been at the 
upper end of the distribution. Simulations predict that for some study participants in RA0043 
receiving the initially determined loading doses up to Week 4 (Visit 5), plasma 
concentrations are likely to exceed the range previously seen in adult study participants 
receiving CZP 400mg Q2W. Furthermore, plasma concentrations of study participants 
receiving the initially determined treatment dose after Week 4 (Visit 5) are predicted to 
exceed the concentration range observed in adults receiving CZP 200mg Q2W. Based on 
these findings, the dosing regimen will be changed with Protocol Amendment 4, and the 
doses to be administered will be reduced by 50% for all weight groups. This dose change is 
intended to achieve plasma concentrations that are similar to the effective concentrations 
observed in previous studies in adult study participants with RA. Additional assessments of 
the CZP plasma concentration after the change in dose will be performed to ensure that the 
50% dose reduction will result in plasma concentrations within the target range of those 
observed in adults.  
Change #7 
Section 5.1 Study description, sixth paragraph, the second and third sentences: 
Certolizumab pegol will be administered as a fixed dose based on weight, Q2W throughout 
the study (see Table 7-1). At Baseline (Week 0, Visit 2) eligible study participants will begin 
with 3 loading doses of CZP at Weeks 0, 2, and 4 (minimum=100mg, maximum=400mg) 
followed by a treatment dose for the duration of the study (minimum=50mg, 
maximum=200mg).  
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Has been changed to: 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study (see Table 7-1). At Baseline (Week 0, Visit 2) eligible study participants will begin 
with 3 loading doses of CZP at Weeks 0, 2, and 4 (minimum=50mg Q2W, maximum=200mg 
Q2W) followed by a treatment dose for the duration of the study (minimum=50mg Q4W, 
maximum=100mg Q2W). With the implementation of Protocol Amendment 4, the reduced 
loading dose applies only for already enrolled study participants who resume CZP treatment 
after nonpersistent CID. Prior to implementation of Protocol Amendment 4, the minimum 
and maximum loading doses in the study were CZP 100mg Q2W and CZP 400mg Q2W, 
respectively, and the minimum and maximum treatment doses were CZP 50mg Q2W and 
CZP 200mg Q2W, respectively. 
Change #8 
Section 5.1 Study description, ninth paragraph, the second and third sentences: 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicate that no change to the dosing algorithm is required. If future analyses indicate that 
plasma concentrations are outside of the exposure range observed in previous studies with 
adults, the dosing algorithm may be changed via a protocol amendment. 
Have been changed to: 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicated that no change to the dosing algorithm was required. The protocol stated that if 
future analyses indicate that plasma concentrations are outside of the exposure range 
observed in previous studies with adults, the dosing algorithm may be changed via a protocol 
amendment. 
Change #9 
Section 5.1 Study description, the following has been added at the end of the section: 
Results of an interim PopPK analysis conducted in Jun 2013 suggest that while observed CZP 
plasma concentrations have remained in the adult range, they have been at the upper end of 
the distribution. Simulations predict that for some study participants in RA0043 receiving the 
initially determined loading doses up to Week 4 (Visit 5), plasma concentrations are likely to 
exceed the range previously seen in adult study participants receiving CZP 400mg Q2W. 
Furthermore, plasma concentrations of study participants receiving the initially determined 
treatment dose after Week 4 (Visit 5) are predicted to exceed the concentration range 
observed in adults receiving CZP 200mg Q2W. Based on these findings, the dosing regimen 
will be changed with Protocol Amendment 4, and the doses to be administered will be 
reduced by 50% for all weight groups. This dose change is intended to achieve plasma 
concentrations that are similar to the effective concentrations observed in previous studies in 
adult study participants with RA. Additional assessments of the CZP plasma concentration 
after the change in dose will be performed to ensure that the 50% dose reduction will result in 
plasma concentrations within the target range of those observed in adults.  
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Change #10 
Section 5.1.1 Study duration per study participant, the last line: 
Planned Last Study participant, First Visit – 3Q/4Q 2013 
Has been changed to: 
Planned Last Study participant, First Visit – 3Q/4Q 2013 (to be confirmed) 
Change #11 
Section 5.2 Schedule of study assessments, footnotes “b,” “u,” “v,” and “y” in Table 5-1: 
b 
Vital signs, concomitant medications, concomitant procedures, and AEs must be assessed at every 
Unscheduled Visit. Other PK and safety assessments should be performed as related to nature of the visit. 
 
u 
CZP plasma level and anti-CZP antibodies to be measured at Weeks 4, 12, 16, and 24. A postdose CZP 
plasma sample will be collected at approximately 5 to 7 days following the Week 16 Visit (ie, requires 
an additional clinic site visit for blood collection at Week 17). 
v 
CZP plasma level and anti-CZP antibodies to be measured at Weeks 32, 40, and 48 and every 24 weeks 
thereafter.  
 
y 
After Week 4 (Visit 5) study participants/caregivers may administer CZP Q2W at home between scheduled 
study visits. See Section 7.2 regarding training and option for continued site administration for site 
administration. 
Have been changed to: 
b 
Vital signs, concomitant medications, concomitant procedures, and AEs must be assessed at every 
Unscheduled Visit. Other PK and safety assessments should be performed as related to nature of the visit. 
For Unscheduled Visits related to the dose change with Protocol Amendment 4, see Sections 7.2.1 and 
8.6.1. For these Unscheduled Visits, the same visit window applies, ie, ±3 days. 
 
u 
CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 4, 12, 16, and 24. A postdose 
CZP plasma sample will be collected at approximately 5 to 7 days following the Week 16 Visit (ie, 
requires an additional clinic site visit for blood collection at Week 17). For study participants already 
enrolled and treated prior to the implementation of Protocol Amendment 4 and hence undergoing a 
reduction of their dose, additional PK samples will be collected prior to dosing at the visit the dose change 
occurs and at the next 3 site visits following the dose change, ie, additional PK samples will be collected at 
the Unscheduled Visits or at the regular visits if not already planned per regular schedule. Afterwards, the 
regular PK sampling schedule applies. 
v 
CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 32, 40, and 48 and every 
24 weeks thereafter. For study participants already enrolled and treated prior to the implementation of 
Protocol Amendment 4 and hence undergoing a reduction of their dose, additional PK samples will be 
collected prior to dosing at the visit the dose change occurs and at the next 3 site visits following the dose 
change, ie, additional PK samples will be collected at the Unscheduled Visits or at the regular visits if not 
already planned per regular schedule. Afterwards, the regular PK sampling schedule applies. 
 
y 
After Week 4 (Visit 5) study participants/caregivers may administer CZP Q2W (or Q4W for the lowest 
weight group) at home between scheduled study visits. See Section 7.2 regarding training and option for 
continued site administration. 
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Change #12 
Section 5.4.2 Dose selection, the third and fourth sentences in the paragraph below Table 5-2: 
The intention is to study the equivalent dose regimen in children and adolescents, reducing 
the dose of CZP for pediatric study participants with body weights between 20 to <40kg 
(44 to <88lb) to CZP 200mg at Weeks 0, 2, and 4 followed by CZP 100mg Q2W (ie, 50% of 
the recommended adult dose). The dose of CZP will be reduced further to 25% of the adult 
dose for study participants with body weights 10 to <20kg (22 to <44lb) (ie, CZP 100mg at 
Weeks 0, 2, and 4 followed by CZP 50mg Q2W) (see Table 7-1). 
Have been changed to: 
The intention in RA0043 is to study the equivalent dose regimen in children and adolescents. 
Initial predictions, based on allometric scaling of PK data from adults, suggested that this 
could be achieved by reducing the dose of CZP for pediatric study participants with body 
weights between 20 to <40kg (44 to <88lb) to CZP 200mg at Weeks 0, 2, and 4 followed by 
CZP 100mg Q2W (ie, 50% of the recommended adult dose), and by reducing the dose further 
to 25% of the adult dose for study participants with body weights 10 to <20kg (22 to <44lb) 
(ie, CZP 100mg at Weeks 0, 2, and 4 followed by CZP 50mg Q2W). During the course of the 
study, results from the ongoing interim PK analysis and an interim PopPK analysis conducted 
in Jun 2013 indicated that plasma concentrations within the range previously seen in adult 
study participants receiving CZP 200mg Q2W would be achieved if the dose in RA0043 was 
reduced to 50%. Therefore, the treatment doses in this study will be reduced further with 
Protocol Amendment 4 so that study participants with body weights between 20 and <40kg 
(44 to <88lb) will receive CZP 50mg Q2W, and study participants with body weights of 
≥40kg (≥88lb) will receive CZP 100mg Q2W (see Table 7-1). The optimal treatment dose 
estimated in the PopPK model for the lowest weight group would be CZP 25mg Q2W, 
however, the lowest available dose size is CZP 50mg. Thus, study participants with body 
weights of 10 to <20kg (22 to <44lb) will receive CZP 50mg Q4W to achieve a 50% 
reduction. 
Change #13 
Section 5.4.2 Dose selection, the paragraph at the end of the section: 
The choice of dose and the weight-based dose-adjustment algorithm is supported by 
simulations of the PK exposure and response rates in children using the PopPK model and 
PK/PD exposure response model developed in adult RA study participants, corrected for 
pediatric demographics (C87079 addendum 08 Oct 2008). Results of these simulations show 
that all age groups exhibit similar exposures (Cmax and AUCT) to those of adults over the 
Week 14 to Week 16 dosing interval, with the pediatric/adult ratio of the median predicted 
values of PK parameters ranging from 1.03 to 1.19 for Cmax and from 0.97 to 1.18 for AUCT. 
The similarities in exposures are reflected in the probability of ACR20 response, which are 
similar for all age groups at Week 16 (pediatric/adult ratio of the median predicted values 
ranging from 1.08 to 1.10). These simulations were performed upon the assumption that 
disease progression and response rate for a given exposure are similar in children and adults. 
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Has been changed to: 
The original choice of dose and the weight-based dose-adjustment algorithm, prior to 
Protocol Amendment 4, was supported by simulations of the PK exposure and response rates 
in children using the PopPK model and PK/PD exposure response model developed in adult 
RA study participants, corrected for pediatric demographics (C87079 addendum 08 Oct 
2008). Results of these simulations showed that all age groups exhibit similar exposures 
(Cmax and AUCT) to those of adults over the Week 14 to Week 16 dosing interval, with the 
pediatric/adult ratio of the median predicted values of PK parameters ranging from 1.03 to 
1.19 for Cmax and from 0.97 to 1.18 for AUCT. The similarities in exposures were reflected in 
the probability of ACR20 response, which are similar for all age groups at Week 16 
(pediatric/adult ratio of the median predicted values ranging from 1.08 to 1.10). These 
simulations were performed upon the assumption that disease progression and response rate 
for a given exposure are similar in children and adults. The revised dose and weight-based 
dose adjustment algorithm was based on a PopPK analysis and simulation using data from 
35 study participants in this study with post-Baseline plasma concentrations of CZP available 
prior to Protocol Amendment 4. 
Change #14 
Section 7.2 Treatments to be administered, first paragraph, the first sentence: 
Throughout the study, CZP dosing is fixed dose based on weight and given Q2W. 
Has been changed to: 
Throughout the study, CZP dosing is fixed dose based on weight and given Q2W, with 
exception of the lowest weight group, who will receive the treatment dose Q4W following 
implementation of Protocol Amendment 4. 
Change #15 
Section 7.2 Treatments to be administered, first paragraph, the third sentence: 
Study participants start with 3 loading doses of CZP at Weeks 0, 2, and 4 (minimum=100mg, 
maximum=400mg) followed by a treatment dose for the duration of the study 
(minimum=50mg, maximum=200mg).  
Has been changed to: 
Study participants start with 3 loading doses of CZP at Weeks 0, 2, and 4 (minimum=50mg 
Q2W, maximum=200mg Q2W) followed by a treatment dose for the duration of the study 
(minimum=50mg Q4W, maximum=100mg Q2W). With the implementation of Protocol 
Amendment 4, the reduced loading dose applies only for already enrolled study participants 
who resume CZP treatment after nonpersistent CID. 
Change #16 
Section 7.2 Treatments to be administered, Table 7-1: 
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Table 7-1 Dosing administration of CZP  
Weight range 
Loading dose – 
Weeks 0, 2, and 4 
(mg/kg dose range) 
Treatment – 
Week 6 and onwards 
(mg/kg dose range) 
10 to <20kg 
(22 to <44lb) 
100mg 
(5-10mg/kg) 
1 x 0.5mL inj 
50mg 
(2.5-5mg/kg) 
1 x 0.25 mL inj 
20 to <40kg 
(44 to <88lb) 
200mg 
(5-10mg/kg) 
1 x 1mL inj 
100mg 
(2.5-5mg/kg) 
1 x 0.5mL inj 
≥40kg 
(≥88lb) 
400mg 
(<10mg/kg) 
2 x 1mL inj 
200mg 
(<5mg/kg) 
1 x 1mL inj 
CZP=certolizumab pegol; inj=injection 
Note: A study participant should only change dosing category during the course of the study if their weight 
crosses the 40kg/88lb boundary due to a weight change of >5kg (11lb) (eg, a 39.0kg study participant 
becomes 44.1kg) or crosses the 20kg/44lb boundary due to a weight change of >2.5kg (5.5lb) (eg, a 19.0kg 
study participant becomes 21.6kg). 
Has been changed to: 
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Table 7-1 
Dosing administration of CZPa  
Weight range 
Loading dose – 
Weeks 0, 2, and 4b 
(mg/kg dose range) 
Treatment – 
Week 6 and onwards 
(mg/kg dose range) 
10 to <20kg 
(22 to <44lb) 
50mg Q2W 
(2.5-5mg/kg) 
1 x 0.25mL inj  
50mg Q4W 
(2.5-5mg/kg) 
1 x 0.25mL inj  
20 to <40kg 
(44 to <88lb) 
100mg Q2W 
(2.5-5mg/kg) 
1 x 0.5mL inj  
50mg Q2W 
(1.25-2.5mg/kg) 
1 x 0.25mL inj  
≥40kg 
(≥88lb) 
200mg Q2W 
(<5mg/kg) 
1 x 1mL inj  
100mg Q2W 
(<2.5mg/kg) 
1 x 0.5mL inj  
CZP=certolizumab pegol; inj=injection; Q2W=every 2 weeks; Q4W=every 4 weeks 
Note: A study participant should only change dosing category during the course of the study if their weight 
crosses the 40kg/88lb boundary due to a weight change of >5kg (11lb) (eg, a 39.0kg study participant 
becomes 44.1kg) or crosses the 20kg/44lb boundary due to a weight change of >2.5kg (5.5lb) (eg, a 19.0kg 
study participant becomes 21.6kg). 
a Note that Table 7-1 describes the dosing administration of CZP after implementation of Protocol 
Amendment 4. Refer to Section 7.2.1 for the procedure to be taken for study participants already enrolled 
and treated prior to the implementation of Protocol Amendment 4, and who are undergoing a dose change. 
b With implementation of Protocol Amendment 4, the reduced loading dose applies only for study 
participants who are already enrolled and who resume CZP treatment after nonpersistent Clinically Inactive 
Disease. 
Change #17 
Section 7.2 Treatments to be administered, the last sentence: 
Study participants not achieving persistent CID and resuming treatment will re-start the 
fixed-dose CZP dosing based on their current weight with 3 loading doses of CZP 
administered Q2W over 6 weeks, followed by a treatment dose administered Q2W for the 
duration of the study (see Table 7-1). 
Has been changed to: 
Study participants not achieving persistent CID and resuming treatment will re-start the 
fixed-dose CZP dosing based on their current weight with 3 loading doses of CZP 
administered Q2W over 6 weeks, followed by a treatment dose administered Q2W, or Q4W 
for the lowest weight group after implementation of Protocol Amendment 4, for the duration 
of the study (see Table 7-1). 
Change #18 
A new subsection has been added at the end of Section 7.2 Treatments to be administered: 
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7.2.1 Procedure for dose change (Protocol Amendment 4) 
With Protocol Amendment 4, the treatment dose in the study will be reduced by 50% for all 
weight groups. 
 The timepoint of the dose change is the next scheduled time of injection after the 
Informed Consent form related to the dose change was signed. In case the next scheduled 
injection was planned for home dosing, the study participant will be requested to return to 
the clinic for an Unscheduled Visit for signing the Informed Consent form related to the 
dose change, administration of CZP, and to dispense the new supplies. Unused IMP 
dispensed previously needs to be returned. 
In case the study participant is not able to visit the site for that next scheduled injection, 
then the dose change must be performed at the next scheduled injection. 
 Study participants will be monitored at least every 4 weeks over a period of 12 weeks 
after the dose change, either at the regularly scheduled visits or at additional Unscheduled 
Visits. The Unscheduled Visits will be scheduled to match with the dosing schedule, ie, 
the study medication will be administered at the day of the Unscheduled Visit. The 
Investigator should consult with the Medical Monitor in case of any questions related to 
the timing of the dose change or the Unscheduled Visits.    
 For study participants undergoing a dose change prior to or at Week 12 (Visit 8), and 
who return for regularly scheduled visits every 4 weeks for a period of 12 weeks after 
the dose change, no additional Unscheduled Visits will be required. 
 For study participants undergoing a dose change after Week 12 (Visit 8), 1 or 2 
additional Unscheduled Visits will be required.  
For example, a study participant undergoing a dose change at Week 20 (Visit 9) will 
return for a regularly scheduled visit at Week 24 (Visit 10), will require an additional 
Unscheduled Visit at Week 28, and will return for the next regularly scheduled visit at 
Week 32 (Visit 11). 
A study participant who is undergoing a dose change at Week 40 (Visit 12) will 
require an Unscheduled Visit at Week 44, will return for a regularly scheduled visit at 
Week 48 (Visit 13), and will require another Unscheduled Visit at Week 52. 
 Study participants undergoing the dose change at an Unscheduled Visit between the 
regular visits will be required to return at the latest after 4 weeks for an Unscheduled 
Visit in case no regular visit is scheduled within 4 weeks. These study participants 
will then continue with the next regular visit as planned and return for a last 
Unscheduled Visit another 4 weeks later. For example, a study participant undergoing 
the dose change at Week 42 at the clinic will return for an Unscheduled Visit at Week 
46, then continue with the regular visit at Week 48 (Visit 13), and return for an 
additional Unscheduled Visit at Week 52 before continuing with the regular Week 56 
visit (Visit 14). 
 At Unscheduled Visits when the dose change occurs and following the dose change, the 
following will be assessed: AEs, concomitant medications and procedures, vital signs, 
hematology/biochemistry, as well as CRP, PRINTO/PRCSG standard joint examination, 
Physician’s Global Assessment of Disease Activity, CHAQ, and Parent’s Global 
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Assessment of Overall Well-Being to determine PedACR response rates. Assessments at 
regular visits will be done as scheduled, except for PK sampling (see below). 
 A predose PK sample will be collected prior to administration of CZP at the visit the dose 
change occurs. Additional predose PK sampling after the change in dose will be 
performed at the next 3 site visits, ie, additional PK samples will be collected at the 
Unscheduled Visits or at the regular visit if not already planned per regular schedule. 
Change #19 
Section 8.4 Visits 5 to 10 (Weeks 4, 8, 12, 16, 20, and 24), the 27th bullet point: 
 CZP plasma levels and anti-CZP antibodies (Weeks 4, 12, 16, and 24 only; predose.  
Study participants will return to the clinic site for a postdose CZP plasma sample 
approximately 5 to 7 days following the Week 16 visit.) 
Has been changed to: 
 CZP plasma concentrations and anti-CZP antibodies (Weeks 4, 12, 16, and 24 only, OR if 
a dose change is performed at the current visit OR if the study participant’s dose was 
changed during 1 of the last 3 visits following Protocol Amendment 4; predose.  
Study participants will return to the clinic site for a postdose CZP plasma sample 
approximately 5 to 7 days following the Week 16 visit.) 
Change #20 
Section 8.5 Visits 11 and continuing (Week 32 and every 8 weeks thereafter), the 27th bullet 
point: 
 CZP plasma levels and anti-CZP antibodies (Weeks 32, 40, and 48 and every 24 weeks 
thereafter) 
Has been changed to: 
 CZP plasma concentrations and anti-CZP antibodies (Weeks 32, 40, and 48 and every 
24 weeks thereafter, OR if a dose change is performed at the current visit OR if the study 
participant’s dose was changed during 1 of the last 3 visits following Protocol 
Amendment 4) 
Change #21 
Section 8.6 Unscheduled Visit, the first bullet point: 
 Vital signs 
Has been changed to: 
 Vital signs (within approximately 15 minutes prior to dosing and [pulse and blood 
pressure only] approximately 30 minutes after dosing, if dosing is applicable) 
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Change #22 
Section 8.6 Unscheduled Visit, a new subsection has been added at the end of the section: 
8.6.1 Unscheduled Visit related to dose change (Protocol Amendment 4) 
If required, study participants will return for an Unscheduled Visit to undergo the dose 
change upon implementation of Protocol Amendment 4. Study participants will be monitored 
at least every 4 weeks over a period of 12 weeks after the dose change, either at the regularly 
scheduled visits or at additional Unscheduled Visits. 
The following will be assessed at this visit: 
 Administration of study medication  
 CZP plasma concentrations and anti-CZP antibodies (predose)  
 Adverse events 
 Concomitant medications and procedures 
 Vital signs (within approximately 15 minutes prior to dosing and [pulse and blood 
pressure only] approximately 30 minutes after dosing) 
 Hematology/biochemistry 
 CRP 
 PRINTO/PRCSG standard joint examination 
 Physician’s Global Assessment of Disease Activity (VAS) 
 CHAQ-parent reported 
 Parent’s Global Assessment of Overall Well-Being (VAS)  
 IXRS contact, if applicable 
Change #23 
Section 9 Assessment of pharmacokinetics and immunological variables, the following has 
been added below the first paragraph: 
For study participants already enrolled and treated prior to the implementation of Protocol 
Amendment 4 and hence undergoing a reduction of their dose, additional PK samples will be 
collected prior to dosing at the visit the dose change occurs and at the next 3 site visits 
following the dose change, ie, additional PK samples will be collected at either Unscheduled 
Visits or regular visits if not already planned per regular schedule. Afterwards, the regular PK 
sampling schedule applies. 
Change #24 
Section 9 Assessment of pharmacokinetics and immunological variables, fifth paragraph, the 
first and second sentences: 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicate that no change to the dosing algorithm is required. If future analyses indicate that 
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plasma concentrations are outside of the exposure range of those observed in previous studies 
with adults, the dosing algorithm may be changed via a protocol amendment, and if necessary 
additional interim analyses including PopPK, may be performed. 
Have been changed to: 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicated that no change to the dosing algorithm was required. The protocol stated that if 
future analyses indicate that plasma concentrations are outside of the exposure range of those 
observed in previous studies with adults, the dosing algorithm may be changed via a protocol 
amendment, and if necessary additional interim analyses including PopPK, may be 
performed. 
Change #25 
Section 9 Assessment of pharmacokinetics and immunological variables, the following has 
been added below the fifth paragraph: 
Results of an interim PopPK analysis conducted in Jun 2013 suggest that while observed CZP 
plasma concentrations have remained in the adult range, they have been at the upper end of 
the distribution. Simulations predict that for some study participants in RA0043 receiving the 
initially determined loading doses up to Week 4 (Visit 5), plasma concentrations are likely to 
exceed the range previously seen in adult study participants receiving CZP 400mg Q2W. 
Furthermore, plasma concentrations of study participants receiving the initially determined 
treatment dose after Week 4 (Visit 5) are predicted to exceed the concentration range 
observed in adults receiving CZP 200mg Q2W. Based on these findings, the dosing regimen 
will be changed with Protocol Amendment 4, and the doses to be administered will be 
reduced by 50% for all weight groups. This dose change is intended to achieve plasma 
concentrations that are similar to the effective concentrations observed in previous studies in 
adult study participants with RA. Additional assessments of the CZP plasma concentration 
after the change in dose will be performed to ensure that the 50% dose reduction will result in 
plasma concentrations within the target range of those observed in adults.  
Change #26 
Section 10.6 Laboratory measurements, the following sentence has been added at the end of 
the first paragraph: 
In addition, hematology, biochemistry, and CRP samples will be collected at Unscheduled 
Visits related to the dose change implemented with Protocol Amendment 4. 
Change #27 
Section 10.7.1 Vital signs, the last sentence: 
Vital signs will be measured at Screening, Baseline, every visit through the Early 
Discontinuation/End of Treatment Visit, and the Final Visit 12 weeks after the last dose of 
study medication. 
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Has been changed to: 
Vital signs will be measured at Screening, Baseline, every visit (including all Unscheduled 
Visits) through the Early Discontinuation/End of Treatment Visit, and the Final Visit 12 
weeks after the last dose of study medication. 
Change #28 
Section 11.8 C-reactive protein (CRP), the third sentence: 
Values will be used in determining PedACR clinical response, JADAS, CID and CRM, ratio 
to Baseline in CRP, and shift by visit of CRP from Baseline. 
Has been changed to: 
Values will be used in determining PedACR clinical response, JADAS, CID and CRM, and 
ratio to Baseline in CRP. 
Change #29 
Section 11.10 Clinically Inactive Disease and clinical remission, the last sentence: 
Study participants not achieving persistent CID and resuming treatment will re-start the 
fixed-dose CZP dosing based on their current weight with 3 loading doses of CZP 
administered Q2W over 6 weeks, followed by a treatment dose administered Q2W for the 
duration of the study. 
Has been changed to: 
Study participants not achieving persistent CID and resuming treatment will re-start the 
fixed-dose CZP dosing based on their current weight with 3 loading doses of CZP 
administered Q2W over 6 weeks, followed by a treatment dose administered Q2W for the 
duration of the study, with exception of the lowest weight group, who will receive the 
treatment dose Q4W following implementation of Protocol Amendment 4. 
Change #30 
Section 13.4 Planned PK, PD, and immunological variable analysis, eighth paragraph, the 
second sentence: 
Plasma concentration time curves will be plotted, overall, and by antibody status for each age 
stratum and the overall population. 
Has been changed to: 
Plasma concentration time curves will be plotted, overall, by Baseline age stratum, and by 
anti-CZP antibody status. Subgroup analyses will include an analysis of the study participants 
enrolled and treated up to the Week 16 timepoint under the original treatment dosing 
regimen.   
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Change #31 
Section 13.7 Planned interim analysis and data monitoring, third paragraph, the second and 
third sentences: 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicate that no change to the dosing algorithm is required. If future interim analyses, which 
may include PopPK, indicate that plasma levels of JIA study participants are outside of the 
exposure range observed in previous adult RA studies, a revised pediatric dose algorithm will 
be derived. 
Have been changed to: 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicated that no change to the dosing algorithm was required. The protocol stated that if 
future interim analyses, which may include PopPK, indicate that plasma concentrations of 
JIA study participants are outside of the exposure range observed in previous adult RA 
studies, a revised pediatric dose algorithm will be derived. 
Change #32 
Section 13.7 Planned interim analysis and data monitoring, the following has been added 
below the third paragraph: 
Based on results of an interim PopPK analysis conducted in Jun 2013 described in 
Section 5.1, the dosing regimen will be changed with Protocol Amendment 4, and the doses 
to be administered will be reduced by 50% for all weight groups. This change is intended to 
achieve plasma concentrations similar to the effective concentrations observed in previous 
studies in adult study participants with RA.  
The CZP plasma concentrations will be monitored on an ongoing basis following the change 
in dose regimen to confirm they are within the adult range. 
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17.15 
Protocol Amendment 5 
Rationale for the amendment 
The primary purpose of this substantial amendment is to reopen enrollment under the new 
reduced CZP dose regimen and to update the statistical analysis to account for the changes in 
the CZP dose regimen. FDA has agreed to the implementation of the reduced dosing regimen. 
Two CZP dosing regimen subgroups will be defined as follows: 
 Original CZP dose regimen: includes all study participants in the SS who began treatment 
in accordance with the original dosing regimen defined for the study (including study 
participants who underwent a dose reduction under Amendment 4).  
 Reduced CZP dose regimen: includes all study participants in the SS who began 
treatment in accordance with the reduced dosing regimen defined for the study. 
With implementation of Protocol Amendment 5, all newly enrolled study participants will 
receive loading and maintenance doses that correspond to 50% of the original CZP dose 
regimen used in RA0043. The maintenance dose of previously enrolled study participants 
was reduced with Protocol Amendment 4. The reduced CZP dose regimen as implemented 
with Protocol Amendments 4 and 5 is based on PopPK model simulations and is provided 
below. 
Table 17‒2 Proposed revised dosing recommendation based on PopPK 
model simulations 
Weight range 
Loading dose  
(Weeks 0, 2, and 4) 
Maintenance dose 
(Week 6 and onwards) 
10 to <20kg (22 to <44lb) 
50mg Q2W 
50mg Q4W 
20 to <40kg (44 to <88lb) 
100mg Q2W 
50mg Q2W 
≥40kg (≥88lb) 
200mg Q2W 
100mg Q2W 
PopPK=population pharmacokinetic; Q2W=every 2 weeks; Q4W=every 4 weeks 
At the time of Protocol Amendment 4, 78 study participants had been enrolled and started 
treatment on the original CZP dose regimen. To allow for a comparison of the group of 78 
study participants on the original CZP dose regimen with a comparable group of study 
participants on the revised CZP dose regimen, a further 78 study participants are planned to 
be enrolled on the reduced CZP dose regimen. Thus, the overall number of study participants 
to be enrolled will be increased from 125 to 156. Study participants who had fulfilled the 
eligibility criteria but could not be enrolled due to the suspended enrollment as of 17 Jul 2013 
will be allowed to be rescreened. 
Key changes include the clarification that only study participants who will be enrolled under 
Protocol Amendment 5 and will begin treatment on the reduced CZP dose regimen will be 
taken into account for the study stopping rule based on the Week 16 PedACR30 interim 
analysis, and that a minimum number of 10 study participants in each weight category will 
need to be enrolled for the reduced CZP dose regimen. 
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In addition, the requirement that a study participant’s dosing category may only be changed if 
the 40kg/88lb and 20kg/44lb weight boundaries are crossed due to weight changes of >5kg 
and >2.5kg, respectively, was removed from the protocol. Applying this requirement at the 
time of dose reduction would lead to potential underdosing of study participants who have 
just crossed the weight boundary, as they would have their doses reduced by 50% even 
though, based on their actual weight, they already fall into the next higher weight category. 
Furthermore, additional changes have been made to the exclusion criteria and guidelines 
related to TB detection and monitoring to adapt the protocol to the current UCB standard, and 
descriptions of CID and CRM have been modified for clarity. 
In addition, administrative and editorial changes have been made to update study personnel, 
update terminology, and to correct errors. 
Modifications and changes 
Global changes 
The following changes have been made throughout the protocol and are not listed under the 
specific changes: 
 The terms “treatment dose” and “Treatment Period” have been changed to “maintenance 
dose” and “Maintenance Period” throughout the protocol. 
 The definition of the minimum number of study participants to be enrolled in each weight 
category has been updated throughout the protocol to clarify that a minimum number of 
10 study participants on the reduced CZP dose regimen will be enrolled in each weight 
category. For the other enrollment categories (age categories, CZP monotherapy, study 
participants with ERA) the minimum enrollment numbers apply irrespective of the dose 
regimen. 
 The definition of the study stopping rule has been updated throughout the protocol to 
clarify that the study will be discontinued if less than 50% of the study population 
enrolled on the reduced CZP dose regimen (Protocol Amendment 5) achieves a 
PedACR30 response at Week 16. 
 The explanation that “With the implementation of Protocol Amendment 4, the reduced 
loading dose applies only for already enrolled study participants who resume CZP 
treatment after nonpersistent Clinically Inactive Disease (CID)” has been removed 
throughout the protocol as this is no longer applicable with implementation of Protocol 
Amendment 5.  
 The description of minimum and maximum doses under the original CZP dose regimen 
has been updated to refer to both Protocol Amendments 4 and 5.  
 The description that the dosing regimen will be changed based on findings from an 
interim PopPK analysis and the doses to be administered will be reduced by 50% for all 
weight groups has been updated throughout the protocol to refer to Protocol 
Amendments 4 and 5.  
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Specific changes 
This section displays the modifications in this amendment compared with the previous 
version of the protocol dated 01 Aug 2013. The changes are displayed in the order of 
appearance. 
Change #1 
On the SPONSOR DECLARATION page, the name of the Study Physician: 
 
Has been changed to: 
 
Change #2 
Under STUDY CONTACT INFORMATION, the name and contact details of the Study 
Physician: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
 
Have been changed to: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
 
Change #3 
Under SERIOUS ADVERSE EVENT REPORTING, the global e-mail address: 
DS_ICT@ucb.com 
Has been changed to: 
DSICT@ucb.com 
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Change #4 
LIST OF ABBREVIATIONS, the following abbreviation has been added: 
EAIR 
exposure-adjusted incidence rate 
Change #5 
Section 1 Summary, fourth paragraph, the first sentence: 
Approximately 167 study participants will be screened to enroll 125 study participants in this 
study. 
Has been changed to: 
Approximately 195 study participants will be screened to enroll 156 study participants in this 
study. 
Change #6 
Section 1 Summary, ninth paragraph, the last sentence: 
Additional assessments of the CZP plasma concentration after the change in dose will be 
performed to ensure that the 50% dose reduction will result in plasma concentrations within 
the target range of those observed in adults. 
Has been changed to: 
Continued analysis of CZP plasma concentrations (including additional assessments for study 
participants undergoing a dose reduction with Protocol Amendment 4) will be performed to 
confirm that the 50% dose reduction will result in plasma concentrations within the target 
range of those observed in adults. 
Change #7 
Section 5.1 Study description, last paragraph, the last sentence: 
Additional assessments of the CZP plasma concentration after the change in dose will be 
performed to ensure that the 50% dose reduction will result in plasma concentrations within 
the target range of those observed in adults. 
Has been changed to: 
Continued analysis of CZP plasma concentrations (including additional assessments for study 
participants undergoing a dose reduction with Protocol Amendment 4) will be performed to 
confirm that the 50% dose reduction will result in plasma concentrations within the target 
range of those observed in adults. 
Change #8 
Section 5.1.1 Study duration per study participant, the First Study participant, First Visit and 
Last Study participant, First Visit dates at the end of the section: 
Planned First Study participant, First Visit – 1Q 2012 
Planned Last Study participant, First Visit – 3Q/4Q 2013 (to be confirmed) 
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Have been changed to: 
First Study participant, First Visit – 1Q 2012 
Planned Last Study participant, First Visit – 1Q/2Q 2015 
Change #9 
Section 5.1.2 Planned number of study participants and sites, the first and second sentences: 
Approximately 167 study participants will be screened at about 55 centers in order to enroll 
125 study participants in this study. 
The enrollment per site is limited to a maximum of 10 study participants. 
Have been changed to: 
Approximately 195 study participants will be screened at about 55 centers in order to enroll 
156 study participants in this study. 
The enrollment per site is limited to a maximum of 12 study participants. 
Change #10 
Section 5.4.2 Dose selection, the paragraph below Table 5-2 (fifth sentence onwards): 
During the course of the study, results from the ongoing interim PK analysis and an interim 
PopPK analysis conducted in Jun 2013 indicated that plasma concentrations within the range 
previously seen in adult study participants receiving CZP 200mg Q2W would be achieved if 
the dose in RA0043 was reduced to 50%. Therefore, the treatment doses in this study will be 
reduced further with Protocol Amendment 4 so that study participants with body weights 
between 20 and <40kg (44 to <88lb) will receive CZP 50mg Q2W, and study participants 
with body weights of ≥40kg (≥88lb) will receive CZP 100mg Q2W (see Table 7-1). The 
optimal treatment dose estimated in the PopPK model for the lowest weight group would be 
CZP 25mg Q2W, however, the lowest available dose size is CZP 50mg. Thus, study 
participants with body weights of 10 to <20kg (22 to <44lb) will receive CZP 50mg Q4W to 
achieve a 50% reduction.  
Has been changed to: 
During the course of the study, results from the ongoing interim PK analysis and an interim 
PopPK analysis conducted in Jun 2013 indicated that plasma concentrations within the range 
previously seen in adult study participants receiving CZP 200mg Q2W would be achieved if 
the dose in RA0043 was reduced to 50% of the original dose used in the study. Therefore, the 
maintenance doses in this study will be reduced further with Protocol Amendment 4 so that 
study participants with body weights between 20 and <40kg (44 to <88lb) will receive CZP 
50mg Q2W, and study participants with body weights of ≥40kg (≥88lb) will receive CZP 
100mg Q2W (see Table 7-1). The optimal maintenance dose estimated in the PopPK model 
for the lowest weight group would be CZP 25mg Q2W, however, the lowest available dose 
size is CZP 50mg. Thus, study participants with body weights of 10 to <20kg (22 to <44lb) 
will receive CZP 50mg Q4W to achieve this 50% reduction. In addition, with Protocol 
Amendment 5, the loading dose in the study will be reduced by 50% for newly enrolled study 
participants, so that study participants with body weights of 10 to <20kg (22 to <44lb) will 
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receive CZP 50mg at Weeks 0, 2, and 4, study participants with body weights between 20 to 
<40kg (44 to <88lb) will receive CZP 100mg at Weeks 0, 2, and 4, and study participants 
with body weights ≥40kg (≥88lb) will receive CZP 200mg at Weeks 0, 2, and 4. 
Change #11 
Section 6.2 Exclusion criteria, exclusion criterion no. 11, the first sentence: 
11. Study participants with known TB infection, at high risk of acquiring TB infection, or 
latent TB (LTB) infection are excluded: 
Has been changed to: 
11. Study participants with known TB infection, or at high risk of acquiring TB infection, are 
excluded. Study participants with latent TB (LTB) infection that have not received a 
minimum of 4 weeks of prophylactic treatment are only eligible following prophylaxis: 
Change #12 
Section 6.2 Exclusion criteria, exclusion criterion no. 11, the first sentence under “c”: 
c. Latent TB infection (unless appropriate prophylaxis is initiated prior to study 
treatment according to Section 10.7.9.1.1 and continued to completion of prophylaxis) 
is defined as: 
Has been changed to: 
c. Latent TB infection is defined as: 
Change #13 
Section 6.3 Retesting and rescreening, second paragraph, the following has been added as a 
new bullet below the first bullet: 
 Study participants who fulfilled all eligibility criteria but were registered as Screen 
failures due to suspension of enrollment as of 17 Jul 2013 are allowed to be rescreened. 
Change #14 
Section 6.4 Withdrawal criteria, withdrawal criterion no.3: 
3. Study participant who develops confirmed reactivation of latent or active TB or NTMB 
infection during the study (including, but not limited to, conversion demonstrated by 
IGRA or PPD or other diagnostic means, eg, TB questionnaire, during the course of the 
study) must be withdrawn. 
Has been changed to: 
3. Study participant who develops active TB or NTMB infection during the study must be 
withdrawn.  
Change #15 
Section 7.2 Treatments to be administered, the second paragraph: 
To prevent unnecessary switching of study participants between weight categories, a study 
participant’s dosing category may only be changed after assessment of weight changes by the 
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Investigator at a scheduled clinic visit and if their weight crosses the 40kg/88lb boundary due 
to a weight change of >5kg (11lb) compared to their last weight measurement of the lower 
weight category (eg, a 39.0kg study participant becomes 44.1kg) or crosses the 20kg/44lb 
boundary due to a weight change of >2.5kg (5.5lb) (eg, a 19.0kg study participant becomes 
21.6kg). Weight, weight change, and any change in study medication dose will be 
documented. 
Has been changed to: 
A study participant’s dosing category will only be changed after the confirmation of a weight 
change by the Investigator at a scheduled clinic visit.  
The study participant will receive the dose of the next weight category once their weight 
crosses the 40kg/88lb boundary or crosses the 20kg/44lb boundary at a scheduled clinic visit. 
The study participant will continue on the dose of the new weight category regardless of 
potential decrease of the weight below the boundary. In case of significant weight 
fluctuations the Investigator should contact the Medical Monitor to discuss and confirm 
potential change in dosing if medically advised or discontinuation of treatment (eg, if related 
to AE).  
Change #16 
Section 7.2 Treatments to be administered, the note below Table 7-1: 
Note: A study participant should only change dosing category during the course of the study if their weight 
crosses the 40kg/88lb boundary due to a weight change of >5kg (11lb) (eg, a 39.0kg study participant becomes 
44.1kg) or crosses the 20kg/44lb boundary due to a weight change of >2.5kg (5.5lb) (eg, a 19.0kg study 
participant becomes 21.6kg). 
Has been changed to: 
Note: A study participant should change dosing category during the course of the study if their weight crosses 
the 40kg/88lb boundary or crosses the 20kg/44lb boundary. 
Change #17 
Section 7.2 Treatments to be administered, the last paragraph: 
Study participants achieving clinical remission on medication (CRM), ie, after 6 months of 
CID, may discontinue CZP treatment at the Investigator’s discretion following consultation 
with the Sponsor to confirm remission status. Study participants will remain in the study and 
continue with scheduled study visits. Study participants not achieving persistent CID will be 
allowed to resume CZP treatment at any time at the Investigator’s discretion. If a study 
participant is on concomitant MTX treatment, the Investigator may decide to decrease and 
ultimately discontinue the MTX dose after complete discontinuation of CZP. Study 
participants not achieving persistent CID and resuming treatment will re-start the fixed-dose 
CZP dosing based on their current weight with 3 loading doses of CZP administered Q2W 
over 6 weeks, followed by a treatment dose administered Q2W, or Q4W for the lowest 
weight group after implementation of Protocol Amendment 4, for the duration of the study 
(see Table 7-1). 
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Has been changed to: 
Study participants achieving clinical remission on medication (CRM), ie, after 6 months of 
continuous CID, may discontinue CZP treatment at the Investigator’s discretion following 
consultation with the Sponsor to confirm remission status. Study participants who have 
discontinued CZP due to achieving CRM will be allowed to remain in the study and continue 
with scheduled study visits. Study participants not maintaining persistent CID following 
achievement of CRM will be allowed to resume CZP treatment at any time at the 
Investigator’s discretion and consultation with the Sponsor. If a study participant is on 
concomitant MTX treatment, the Investigator may decide to decrease and ultimately 
discontinue the MTX dose after complete discontinuation of CZP. Study participants not 
maintaining persistent CID following achievement of CRM and resuming treatment will 
restart the fixed-dose CZP dosing based on their current weight with 3 loading doses of CZP 
administered Q2W over 6 weeks, followed by a maintenance dose administered Q2W, or 
Q4W for the lowest weight group after implementation of Protocol Amendment 4, for the 
duration of the study (see Table 7-1). 
Change #18 
Section 7.2.1 Procedure for dose change (Protocol Amendment 4), the first sentence: 
With Protocol Amendment 4, the treatment dose in the study will be reduced by 50% for all 
weight groups. 
Has been changed to: 
With Protocol Amendment 4, the maintenance dose in the study will be reduced by 50% for 
all weight groups (not applicable for study participants enrolled on the reduced CZP dose 
regimen per Protocol Amendment 5). 
Change #19 
Section 7.8.1 Permitted concomitant treatments (medications and therapies), first bullet 
“MTX, if being used” the fourth and fifth points in the list:  
 During the study, the MTX dose may be decreased, but not discontinued. 
Methotrexate may be discontinued only for documented reasons of intolerance or 
toxicity, or in study participants who achieve CRM and only after discontinuation of 
CZP. 
 Study participants who do not achieve persistent CRM status can reinitiate therapy 
with MTX.  
Have been changed to: 
 During the study, the MTX dose may be decreased, but not discontinued. 
Methotrexate may be discontinued only for documented reasons of intolerance or 
toxicity, or in study participants who achieve CRM (persistent CID over a period of 6 
months, as defined in Section 11.10) and only after discontinuation of CZP. 
 Study participants who do not maintain persistent CID following achievement of 
CRM can reinitiate therapy with MTX.  
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Change #20 
Section 9 Assessment of pharmacokinetics and immunological variables, sixth paragraph, the 
last sentence: 
Additional assessments of the CZP plasma concentration after the change in dose will be 
performed to ensure that the 50% dose reduction will result in plasma concentrations within 
the target range of those observed in adults. 
Has been changed to: 
Continued analysis of CZP plasma concentrations (including additional assessments for study 
participants undergoing a dose reduction with Protocol Amendment 4) will be performed to 
confirm that the 50% dose reduction will result in plasma concentrations within the target 
range of those observed in adults. 
Change #21 
Section 10.1.8 Ongoing safety data review and oversight, second paragraph, the fourth 
sentence: 
In addition, a Data and Safety Monitoring Board (DSMB) will periodically review all 
emerging safety data (see Section 13.7).  
Has been changed to: 
In addition, a Data and Safety Monitoring Board (DSMB) will periodically review emerging 
safety and efficacy data (see Section 13.7).  
Change #22 
Section 10.7.9.1.1 Latent tuberculosis infection, the first and second sentences: 
Per exclusion criterion 11c, LTB infection is defined as a positive TB test (IGRA or PPD) 
and chest imaging without positive findings for TB along with the absence of signs, 
symptoms, or physical findings suggestive of TB infection. If available, smears and cultures 
of secretions or tissues should also be negative.  
Have been changed to: 
Latent TB infection is defined as a positive TB test (IGRA or PPD) and chest imaging 
without positive findings for TB along with the absence of signs, symptoms, or physical 
findings suggestive of TB infection. If available, smears and cultures of secretions or tissues 
should also be negative (refer to exclusion criterion 11c).  
Change #23 
Section 10.7.9.1.1 Latent tuberculosis infection, the fourth sentence: 
Study participants who have received prophylactic therapy for LTB infection for at least 4 
weeks prior to enrollment (initiation of CZP treatment at Baseline) and are committed to 
completing the full course of therapy, may be considered for study participation. 
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Has been changed to: 
Study participants who have received prophylactic therapy for LTB infection for at least 4 
weeks prior to initiation or continuation of CZP treatment and who are committed to 
completing the full course of therapy, may be considered for study participation or can 
continue on the study. 
Change #24 
Section 10.7.9.1.1 Latent tuberculosis infection, the text under “LTB infection and active 
TB identified during study”: 
During the study, study participants who develop evidence of LTB infection or active TB 
must immediately discontinue further administration of IMP, be scheduled for the Early 
Discontinuation Visit and Final Visit, and referred to a TB specialist for evaluation. Evidence 
of LTB infection is defined as study participant’s IGRA test converts to positive or 
indeterminate (and confirmed indeterminate on repeat), or PPD converts to positive (this only 
applies for regions or sites where UCB has determined PPD may be used for screening and 
follow-up), or the study participant’s questionnaire or history and physical examination 
indicates that TB infection or exposure may have occurred. Evidence of active TB includes, 
in addition to the aforementioned tests, signs and symptoms of organ involvement. In either 
situation, the study participant should be carefully assessed by a TB specialist for active TB 
(see Section 10.7.9.1). Study participants diagnosed with active TB or LTB infection should 
receive appropriate TB or prophylaxis therapy respectively per local and UCB guidelines as 
described above. Any presumptive diagnosis or diagnosis of LTB infection or active TB is a 
reportable event; refer to Section 10.2.2 for details. The Investigator is to complete and 
submit the TB follow-up form provided.  
The study participant should be transferred to the care of their physician and managed 
according to the best available standard of care. Study participants identified as having 
converted to LTB infection or active TB during the study must be scheduled to return for the 
Early Discontinuation Visit as soon as possible but no later than the next scheduled study 
visit. The study participant should be encouraged to keep the Final Visit as specified by the 
protocol. 
If infection with NTMB is identified during the study, the same procedure as for active TB 
acquired during the study must be followed. 
Has been changed to: 
During the study, study participants who develop evidence of LTB infection or active TB 
must immediately stop further administration of study medication and be referred to an 
appropriate TB specialist (pulmonologist and infectious disease specialist) for further 
evaluation (see Section 10.7.9.1). Evidence of LTB infection is defined as study participant’s 
IGRA test converts to positive or indeterminate (and confirmed indeterminate on repeat), or 
PPD converts to positive, or the study participant’s questionnaire or history and physical 
examination indicates that TB infection or exposure may have occurred. Evidence of active 
TB includes, in addition to the aforementioned tests, signs and symptoms of organ 
involvement. In either situation, the study participant should be carefully assessed by a TB 
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specialist for active TB. Study participants diagnosed with active TB or LTB infection should 
receive appropriate TB or prophylaxis therapy. In case a TB specialist excludes an active TB 
the study participant can proceed with the study medication no earlier than 4 weeks after the 
start of an appropriate prophylactic therapy. 
Any presumptive diagnosis or diagnosis of a TB infection is a reportable event, and 
confirmed active TB has to be reported as an SAE (please see Section 10.2.2 Procedures for 
reporting SAEs for details). The Investigator is to complete and submit the TB follow-up 
form provided.  
The study participant should be transferred to the care of their physician and managed 
according to the best available standard of care. Study participants identified as having 
converted to active TB during the study must be withdrawn and scheduled to return for the 
Early Discontinuation Visit as soon as possible but no later than the next scheduled study 
visit.  
The study participant should be encouraged to complete the Final Visit 12 weeks after the last 
dose of study medication. 
If infection with NTMB is identified during the study, the same procedure as for active TB 
acquired during the study must be followed. 
Study participants with LTB infection must not undergo repeat PPD and IGRA testing. The 
PPD and IGRA test should be used for any protocol mandated monitoring. 
Follow-up information of suspected and confirmed TB cases 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 data, and TB diagnostic procedures used to 
follow up and confirm recovery of TB. 
Change #25 
Section 11.10 Clinically Inactive Disease and clinical remission, the last paragraph: 
Study participants achieving CRM, ie, after 6 months of CID, may discontinue CZP treatment 
at the Investigator’s discretion following consultation with the Sponsor to confirm remission 
status. Study participants will remain in the study and continue with scheduled study visits. 
Study participants not achieving persistent CID will be allowed to resume CZP treatment at 
any time at the Investigator’s discretion. If a study participant is on concomitant MTX 
treatment, the Investigator may decide to decrease and ultimately discontinue the MTX dose 
after complete discontinuation of CZP. Study participants not achieving persistent CID and 
resuming treatment will restart the fixed-dose CZP dosing based on their current weight with 
3 loading doses of CZP administered Q2W over 6 weeks, followed by a treatment dose 
administered Q2W for the duration of the study, with exception of the lowest weight group, 
who will receive the treatment dose Q4W following implementation of Protocol Amendment 
4.  
Has been changed to: 
Study participants achieving CRM, ie, after 6 months of continuous CID, may discontinue 
CZP treatment at the Investigator’s discretion following consultation with the Sponsor to 
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confirm remission status. Study participants who have discontinued CZP due to achieving 
CRM will be allowed to remain in the study and continue with scheduled study visits. Study 
participants not maintaining persistent CID following achievement of CRM will be allowed 
to resume CZP treatment at any time at the Investigator’s discretion and consultation with the 
Sponsor. If a study participant is on concomitant MTX treatment, the Investigator may decide 
to decrease and ultimately discontinue the MTX dose after complete discontinuation of CZP. 
Study participants not maintaining persistent CID following achievement of CRM and 
resuming treatment will restart the fixed-dose CZP dosing based on their current weight with 
3 loading doses of CZP administered Q2W over 6 weeks, followed by a maintenance dose 
administered Q2W for the duration of the study, with exception of the lowest weight group, 
who will receive the maintenance dose Q4W following implementation of Protocol 
Amendment 4.  
Change #26 
Section 13.2.1 Data presentation, the following has been added at the end of the first 
paragraph: 
Subgroups defined by CZP dosing regimen will also be displayed. Two CZP dosing regimen 
subgroups will be defined as follows: 
 Original CZP dose regimen: includes all study participants in the SS who began treatment 
in accordance with the original dosing regimen defined for the study (3 loading doses of 
CZP at Weeks 0, 2, and 4 [minimum=100mg Q2W, maximum=400mg Q2W] followed 
by a maintenance dose for the duration of the study [minimum=50mg Q2W, 
maximum=200mg Q2W]). This subgroup includes all study participants who began the 
study with this CZP dose regimen and received 1 or more doses of this regimen, 
regardless of any subsequent switch to the reduced CZP dose regimen. 
 Reduced CZP dose regimen: includes all study participants in the SS who began 
treatment in accordance with the reduced dosing regimen defined for the study (3 loading 
doses of CZP at Weeks 0, 2, and 4 [minimum=50mg Q2W, maximum=200mg Q2W] 
followed by a maintenance dose for the duration of the study [minimum=50mg Q4W, 
maximum=100mg Q2W]). 
Change #27 
Section 13.2.2 Multicenter studies: 
Approximately 55 centers are planned to enroll 125 study participants into this study. The 
enrollment per site is limited to a maximum of 10 study participants. 
Has been changed to: 
Approximately 55 centers are planned to enroll 156 study participants into this study. The 
enrollment per site is limited to a maximum of 12 study participants. 
Change #28 
Section 13.3 Planned safety analyses: 
The incidence of AEs will be assessed as primary safety variable in this study.  
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Safety summaries will include presentations of AEs, extent of exposure, laboratory values 
(hematology and biochemistry), vital signs, concomitant medications and procedures, and 
autoantibody (ANA and anti-dsDNA antibodies) concentrations. Urinalysis results will be 
listed. Tanner stages will be presented by category. Growth as measured by height and weight 
will be assessed in relation to a comparative population and this may include an assessment 
of any change after treatment with CZP. 
Selected safety summaries will be presented overall and by Baseline weight strata, as well as 
by age (2 to 5 years, 6 to 11 years, and 12 to 17 years), by concomitant MTX use, and by 
anti-CZP antibody status. Safety summaries will be based upon the SS (study participants 
who were enrolled and took at least 1 dose of study medication). 
Has been changed to: 
The incidence of AEs will be assessed as primary safety variable in this study. The primary 
summaries of safety will include all study participants in the SS, regardless of CZP dose. 
Safety variables will be summarized overall and separately for the 2 CZP dose regimens 
(original CZP dose regimen, reduced CZP dose regimen).  
Safety summaries will include presentations of AEs, extent of exposure, laboratory values 
(hematology and biochemistry), vital signs, concomitant medications and procedures, and 
autoantibody (ANA and anti-dsDNA antibodies) concentrations. Urinalysis results will be 
listed. Tanner stages will be presented by category. Growth as measured by height and weight 
will be assessed in relation to a comparative population and this may include an assessment 
of any change after treatment with CZP. 
For AEs, the exposure-adjusted incidence rate (EAIR) will also be calculated. For EAIR, the 
numerator will be the total number of study participants experiencing a particular AE. The 
denominator will be study participant-years, ie, the total summation of individual study 
participant-years at risk up to the first occurrence of the given AE for study participants with 
that AE, plus the total study participant-years at risk for those study participants not 
experiencing that AE.  
For the original CZP dose regimen subgroup, in addition to the overall presentation of AEs, 
AEs will be summarized separately for the periods of exposure to original and reduced CZP 
dose regimens. Additionally, the frequency and percentage of AEs reported during the first 
16 weeks of study medication exposure will be summarized separately for the 2 CZP dose 
regimens (original CZP dose regimen, reduced CZP dose regimen). This analysis will be 
repeated, excluding any study participants who switched from the original to the reduced 
CZP dose regimen prior to Week 16. Selected safety summaries will be presented overall and 
by Baseline weight strata, as well as by age (2 to 5 years, 6 to 11 years, and 12 to 17 years), 
by concomitant MTX use, and by anti-CZP antibody status. 
Change #29 
Section 13.4 Planned PK, PD, and immunological variable analysis, the third and fourth 
paragraphs: 
In the Bayesian approach, the distributions of PK parameters estimated from adult data (from 
the PopPK analysis in C87068) will be incorporated as prior information in the model to 
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estimate pediatric PK parameters. This combination of prior knowledge and sparse pediatric 
data will be analyzed within Winbugs. 
The meta-analysis will be performed by adding the pediatric data to the adult data that were 
previously used to perform the adult PopPK analysis within NONMEM (C87068). 
Have been changed to: 
In the Bayesian approach, the distributions of PK parameters estimated from adult data (from 
the PopPK analysis in C87068 and CL0153) will be incorporated as prior information in the 
model to estimate pediatric PK parameters. This combination of prior knowledge and sparse 
pediatric data will be analyzed within Winbugs. 
The meta-analysis will be performed by adding the pediatric data to the adult data that were 
previously used to perform the adult PopPK analysis within NONMEM (C87068 and 
CL0153). 
Change #30 
Section 13.4 Planned PK, PD, and immunological variable analysis, the eighth paragraph: 
Certolizumab pegol plasma concentration data will be tabulated and summarized for each 
visit on which samples were taken (geometric mean, arithmetic mean, minimum, maximum, 
standard deviation and % coefficient of variation). Plasma concentration time curves will be 
plotted, overall, by Baseline age stratum, and by anti-CZP antibody status. Subgroup analyses 
will include an analysis of the study participants enrolled and treated up to the Week 16 
timepoint under the original treatment dosing regimen. 
Has been changed to: 
Certolizumab pegol plasma concentration data will be tabulated and summarized by dose 
regimen (original CZP dose regimen or reduced CZP dose regimen) for each visit on which 
samples were taken (geometric mean, arithmetic mean, minimum, maximum, standard 
deviation and % coefficient of variation). Plasma concentration time curves will be plotted 
separately for study participants who began treatment according to the original CZP dose 
regimen or the reduced CZP dose regimen, overall, by Baseline age stratum, and by anti-CZP 
antibody status. Subgroup analyses will include an analysis of the study participants enrolled 
and treated up to the Week 16 timepoint under the original maintenance dosing regimen. 
Change #31 
Section 13.5 Planned efficacy and health outcomes analyses, the following has been added 
below the first paragraph: 
All efficacy and health outcomes variables results will be presented overall and separately for 
the 2 CZP dose regimens (original CZP dose regimen, reduced CZP dose regimen). 
Change #32 
Section 13.7 Planned interim analysis and data monitoring, the fifth paragraph: 
The CZP plasma concentrations will be monitored on an ongoing basis following the change 
in dose regimen to confirm they are within the adult range. 
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Has been changed to: 
The CZP plasma concentrations will be monitored on an ongoing basis following the change 
in dose regimen to confirm they are within the targeted adult range. 
Change #33 
Section 13.7 Planned interim analysis and data monitoring, the last paragraph: 
A DSMB will periodically review all emerging safety data. The DSMB members will be 
independent of the Sponsor and Investigators. The DSMB members will be informed by the 
Drug Safety representative (or designee) of all SAEs at the time of expedited reporting and 
will review periodically all emerging safety data (eg, SAEs, AEs, safety laboratory data). 
Based on the safety data, the DSMB can recommend modifying/stopping the study. 
Has been changed to: 
A DSMB will periodically review emerging safety and efficacy data. The DSMB members 
will be independent of the Sponsor and Investigators. The DSMB members will be informed 
by the Drug Safety representative (or designee) of all SAEs at the time of expedited reporting 
and will periodically review emerging safety data (eg, SAEs, AEs, safety laboratory data) and 
efficacy data, as applicable, during the course of the study. Based on the safety data, the 
DSMB can recommend modifying/stopping the study. 
Change #34 
Section 13.8 Determination of sample size, the first paragraph: 
Based upon the ICH guideline for the assessment of safety, it is planned to enroll a sufficient 
number of study participants to this study to have a minimum of 100 with at least 12 months 
continuous exposure to CZP. Assuming a dropout rate of approximately 20%, this means that 
125 study participants would need to be enrolled. Further assuming a Screening failure rate of 
25%, it is planned to screen 167 study participants. 
Has been changed to: 
Based upon the ICH guideline for the assessment of safety, it is planned to enroll a sufficient 
number of study participants to this study to have a minimum of 100 with at least 12 months 
continuous exposure to CZP. Assuming a dropout rate of approximately 20%, it was 
originally determined that 125 study participants would need to be enrolled. At the time of 
Protocol Amendment 5, 78 study participants had been enrolled according to the original 
CZP dose regimen, and it is planned to enroll a further 78 study participants on the reduced 
CZP dose regimen, so that a comparable number of study participants on the reduced CZP 
dose regimens can be analyzed. Thus, the total number of study participants planned to be 
enrolled will be increased to 156 study participants. Assuming a Screening failure rate of 
25%, it is planned to screen 195 study participants in total. 
Change #35 
Section 13.8 Determination of sample size, second paragraph, the first sentence:  
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Simulations using the adult population PK model in pediatric study participants with JIA 
suggest that the planned sample size of 125 study participants is adequate for PK assessment 
purposes.  
Has been changed to: 
Prior to the start of study conduct, simulations using the adult population PK model in 
pediatric study participants with JIA suggested that the planned sample size of 125 study 
participants was adequate for PK assessment purposes.  
Change #36 
Section 13.8 Determination of sample size, the following has been added at the end of the 
section:  
Data from all 156 study participants will be included in the final PopPK analysis, and 
therefore should allow CL/F and V/F to be determined with sufficient precision. 
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17.16 
Protocol Amendment 6 
Rationale for the amendment 
The primary purpose of this administrative amendment is to update the packaging and 
labeling sections of the protocol to account for a new presentation of the prefilled syringe 
(PFS). 
In addition, administrative changes have been made to move the Sponsor declaration page to 
the back of the document to comply with the new electronic signature process, to update 
study personnel, and to correct typographical errors.  
Modifications and changes 
Global change 
The terms “Treatment Period” and treatment dose” were changed globally to “Maintenance 
Period” and “maintenance dose ” with RA0043 Protocol Amendment 5. However, in text that 
refers to the overall open-label Treatment Period in the study, which includes a Loading and a 
Maintenance Period, the term “Treatment Period” should still be used. This has been 
corrected throughout the protocol.  
Specific changes 
This section displays the modifications in this amendment compared with the previous 
version of the protocol dated 20 Jan 2014. The changes are displayed in the order of 
appearance. 
Change #1 
The SPONSOR DECLARATION page was removed from page 2 and added as a new section 
at the back of the document: 
19 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. 
Change #2 
Under STUDY CONTACT INFORMATION, contact details of the Study Physician: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
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Have been changed to: 
Name: 
 
Address: 
Chemin du Foriest 
B - 1420 Braine-l’Alleud 
Belgium 
Phone: 
Fax: 
Change #3 
Under STUDY CONTACT INFORMATION, contact details of the Clinical Trial 
Biostatistician: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
Have been changed to: 
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
Change #4 
LIST OF ABBREVIATIONS, the following abbreviation has been added: 
GMP 
Good Manufacturing Practice 
Change #5 
Section 7.3 Packaging: 
Each site will receive uniquely numbered PFS of CZP 200mg/mL. The PFS will be packaged 
in individual protective containers (clamshell). Each clamshell will be packaged in an 
individual carton.  
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The site will contact the IXRS at each visit in order to obtain the PFS number(s) (MED ID) to 
be dispensed to a specific study participant. 
Has been changed to: 
Certolizumab pegol is packaged and labeled according to Good Manufacturing Practice 
(GMP) guidelines and applicable laws or regulations. They are suitably packaged in such a 
way as to protect the IMPs from deterioration during transport and storage. 
Change #6 
Section 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. Where necessary, 
labels will be translated into the local language. 
All PFS will be inserted into a labeled individual container (clamshell). The label of an 
individual container has 2 sections. The tear-off section will be removed and attached to the 
source document at the time of study medication administration to the study participant and 
the main section 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. Cartons containing the clamshells will also 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 study 
participant identification card (see Section 14.2). 
Has been changed to: 
Clinical drug supplies will be labeled in accordance with the current International Conference 
on Harmonization (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will 
include any locally required statements. If necessary, labels will be translated into the local 
language. Details on Labeling will be provided in the Pharmacy manual. 
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17.17 
Protocol Amendment 7 
Rationale for the amendment 
The primary purpose of this substantial amendment is to update the protocol in accordance 
with current UCB TB detection procedures, including the introduction of yearly TB testing 
and the extension of the prophylactic TB treatment duration from 4 to 8 weeks. Furthermore, 
it has been clarified that long-term efficacy data from study participants who withdraw from 
the study after Week 56 or initiate any rescue medication use after Week 56 will be analyzed 
“as observed” and will no longer be imputed as nonresponse or missing. 
Moreover, a section on “Suspected transmission of an infectious agent via a medicinal 
product” has been added in accordance with current company standards. 
In addition, study contact details have been updated and minor clarifications have been made. 
Modifications and changes 
Global changes 
The following changes have been made throughout the protocol: 
 Yearly TB testing and prophylactic TB treatment duration of 8 weeks have been 
implemented. Of note, no changes have been made to the eligibility criteria in Section 6 
(eg, Exclusion Criterion #11) and the description of  Screening procedures for TB 
infection at study entry (Section 10.7.9.1.1) because enrollment in the study is complete 
at the time of this protocol amendment. 
 References to UCB Drug Safety have been changed to UCB Patient Safety. 
Specific changes 
This section displays the modifications in this amendment compared with the previous 
version of the protocol dated 17 Sep 2015. The changes are displayed in the order of 
appearance. 
Change #1 
Under SERIOUS ADVERSE EVENT REPORTING, the fax numbers for SAE reporting in 
the US and Canada: 
Serious adverse event reporting (24h)  
 Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA: +1 800 880 6949 
Canada: +1 877 582 8842 
 E-mail 
Global: DSICT@ucb.com  
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Have been changed to: 
Serious adverse event reporting (24h)  
 Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA and Canada: +1 800 880 6949 or +1 866 890 3175 
 E-mail 
Global: DSICT@ucb.com  
Change #2 
Section 2 INTRODUCTION, second paragraph, the second sentence:  
Juvenile idiopathic arthritis is the most commonly diagnosed rheumatic disease affecting 
children less than 16 years of age with a prevalence of approximately 100 in 100,000. 
Has been changed to: 
Juvenile idiopathic arthritis is the most commonly diagnosed rheumatic disease affecting 
children less than 16 years of age with a prevalence of approximately 100 in 100,000 (Zitelli 
et al, 2012). 
Change #3 
Section 5.2 Schedule of study assessments, Table 5-1, entries for “TB screening and chest x-
ray” and “TB questionnaire” and the associated footnotes “i” and “n” have been updated 
(new information in italics and bold): 
Table 5-1 Schedule of study assessments  
Study period 
Screening 
Baseline 
 
 
 
 
 
 
Week 
-4 to 0(a) 
0 
… 
4, 8, 12, 
16, (17(u)), 
20, 24 
32 and every 
8 weeks 
thereafter 
… 
Early Disc/ 
End of 
Treatment 
Final 
Visit(c) 
Visit (+/-3 days)(a) 
1 
2 
 
5 to 10 
11 onwards 
 
 
FV 
… 
 
 
 
 
 
 
 
 
TB screening(n) and 
chest x-ray(o) 
X 
 
 
 
X(n) 
 
 
 
TB questionnaire 
X 
X 
 
X(i) 
X(i) 
 
X(i) 
 
… 
 
 
 
 
 
 
 
 
i TB questionnaire to be completed at Weeks 12 and 24, every 16 weeks thereafter, and Early Discontinuation/End 
of Treatment. If the Investigator suspects reactivation of latent TB or active TB, TB testing and/or a chest x-ray 
should be performed as outlined in Section 10.7.9.1. 
n TB screening if not performed within 3 months of Screening: Interferon-gamma release assay (IGRA) testing 
(QuantiFERON®) is required to be performed by the central lab for all study participants from 5 to 17 years of 
age. PPD testing is mandatory for study participants from 2 to 4 years of age in this study unless written 
documentation of BCG vaccination is available (refer to Section 6.2 [exclusion criterion 11] and Section 10.7.9). 
Following implementation of Protocol Amendment 7, IGRA testing (QuantiFERON) should be done once a 
year (approximately every 48 weeks) for all study participants from 5 to 17 years of age. For study participants 
from 2 to 4 years of age,  both IGRA and PPD testing should be performed once a year (approximately every 
48 weeks). In cases where written documentation of BCG vaccination is available or previous PPD test was 
positive, only IGRA should be performed (Section 10.7.9.2). 
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Change #4 
Section 7.8.2 Rescue medication, the first paragraph: 
Rescue medication use is defined as any initiation of treatment or increase in dose of a 
medication used to treat JIA (in addition to the IMP) that is considered to impact the efficacy 
analyses. A study participant requiring rescue medication after first administration of IMP is 
considered as a treatment failure from that time point forward for the purpose of efficacy 
analyses.  
Has been changed to: 
Rescue medication use is defined as any initiation of treatment or increase in dose of a 
medication used to treat JIA (in addition to the IMP) that is considered to impact the efficacy 
analyses. A study participant requiring rescue medication after first administration of IMP is 
considered as a treatment failure from that time point forward for the purpose of efficacy 
analyses. Exception: A study participant initiating rescue medication use after the Week 56 
visit will not be considered a treatment failure and the efficacy data will be analyzed as 
observed without imputation. 
Change #5 
Section 8.5 Visits 11 and continuing (Week 32 and every 8 weeks thereafter), a new bullet 
has been added as sixth bullet: 
 TB screening once a year (approximately every 48 weeks) 
Change #6 
Section 10.1 Adverse events, the following section has been added: 
10.1.7 Suspected transmission of an infectious agent via a medicinal product 
For the purposes of reporting, any suspected transmission of an infectious agent via the study 
medication should be considered as an SAE; such cases must be reported immediately, 
recorded in the AE module of the CRF, and followed as any other SAE. Any organism, virus, 
or infectious particle (eg, prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent. 
Change #7 
Section 10.6 Laboratory measurements, a new paragraph has been added as 12th paragraph: 
During the study and upon implementation of Protocol Amendment 7, IGRA testing should 
be done once a year (approximately every 48 weeks) for all study participants from 5 to 17 
years of age. For study participants from 2 to 4 years of age, both IGRA and PPD testing 
should be performed once a year (approximately every 48 weeks). In cases where written 
documentation of BCG vaccination is available or previous PPD test was positive, only 
IGRA should be performed (Section 10.7.9.2). 
Change #8 
Section 10.6 Laboratory measurements, Table 10-2 Laboratory measurements, the entry “TB 
screening” and the associated footnote “d”:  
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TB screening(d): IGRA (ages 5-17 years ), PPD (ages 2-4 years) 
d IGRA testing is required at Screening for all study participants aged 5 to 17 years; PPD testing is required for 
all study participants aged 2 to 4 years (except for study participants with documented BCG vaccination). 
Have been changed to: 
TB screening(d): IGRA, PPD 
d For TB testing refer to Section 10.7.9. IGRA is performed by the central lab. 
Change #9 
Section 10.7.9.1.1, the section heading: 
10.7.9.1.1 
Latent tuberculosis infection  
Has been changed to: 
10.7.9.1.1 
Latent TB infection at study entry 
Change #10 
Section 10.7.9.1.1 Latent TB infection at study entry, second paragraph, the first and second 
sentences: 
At Screening, study participants who have recently (defined as no more than 12 months prior 
to Screening) completed a full course of prophylaxis for LTB infection may be considered for 
study participation. Study participants who have received prophylactic therapy for LTB 
infection for at least 4 weeks prior to initiation or continuation of CZP treatment and who are 
committed to completing the full course of therapy, may be considered for study participation 
or can continue on the study.  
Have been changed to: 
At Screening, study participants who have recently (defined as no more than 12 months prior 
to Screening) completed a full course of prophylaxis for LTB infection may be considered for 
study participation. Study participants who have received prophylactic therapy for LTB 
infection for at least 4 weeks prior to initiation of CZP treatment and who are committed to 
completing the full course of therapy, may be considered for study participation.  
Change #11 
LTB infection and active TB identified during study, the heading and last sentence of the first 
paragraph: 
In case a TB specialist excludes an active TB the study participant can proceed with the study 
medication no earlier than 4 weeks after the start of an appropriate prophylactic therapy. 
Have been changed to: 
Section 10.7.9.1.2 Latent TB infection and active TB identified during study 
In case a TB specialist excludes an active TB the study participant can proceed with the study 
medication no earlier than 8 weeks after the start of an appropriate prophylactic therapy. 
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Change #12 
Section 10.7.9.1.2 Latent TB infection and active TB identified during study, the second 
paragraph: 
Any presumptive diagnosis or diagnosis of a TB infection is a reportable event, and 
confirmed active TB has to be reported as an SAE (please see Section 10.2.2 Procedures for 
reporting SAEs for details). The Investigator is to complete and submit the TB follow-up 
form provided. 
Has been changed to: 
Any confirmed diagnosis of a latent or active TB infection is a reportable event. Both cases 
have to be reported as AE of Interest and must be captured on an SAE report form (please 
tick the appropriate AE of Interest and/or SAE field(s) on the form to clearly indicate level of 
seriousness) and provided to the Sponsor in accordance with SAE reporting requirements (see 
Section 10.2.2 Procedures for reporting SAEs for details). 
Change #13 
Section 10.7.9.2 TB screening and testing, a new subsection has been added; subsequent 
subsections (for chest x-ray, IGRA test, and PPD skin test) have been renumbered: 
10.7.9.2.1 Tuberculosis testing during the study for study participants above 
and below 5 years of age 
Immediately following the implementation of Protocol Amendment 7 and upon signing the 
updated Informed Consent form, all study participants need to undergo TB testing as 
described below, unless available from the last 12 months. 
In the case of a study participant who has previously had a positive IGRA test result and has 
completed prophylactic treatment in the past again tests positive in the IGRA testing, the 
study participant must be referred to a TB specialist for further assessment. The IGRA test 
might be repeated within 6 months in order to decide whether TB prophylactic treatment 
needs to be repeated. The PPD skin test should not be repeated in case of a previous positive 
result. The TB specialist, Study Physician, and Medical Monitor are requested to provide 
written approval for the study participant to continue being exposed to the study drug. 
Study participants above 5 years of age 
During the conduct of the study, the TB assessment by IGRA should be repeated once a year 
(approximately every 48 weeks). The test results will be reported as positive, negative, or 
indeterminate. Positive or indeterminate results must be reviewed by an experienced TB 
specialist, radiologist, or a pulmonologist. If the assessment by IGRA is positive or 
indeterminate on retest for study participants who were previously negative at Screening and 
not treated for LTB infection, the study participant may not continue study treatment without 
further evaluation by a TB specialist, prophylactic TB treatment, and discussion with the 
Medical Monitor, if LTB infection is identified.  
If active TB is identified, the study participant must undergo appropriate study-specified 
withdrawal procedures.  
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Study participants below 5 years of age 
During the conduct of the study, the TB assessment by both PPD skin test and IGRA should 
be repeated once a year (approximately every 48 weeks). If both tests are negative the study 
participant may continue in the study. The study participant should immediately discontinue 
study medication intake if 1 or both tests are positive and the study participant should be 
referred to a TB specialist. Should evaluation of the study participant by the appropriate TB 
specialist result in a diagnosis of LTB infection, the study medication must be withheld until 
the appropriate prophylactic therapy has been received for at least 8 weeks and the study 
participant is deemed likely to continue therapy to completion. The TB treatment must be 
discussed with the Medical Monitor, before study medication is restarted. 
If active TB is identified, the study participant must undergo appropriate study-specified 
withdrawal procedures. 
In countries with high BCG vaccination or previous high PPD skin test positivity, it might not 
be recommended to do or repeat the PPD skin test. The PPD skin test might be positive due 
to BCG vaccination; however, if the PPD skin test is not performed or positive in a pediatric 
study participants <5 years of age, it will not be allowed that the study participant continues 
in the study without written approval from a physician with expertise in pediatric TB. 
Change #14 
Section 10.7.9.2.2 Chest x-ray, the following paragraph has been added at the end of the 
section: 
Additional chest x-ray or other imaging test should be performed when positive signs and 
symptoms indicate pulmonary infection, including potential TB infection, or when close 
exposure to persons with TB is documented. 
Change #15 
Section 10.7.9.2.3 Interferon-gamma release assay (IGRA test): 
The IGRA (QuantiFERON®-TB GOLD In-Tube test) is the protocol-required method of 
screening for TB in study participants from 5 to 17 years of age and will be performed at the 
central laboratory. The IGRA and PPD skin test may not be performed at the same time and a 
positive or indeterminate outcome in 1 test may not be overruled by a negative result in the 
other. If the result of the IGRA test is indeterminate, the test may be repeated once. If positive 
or indeterminate on retest, the study participant may not be enrolled without further 
evaluation and treatment, as well as discussion by the Investigator with the Study Physician 
or Medical Monitor. The retest must be done during the protocol-defined Screening window. 
Has been changed to: 
The IGRA (QuantiFERON®-TB GOLD In-Tube test) is the protocol-required method of 
screening for TB and will be performed at the central laboratory. If the result of the IGRA 
test is indeterminate, the test may be repeated once. If positive or indeterminate on retest, the 
study participant may not be enrolled without further evaluation and treatment, as well as 
discussion by the Investigator with the Study Physician or Medical Monitor. The retest must 
be done during the protocol-defined Screening window. During the study, TB screening with 
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IGRA will be repeated once yearly, ie, approximately every 48 weeks (after implementation 
of Protocol Amendment 7). 
Change #16 
Section 10.7.9.2.4 Tuberculin Purified Protein Derivative (PPD skin test): 
In study participants from 2 to 4 years of age (except for study participants 2 to 4 years of age 
with a written documentation of BCG vaccination), the PPD skin test must be administered 
during Screening or within the 3 months prior to Screening in accordance with the 
instructions below. 
Has been changed to: 
In study participants from 2 to 4 years of age (except for study participants 2 to 4 years of age 
with a written documentation of BCG vaccination), the PPD skin test must be administered 
during Screening or within the 3 months prior to Screening and once yearly during the study, 
ie, approximately every 48 weeks (after implementation of Protocol Amendment 7) in 
accordance with the instructions below.  
Change #17 
Section 10.7.9.3 TB questionnaire (evaluation of signs and symptoms associated with TB and 
guidelines for evaluating exposure risk), second paragraph, the last 2 sentences: 
Any presumptive diagnosis or diagnosis of LTB infection or active TB is a reportable event; 
refer to Section 10.2.2 for details. The Investigator is to complete and submit the TB follow-
up form provided. 
Have been changed to: 
Any confirmed diagnosis of a latent or active TB infection is a reportable event; refer to 
Section 10.2.2 for details). 
Change #18 
Section 13.6 Handling of dropouts or missing data, the first 3 paragraphs: 
For all binary efficacy endpoints assessing response, study participants who withdraw early 
will be considered as non-responders from that time point onwards.  
For continuous efficacy endpoints, missing assessments will be imputed using the last 
observation carried forward (LOCF) approach. These summaries will be supported by 
observed case (OC) analyses. 
Data collected after the taking of rescue medication will be treated as missing for continuous 
efficacy endpoints and non-response for binary efficacy endpoints in all analyses except 
where specifically stated otherwise. See Section 7.8.2 for a list of medications which would 
result in data at only the next scheduled visit (and not all subsequent visits) being treated as 
missing/non-response. These data will then be imputed as for any other missing data. 
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Have been changed to: 
For all binary efficacy endpoints assessing response, study participants who withdraw early 
will be considered as non-responders from that time point onwards. The exception is efficacy 
data for study participants who withdraw after Week 56: Per Protocol Amendment 7, these 
will not be imputed (as nonresponse or missing) and will be analyzed as observed. 
For continuous efficacy endpoints, missing assessments will be imputed using the last 
observation carried forward (LOCF) approach. These summaries will be supported by 
observed case (OC) analyses. Per Protocol Amendment 7, missing assessments after Week 56 
will no longer be imputed and will be analyzed as observed. 
Data collected after the taking of rescue medication will be treated as missing for continuous 
efficacy endpoints and non-response for binary efficacy endpoints in all analyses except 
where specifically stated otherwise. See Section 7.8.2 for a list of medications which would 
result in data at only the next scheduled visit (and not all subsequent visits) being treated as 
missing/non-response. These data will then be imputed as for any other missing data. The 
exception is any rescue medication use that is initiated after Week 56: Per Protocol 
Amendment 7, efficacy data after any rescue medication use initiated after Week 56 will not 
be imputed (as nonresponse or missing) and will be analyzed as observed. 
Change #19 
Section 16 REFERENCES, the following publication has been added: 
Zitelli B, McIntire S, Nowalk A. Zitelli and Davis’ Atlas of pediatric physical diagnosis, 6th 
edition. Chapter 7: Rheumatology, Section: Juvenile Idiopathic Arthritis. Elsevier Health 
Sciences, 2012, 264. 
 
 
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17.18 
Protocol Amendment 8 
Rationale for the amendment  
The primary purpose of this substantial amendment is to reduce the study participants’ 
burden by limiting the frequency of on-site visits, safety sampling, and efficacy assessments.  
The frequency of on-site visits will be reduced from every 8 weeks to every 16 weeks in this 
long-term study. At the time of implementing Protocol Amendment 8, all ongoing study 
participants have at least completed the visit for Week 180. As before, on-site CZP 
administration between scheduled visits is offered as needed. 
The frequency of safety sampling (blood sampling and urinalysis) will be extended from 
every 8 weeks to every 16 weeks to reduce study participants’ burden in line with the updated 
on-site CZP administration schedule. Safety data collected previously during the study and 
close evaluation by the DSMB support the extension of sampling frequency.  
This longer interval will also be implemented for efficacy assessments to further reduce the 
study participants’ burden and will be appropriate to describe the long-term efficacy of CZP. 
In addition, blood samples to determine CZP plasma concentrations and anti-CZP antibodies 
will no longer be collected in the study to further reduce study participants’ burden. 
Pharmacokinetic data from this study (assayed with an ELISA technique) will not be used for 
submission to the FDA to complete the Pediatric Research Equity Act commitment, primarily 
due to some deficiencies detected on the bioanalytical assay used. UCB determined that 
further collection of additional samples to determine CZP plasma concentrations and anti-
CZP antibodies would be of limited utility and an undue burden on the study participants. 
There is also limited value in collecting anti-CZP antibody and CZP plasma concentration 
data after >4 years of CZP exposure. Discontinuation of blood sample collection for further 
characterization of CZP PK and immunogenicity is supported by the DSMB as the PK and 
immunogenicity data available to date is considered sufficient from a safety perspective and 
for PK characterization.  
For the final analysis at the end of the study, UCB will reanalyze all the available samples 
with sufficient volume with a new MSD bioanalytical assay that is fully validated and that 
meets current regulatory standards. This re-assayed PK data will be used for final study 
reporting and thus will not be compared to the previously reported RA adult concentrations, 
as a different bioanalytical technique was used. 
Also, minor editorial changes have been made to correct typographical errors and to update 
abbreviations. 
 
Modifications and changes 
Global changes 
The following changes have been made throughout the protocol: 
 Study contact details have been updated. 
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 Safety laboratory assessments (including urinalysis), efficacy assessments, and on-site 
CZP administration frequency has been changed from every 8 weeks to every 
16 weeks. 
 Cessation of samples for CZP plasma concentration and anti-CZP antibodies has been 
implemented. 
 Updated PK analysis section as the previous ELISA technique will no longer be used 
and the samples need to be re-assayed using a new MSD assay.  
 Reference to Week 56 interim analysis removed as this interim analysis is no longer 
necessary following the 
. 
 Tanner stage assessment frequency has been updated from every 24 weeks to every 
48 weeks, and only for study participants that have not reached Tanner stage V. 
 
Specific changes  
This section displays the modifications in this amendment compared with the previous 
version of the protocol dated 22 Sep 2016. The changes are displayed in the order of 
appearance. 
Change #1 
STUDY CONTACT INFORMATION, contact details of the Clinical Project Manager: 
Clinical Project Manager 
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
Germany 
Phone: 
Fax: 
Has been changed to: 
Clinical Project Manager 
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
Germany 
Phone: 
Fax: 
 
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Change #2 
STUDY CONTACT INFORMATION, contact details of the Clinical Trial Biostatistician: 
Clinical Trial Biostatistician  
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
Has been changed to: 
Clinical Trial Biostatistician  
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
 
Change #3 
SERIOUS ADVERSE EVENT REPORTING, global email: 
Serious adverse event reporting (24h)  
 Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA and Canada: +1 800 880 6949 or +1 866 890 3175 
 E-mail 
Global: DSICT@ucb.com  
Has been changed to: 
Serious adverse event reporting (24h)  
Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA and Canada: +1 800 880 6949 or +1 866 890 3175 
E-mail 
Global: DS_ICT@ucb.com  
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Change #4 
Section 1, Summary, seventh paragraph 
Full interim analyses will be performed after all active study participants have completed the 
Week 24 (Visit 10) assessments, as well as after all active study participants have completed 
the Week 56 (Visit 14) assessments. The study will continue until the approval of the 
marketing application for the polyarticular-course JIA indication in the study participant’s 
country or region, or until discontinuation of the study based on the Week 16 analysis of 
response, or until further notice from UCB. 
Has been changed to: 
A full interim analysis will be performed after all active study participants have completed 
the Week 24 (Visit 10) assessments. The study will continue until the approval of the 
marketing application for the polyarticular-course JIA indication in the study participant’s 
country or region, or until discontinuation of the study based on the Week 16 analysis of 
response, or until further notice from UCB. 
 
Change #5 
Section 1, Summary, eighth paragraph 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 (minimum=50mg every 2 weeks 
[Q2W], maximum=200mg Q2W) followed by a maintenance dose (minimum=50mg every 
4 weeks [Q4W], maximum=100mg Q2W). Prior to implementation of Protocol 
Amendments 4 and 5, the minimum and maximum loading doses in the study were 
CZP 100mg Q2W and CZP 400mg Q2W, respectively, and the minimum and maximum 
maintenance doses were CZP 50mg Q2W and CZP 200mg Q2W, respectively. Interim 
analysis of PK data will compare plasma concentration data from this study with CZP plasma 
concentrations observed previously in adult study participants with rheumatoid arthritis (RA). 
This CZP plasma concentration analysis will be done on an ongoing basis throughout the 
study, starting when 6 study participants in 1 of the age groups have completed Week 12 
(Visit 7). Interim CZP plasma concentration data available at the time of Protocol 
Amendment 3 indicated that no change to the dosing algorithm was required. The protocol 
stated that if future analyses indicate that plasma concentrations of JIA study participants are 
outside of the exposure range observed in previous adult RA studies, the dosing algorithm 
may be changed via a protocol amendment. 
Has been changed to: 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 (minimum=50mg every 2 weeks 
[Q2W], maximum=200mg Q2W) followed by a maintenance dose (minimum=50mg every 
4 weeks [Q4W], maximum=100mg Q2W). Prior to implementation of Protocol 
Amendments 4 and 5, the minimum and maximum loading doses in the study were 
CZP 100mg Q2W and CZP 400mg Q2W, respectively, and the minimum and maximum 
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maintenance doses were CZP 50mg Q2W and CZP 200mg Q2W, respectively. Interim 
analysis of PK data will compare plasma concentration data from this study with CZP plasma 
concentrations observed previously in adult study participants with rheumatoid arthritis (RA). 
Interim analysis of CZP plasma concentrations was started when 6 study participants in 1 of 
the age groups completed Week 12 (Visit 7). Interim CZP plasma concentration data 
available at the time of Protocol Amendment 3 indicated that no change to the dosing 
algorithm was required. The protocol stated that if future analyses indicate that plasma 
concentrations of JIA study participants are outside of the exposure range observed in 
previous adult RA studies, the dosing algorithm may be changed via a protocol amendment. 
 
Change #6 
Section 4.3, Other variables, other safety variables, bullet 3 
 Assessments of study participants’ developmental stages and growth (height, weight) will 
be performed to determine Tanner stages at Baseline, every 24 weeks thereafter, and the 
Early Discontinuation/End of Treatment Visit (weight at every visit through Final Visit). 
Has been changed to: 
 Assessments of study participants’ developmental stages and growth (height, weight) will 
be performed to determine Tanner stages at Baseline, every 24 weeks thereafter, and the 
Early Discontinuation/End of Treatment Visit (weight at every visit through Final Visit). 
Following Protocol Amendment 8, Tanner stages assessment will be performed every 48 
weeks, and only for those study participants who have not reached Tanner stage V. 
 
Change #7 
Section 4.3, Other variables, other efficacy and health outcomes variables, bullets 15 
and 16; and Section 13.5 Planned efficacy and health outcomes analyses, bullets 16 and 
17 
 Change from Baseline in FPS-R (child-reported, ages 5 to 11 years), daily during the first 
week of treatment; Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter through 
the Early Discontinuation/End of Treatment Visit.  
 Change from Baseline in JIA Pain VAS, daily during the first 7 days of the study (acute 
and standard versions); and at Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter 
through the Early Discontinuation/End of Treatment Visit (standard version) for study 
participants ages 12 to 17 years. 
Have been changed to: 
 Change from Baseline in FPS-R (child-reported, ages 5 to 11 years), daily during the first 
week of treatment; Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter through 
the Early Discontinuation/End of Treatment Visit. Following Protocol Amendment 8, 
change from Baseline on FPS-R is assessed every 16 weeks. 
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 Change from Baseline in JIA Pain VAS, daily during the first 7 days of the study (acute 
and standard versions); and at Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter 
through the Early Discontinuation/End of Treatment Visit (standard version) for study 
participants ages 12 to 17 years. Following Protocol Amendment 8, change from Baseline 
in JIA Pain VAS is assessed every 16 weeks. 
 
Change #8 
Section 5.1, Study description, fifth paragraph 
Full interim analyses will be performed:  
 After all active study participants have completed the Week 24 (Visit 10) assessments  
 After all active study participants have completed the Week 56 (Visit 14) assessments 
Has been changed to: 
A full interim analysis will be performed after all active study participants have completed 
the Week 24 (Visit 10) assessments.  
 
Change #9 
Section 5.1, Study description, eighth paragraph 
Interim analysis of PK data will compare CZP plasma concentration data from this study with 
plasma concentrations observed previously in adult study participants with RA. This CZP 
plasma concentration analysis will be done on an ongoing basis throughout the study, starting 
when 6 study participants in 1 of the age groups have completed Week 12 (Visit 7).  
Has been changed to: 
Interim analysis of PK data will compare CZP plasma concentration data from this study with 
plasma concentrations observed previously in adult study participants with RA. Interim 
analysis of CZP plasma concentrations was started when 6 study participants in 1 of the age 
groups completed Week 12 (Visit 7).  
 
Change #10 
Section 5.1, Study description 
The following text was added: 
Pharmacokinetic data from this study (assayed with an enzyme-linked immunosorbent assay 
[ELISA] technique) will not be used for submission to the Food and Drug Administration 
(FDA) to complete the Pediatric Research Equity Act commitment, primarily due to some 
deficiencies detected on the bioanalytical assay used. UCB determined that further collection 
of additional samples to determine CZP plasma concentrations and anti-CZP antibodies 
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would be of limited utility and an undue burden on the study participants. Following Protocol 
Amendment 8, these samples will no longer be collected.  
For the final analysis at the end of the study, UCB will reanalyze all the available samples 
with sufficient volume with a new Meso Scale Discovery (MSD) bioanalytical assay that is 
fully validated and that meets current regulatory standards. This PK data, from the re-assayed 
samples, will be used for final study reporting and thus will not be compared to the 
previously reported RA adult concentrations, as a different bioanalytical technique was used. 
 
Change #11 
Section 5.2, Schedule of study assessments, Table 5-1, CZP plasma concentrations and 
anti-CZP antibodies row 
Study period 
 
 
Week 
Early Disc/ 
End of 
Treatment 
Final 
Visit(c) 
Visit (+/-3 days)(a) 
 
FV 
… 
 
 
CZP plasma concentrations and anti-CZP antibodies 
X 
X 
… 
 
 
Has been changed to: 
Study period 
 
 
Week 
Early Disc/ 
End of 
Treatment 
Final 
Visit(c) 
Visit (+/-3 days)(a) 
 
FV 
… 
 
 
CZP plasma concentrations and anti-CZP antibodies 
 
 
… 
 
 
 
Change #12 
Section 5.2, Schedule of study assessments, Table 5-1, footnotes f, q, r, and v  
f Height and Tanner stages to be measured at Weeks 24 and 48, every 24 weeks thereafter and at Early 
Discontinuation/End of Treatment. 
q  For study participants ages 5 to 11 years. Daily assessment during the first week (Baseline and Day 1 to Day 
7, to be collected at Week 1). In addition, to be completed at Weeks 4, 12, 16, 24, and then every 8 weeks 
thereafter through the End of Treatment/Early Discontinuation Visit. 
r  For study participants ages 12 to 17 years. Daily assessment of acute VAS version during the first week (at 
Baseline and Day 1 to Day 7, to be collected at Week 1). In addition, standard VAS version to be completed at 
Baseline, Weeks 4, 12, 16, 24, and then every 8 weeks thereafter through the End of Treatment/Early 
Discontinuation Visit for study participants ages 12 to 17 years. 
v CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 32, 40, and 48 and every 24 
weeks thereafter. For study participants already enrolled and treated prior to the implementation of Protocol 
Amendment 4 and hence undergoing a reduction of their dose, additional PK samples will be collected prior to 
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dosing at the visit the dose change occurs and at the next 3 site visits following the dose change, ie, additional 
PK samples will be collected at the Unscheduled Visits or at the regular visits if not already planned per 
regular schedule. Afterwards, the regular PK sampling schedule applies. 
Have been changed to: 
f Height and Tanner stages to be measured at Weeks 24 and 48, every 24 weeks thereafter (Tanner stages will 
be measured every 48 weeks and only for study participants who have not reached Tanner stage V following 
Protocol Amendment 8) and at Early Discontinuation/End of Treatment. 
q For study participants ages 5 to 11 years. Daily assessment during the first week (Baseline and Day 1 to Day 
7, to be collected at Week 1). In addition, to be completed at Weeks 4, 12, 16, 24, and then every 8 weeks 
thereafter (every 16 weeks following Protocol Amendment 8) through the End of Treatment/Early 
Discontinuation Visit. 
r  For study participants ages 12 to 17 years. Daily assessment of acute VAS version during the first week (at 
Baseline and Day 1 to Day 7, to be collected at Week 1). In addition, standard VAS version to be completed at 
Baseline, Weeks 4, 12, 16, 24, and then every 8 weeks thereafter (every 16 weeks following Protocol 
Amendment 8) through the End of Treatment/Early Discontinuation Visit for study participants ages 12 to 17 
years. 
v CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 32, 40, and 48 and every 24 
weeks thereafter. For study participants already enrolled and treated prior to the implementation of Protocol 
Amendment 4 and hence undergoing a reduction of their dose, additional PK samples will be collected prior to 
dosing at the visit the dose change occurs and at the next 3 site visits following the dose change, ie, additional 
PK samples will be collected at the Unscheduled Visits or at the regular visits if not already planned per 
regular schedule. Afterwards, the regular PK sampling schedule applies. Following Protocol Amendment 8, 
samples for CZP plasma concentration and anti-CZP antibodies will no longer be collected. 
 
Change #13 
Section 5.2, Schedule of study assessments, Table 5-1, footnote z was added:  
z  Following Protocol Amendment 8, on-site CZP administration, safety sampling, and efficacy assessment 
frequency changes to every 16 weeks instead of every 8 weeks, if administration at home is feasible. The 
option to come to the site for CZP administration between scheduled visits is available as needed.  
 
Change #14 
Section 5.3, Schematic diagram, footnote a was added: 
a Following Protocol Amendment 8, visits will be every 16 weeks instead of every 8 weeks. 
 
Change #15 
Section 8.5, section heading 
Visits 11 and continuing (Week 32 and every 8 weeks thereafter) 
Has been changed to: 
Visits 11 and continuing (Week 32 and every 8 weeks thereafter [every 16 weeks following 
Protocol Amendment 8]) 
 
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Change #16 
Section 8.5, Visits 11 and continuing, bullets 2, 4, and 28 
 Height (Week 48 and every 24 weeks thereafter) 
 Tanner stages (except growth; Week 48 and every 24 weeks thereafter) 
 CZP plasma concentrations and anti-CZP antibodies (Weeks 32, 40, and 48 and every 
24 weeks thereafter, OR if a dose change is performed at the current visit OR if the study 
participant’s dose was changed during 1 of the last 3 visits following Protocol 
Amendment 4) 
Have been changed to: 
 Height (Week 48 and every 24 weeks thereafter [every 48 weeks following Protocol 
Amendment 8]) 
 Tanner stages (except growth; Week 48 and every 24 weeks thereafter [every 48 weeks, 
and only for study participants who have not reached Tanner stage V following Protocol 
Amendment 8]) 
 CZP plasma concentrations and anti-CZP antibodies (Weeks 32, 40, and 48 and every 
24 weeks thereafter, OR if a dose change is performed at the current visit OR if the study 
participant’s dose was changed during 1 of the last 3 visits following Protocol 
Amendment 4; following Protocol Amendment 8, these samples will no longer be 
collected) 
 
Change #17 
Section 8.7, Early Discontinuation/End of Treatment Visit, second to last bullet 
 CZP plasma concentrations and anti-CZP antibodies  
Has been changed to: 
 CZP plasma concentrations and anti-CZP antibodies (following Protocol Amendment 8, 
these samples will no longer be collected) 
 
Change #18 
Section 8.8, Final Visit, last bullet 
 CZP plasma concentrations and anti-CZP antibodies  
Has been changed to: 
 CZP plasma concentrations and anti-CZP antibodies (following Protocol Amendment 8, 
these samples will no longer be collected) 
 
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Change #19 
Section 9, Assessment of Pharmacokinetics and Immunological Variables 
The following text was added: 
Following Protocol Amendment 8, blood samples for determination of CZP plasma 
concentrations and anti-CZP antibodies will not be collected throughout the remainder of the 
study.  
 
Change #20 
Section 10.6, Laboratory measurements, first paragraph 
Hematology, biochemistry, and urinalysis samples will be collected at Screening, Baseline, 
Weeks 4, 8, 12, 16, 20, 24, 32, every 8 weeks thereafter, the Early Discontinuation/End of 
Treatment Visit, and the Final Visit 12 weeks after the last dose of study medication. At 
Week 1, only CRP and PK samples will be collected and at Week 2, only CRP samples will 
be collected. In addition, hematology, biochemistry, and CRP samples will be collected at 
Unscheduled Visits related to the dose change implemented with Protocol Amendment 4. 
Has been changed to: 
Hematology, biochemistry, and urinalysis samples will be collected at Screening, Baseline, 
Weeks 4, 8, 12, 16, 20, 24, 32, every 8 weeks thereafter (every 16 weeks following Protocol 
Amendment 8), the Early Discontinuation/End of Treatment Visit, and the Final Visit 
12 weeks after the last dose of study medication. At Week 1, only CRP and PK samples will 
be collected and at Week 2, only CRP samples will be collected. In addition, hematology, 
biochemistry, and CRP samples will be collected at Unscheduled Visits related to the dose 
change implemented with Protocol Amendment 4. 
 
Change #21 
Section 10.7.2, Growth (height and weight), first paragraph 
Height will be recorded at Screening, Baseline, every 24 weeks thereafter, and the Early 
Discontinuation/End of Treatment Visit. Height will be recorded after the shoes have been 
removed. Height should preferably be measured with a wall-mounted stadiometer. 
Has been changed to: 
Height will be recorded at Screening, Baseline, every 24 weeks thereafter (every 48 weeks 
following Protocol Amendment 8), and the Early Discontinuation/End of Treatment Visit. 
Height will be recorded after the shoes have been removed. Height should preferably be 
measured with a wall-mounted stadiometer. 
 
Change #22 
Section 10.7.3, Tanner stages 
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Assessments of study participants’ developmental stages on external genitalia and pubic hair 
(boys) and on breast and pubic hair (girls) will be performed to determine Tanner stages 
(Marshall and Tanner, 1969; Marshall and Tanner, 1970). These assessments will be 
performed at Baseline, every 24 weeks thereafter, and the Early Discontinuation/End of 
Treatment Visit.  
Has been changed to: 
Assessments of study participants’ developmental stages on external genitalia and pubic hair 
(boys) and on breast and pubic hair (girls) will be performed to determine Tanner stages 
(Marshall and Tanner, 1969; Marshall and Tanner, 1970). These assessments will be 
performed at Baseline, every 24 weeks thereafter, and the Early Discontinuation/End of 
Treatment Visit. Following Protocol Amendment 8, the assessments will be performed every 
48 weeks, and only for study participants who have not reached Tanner stage V. 
 
Change #23 
Section 11.12, Faces Pain Scale-Revised (FPS-R), second paragraph 
The FPS-R is provided in Appendix 17.4. The FPS-R will be administered at Baseline and 
then daily during the first week of the study; at Weeks 4, 12, 16, and 24; and then every 
8 weeks thereafter through the Early Discontinuation/End of Treatment Visit. The 
questionnaire should be checked by site personnel for completeness. 
Has been changed to: 
The FPS-R is provided in Appendix 17.4. The FPS-R will be administered at Baseline and 
then daily during the first week of the study; at Weeks 4, 12, 16, and 24; and then every 
8 weeks thereafter (every 16 weeks following Protocol Amendment 8) through the Early 
Discontinuation/End of Treatment Visit. The questionnaire should be checked by site 
personnel for completeness. 
 
Change #24 
Section 11.13, Patient’s Assessment of Arthritis Pain (JIA Pain VAS), second paragraph 
Both versions of the JIA Pain VAS are provided in Appendix 17.5 and Appendix 17.6. The 
Pain (VAS) will be completed at Baseline (acute and standard versions), daily during the first 
week of treatment (acute version); Weeks 4, 12, 16, and 24; and then every 8 weeks 
thereafter through the Early Discontinuation/End of Treatment Visit (standard version). The 
scale should be checked by site personnel for completeness. 
Has been changed to: 
Both versions of the JIA Pain VAS are provided in Appendix 17.5 and Appendix 17.6. The 
Pain (VAS) will be completed at Baseline (acute and standard versions), daily during the first 
week of treatment (acute version); Weeks 4, 12, 16, and 24; and then every 8 weeks 
thereafter (every 16 weeks following Protocol Amendment 8) through the Early 
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Discontinuation/End of Treatment Visit (standard version). The scale should be checked by 
site personnel for completeness. 
 
Change #25 
Section 11.14, Fatigue Assessment Scale (NRS), fourth paragraph 
The Fatigue Assessment Scale is provided in Appendix 17.7. The Fatigue Assessment Scale 
will be assessed at Baseline, Weeks 1, 2, 4, 8, then every 8 weeks thereafter, and the Early 
Discontinuation/End of Treatment Visit. Preferably, the same parent/caregiver should 
complete the scale for each visit. The scale will not be completed if the study participant is 
not living with a parent/caregiver at least part-time, ie, the parent/caregiver is not able to 
answer the question appropriately. The scale should be checked by site personnel for 
completeness. 
Has been changed to: 
The Fatigue Assessment Scale is provided in Appendix 17.7. The Fatigue Assessment Scale 
will be assessed at Baseline, Weeks 1, 2, 4, 8, 16, 24, 32, then every 8 weeks thereafter (every 
16 weeks following Protocol Amendment 8), and the Early Discontinuation/End of Treatment 
Visit. Preferably, the same parent/caregiver should complete the scale for each visit. The 
scale will not be completed if the study participant is not living with a parent/caregiver at 
least part-time, ie, the parent/caregiver is not able to answer the question appropriately. The 
scale should be checked by site personnel for completeness. 
 
Change #26 
Section 13.4, Planned PK, PD, and immunological variable analysis, second, third, and 
fourth paragraphs 
Plasma concentrations will be used to build a PopPK model using either a Bayesian approach 
with the Winbugs software or meta-analysis with the nonlinear mixed-effect modeling 
(NONMEM) software. 
In the Bayesian approach, the distributions of PK parameters estimated from adult data (from 
the PopPK analysis in C87068 and CL0153) will be incorporated as prior information in the 
model to estimate pediatric PK parameters. This combination of prior knowledge and sparse 
pediatric data will be analyzed within Winbugs. 
The meta-analysis will be performed by adding the pediatric data to the adult data that were 
previously used to perform the adult PopPK analysis within NONMEM (C87068 and 
CL0153). 
Have been changed to: 
Plasma concentrations will be used to build a PopPK model with the nonlinear mixed-effect 
modeling (NONMEM) software. 
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A meta-analysis was previously performed by adding the pediatric data to the adult data in a 
PopPK analysis within NONMEM (C87068 and CL0153) for the Week 24 interim analysis 
(with ELISA data). 
Change #27 
Section 13.4, Planned PK, PD, and immunological variable analysis 
The following text was added: 
For the final analysis, UCB will be re-assaying all available PK samples (ie, for which 
sufficient volume is available) with a newly developed MSD bioanalytical assay. The data 
from the re-assayed RA0043 PK samples will be used to build a PopPK model. 
 
Change #28 
Section 13.5, Planned efficacy and health outcomes analyses, bullets 16 and 17 
 Change from Baseline on FPS-R (child-reported, for study participants ages 5 to 11 
years), daily during the first 7 days of treatment; Weeks 4, 12, 16, and 24; and then every 
8 weeks thereafter through the Early Discontinuation/End of Treatment Visit.  
 Change from Baseline in JIA Pain VAS, daily during the first week of the study (acute 
and standard versions); Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter 
through the Early Discontinuation/End of Treatment Visit (standard version) for study 
participants ages 12 to 17 years.  
Have been changed to: 
 Change from Baseline on FPS-R (child-reported, for study participants ages 5 to 11 
years), daily during the first 7 days of treatment; Weeks 4, 12, 16, and 24; and then every 
8 weeks thereafter through the Early Discontinuation/End of Treatment Visit. Following 
Protocol Amendment 8, change from Baseline on FPS-R is assessed every 16 weeks. 
 Change from Baseline in JIA Pain VAS, daily during the first week of the study (acute 
and standard versions); Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter 
through the Early Discontinuation/End of Treatment Visit (standard version) for study 
participants ages 12 to 17 years. Following Protocol Amendment 8, change from Baseline 
in JIA Pain VAS is assessed every 16 weeks. 
 
Change #29 
Section 13.7, Planned interim analysis and data monitoring, first paragraph 
Interim analysis of PK data will compare CZP plasma concentration data from this study with 
CZP plasma concentrations observed previously in adult study participants with RA. This 
plasma concentration analysis will be done on an ongoing basis throughout the study, starting 
when 6 study participants in 1 of the age groups have completed Week 12 (Visit 7).  
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Has been changed to: 
Interim analysis of PK data will compare CZP plasma concentration data from this study with 
CZP plasma concentrations observed previously in adult study participants with RA. Interim 
analysis of CZP plasma concentrations was started when 6 study participants in 1 of the age 
groups completed Week 12 (Visit 7).  
 
Change #30 
Section 13.7, Planned interim analysis and data monitoring, fifth paragraph 
The CZP plasma concentrations will be monitored on an ongoing basis following the change 
in dose regimen to confirm they are within the targeted adult range. 
Has been changed to: 
For the Week 24 interim clinical study report, the CZP plasma concentrations were monitored 
following the change in dose regimen to confirm they were within the targeted adult range. 
Following Protocol Amendment 8, no more interim PK analyses will be performed, and the 
final PK data to be reported will use a new MSD assay, and consequently no further 
comparison will be performed with respect to the adult RA concentrations range. 
 
Change #31 
Section 13.7, Planned interim analysis and data monitoring, eighth paragraph 
The following text was removed: 
A second full interim analysis of all safety and efficacy endpoints will be performed based 
upon 56 weeks of exposure (Visit 14). 
 
 
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17.19 
Protocol Amendment 9  
Rationale for the amendment 
Protocol Amendment 9 is being undertaken in support of the pJIA PREA requirement for 
CZP. The primary purpose of this substantial amendment is to enroll an additional 30 study 
participants on the original CZP dose regimen in order to adequately assess the exposure 
levels and clinical experience of CZP in pJIA at both the reduced and original CZP dose 
regimens and also adequately support the safety assessment of the original CZP dosing 
regimen. More of the safety data collected in the study to date has been on the reduced dose, 
and which of these dose regimens to be included in the marketing application for CZP in 
pJIA is still to be determined.  
Pharmacokinetic data from this study that were assayed with an ELISA technique will not be 
used for submission to the FDA to complete the PREA commitment, primarily due to 
deficiencies detected with the use of the bioanalytical assay within RA0043, which rendered 
the PK data for the PopPK analysis and simulations that informed the dose reduction in 
Protocol Amendment 4 and 5 unusable from a regulatory standpoint. An ECLIA method, for 
which selectivity had previously been assessed in the RA matrix, has now been validated to 
meet the standards set in the regulatory guidance for analytical procedures and methods 
validations for drugs and biologics. All study participants enrolled following Protocol 
Amendment 9 will have plasma concentrations of CZP and anti-CZP antibodies analyzed 
using the ECLIA method. In addition, PK and ADA samples (for which sufficient volume is 
available) collected in this study prior to Protocol Amendment 9 will be analyzed with the 
ECLIA method. The collective ECLIA-based PK data for this study will form the basis of 
any future CZP modeling and simulation work. 
Additional updates were made to fix typographical errors and to reduce redundancy within 
the protocol.  
Modifications and changes 
Global changes 
The following changes have been made throughout the protocol: 
 ‘Subject’ was changed to ‘study participant’. 
 Study contact details have been updated. 
 Updated primary PK endpoints and primary safety endpoints to be more specific. 
 An additional 30 study participants will be enrolled on the original dose regimen. 
 Updated exclusion criteria to align with current clinical guidelines. The updated 
exclusion criteria are specific for the newly enrolled study participants and will not 
count as protocol deviations for study participants enrolled prior to Protocol 
Amendment 9.  
 The rationale for study design and selection of dose section was restructured for 
clarity and to describe the rationale for adding the 30 study participants on the original 
CZP dose.  
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 Withdrawal criteria were updated to encourage study participants to remain in the 
study in the event of study medication discontinuation. 
 Study participants on the reduced CZP dose regimen will be able to switch to the 
original CZP dose regimen at the discretion of the Investigator. 
 Sampling for CZP plasma concentration and anti-CZP antibodies will occur for study 
participants enrolled following Protocol Amendment 9. 
 Updated statistical considerations section to reflect that study participants on the 
reduced CZP dose can switch dose regimens to the original CZP dose. 
 Updated safety analysis section to reflect updated primary safety endpoints of 
incidence of serious TEAEs and TEAEs leading to permanent withdrawal of IMP. 
 Updated PK analysis section to reflect updated primary PK endpoints of CZP plasma 
concentrations and anti-CZP antibody levels at Week 16 and Week 48.  
 Updated interim analysis section to reflect previous interim analyses and the analyses 
to be conducted with the newly enrolled study participants on the original CZP dose.  
 Removed the Week 16 futility analysis and the Week 56 analysis 
 Assessment and management of TB and TB risk factors has been updated to reflect 
current UCB guidelines. 
Specific changes  
This section displays the modifications in this amendment compared with the previous 
version of the protocol dated 24 Jun 2019. The changes are displayed in the order of 
appearance. 
Change #1 
STUDY CONTACT INFORMATION, contact details of the Sponsor Study Physician: 
Sponsor Study Physician 
Name: 
 
Address: 
Chemin du Foriest 
B - 1420 Braine-l’Alleud 
Belgium  
Phone: 
Fax: 
Has been changed to: 
Sponsor Study Physician 
Name: 
 
Address: 
UCB 
208 Bath Road 
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Slough 
SL1 3WE  
Phone: 
Fax: 
Change #2 
STUDY CONTACT INFORMATION, contact details of the Clinical Trial Biostatistician: 
Clinical Trial Biostatistician  
Name: 
 
Address: 
8010 Arco Corporate Drive 
Suite 
 
Raleigh, NC 27617 
USA 
Phone: 
Fax: 
Has been changed to: 
Clinical Trial Biostatistician  
Name: 
 
Address: 
UCB 
208 Bath Road 
Slough 
SL1 3WE 
Phone: 
 
Fax: 
N/A 
Change #3 
Section 1, paragraph 4 and 5: 
Approximately 195 subjects will be screened to enroll 156 subjects in this study. The study 
consists of a Screening Period of up to 4 weeks; eligible subjects will then enter an open-label 
Treatment Period which will continue until the approval of the marketing application for the 
indication of polyarticular-course JIA in the subject’s country or region or until further notice 
from UCB. A Final Visit will be conducted 12 weeks after last dose of study medication. 
A minimum of 10 subjects will be enrolled on the reduced CZP dose regimen (Protocol 
Amendment 5) in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), 
and ≥40kg (≥88lb). A minimum of 10 subjects will be enrolled in each age category of 2 to 
5 years, 6 to 11 years, and 12 to 17 years, irrespective of the dose regimen. A minimum of 
25 subjects will be enrolled who receive CZP as monotherapy (ie, subjects with established 
intolerability or inadequate response to MTX), irrespective of the dose regimen. A minimum 
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of 10 subjects with ERA will be enrolled, irrespective of the dose regimen. Each of these 
categories is assessed independently.  
Has been changed to: 
Approximately 195 study participants are planned to be screened to enroll 156 study 
participants in this study, as follows: 
 A minimum of 10 study participants will be enrolled on the reduced CZP dose regimen 
(Protocol Amendment 5) in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg 
(44 to <88lb), and ≥40kg (≥88lb).  
 A minimum of 10 study participants will be enrolled in each age category of 2 to 5 years, 
6 to 11 years, and 12 to 17 years, irrespective of the dose regimen.  
 A minimum of 25 study participants will be enrolled who receive CZP as monotherapy 
(ie, study participants with established intolerability or inadequate response to MTX), 
irrespective of the dose regimen. 
 A minimum of 10 study participants with ERA will be enrolled, irrespective of the dose 
regimen.  
Each of these categories is assessed independently. In order to further support the safety 
assessment of the original CZP dose, as more of the safety data collected in the study to date 
has been on the reduced dose, an additional 30 study participants will be enrolled on the 
original dose regimen with the aim to enroll at least 5 study participants in each weight range 
of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and ≥40kg (≥88lb) following 
Protocol Amendment 9. 
Change #4 
Section 1, paragraph 6, was removed: 
An interim analysis of the American College of Rheumatology Pediatric 30% (PedACR30) 
response rate will be performed after all active subjects have completed the Week 16 (Visit 8) 
assessments. The study will be discontinued if less than 50% of the study population enrolled 
on the reduced CZP dose regimen (Protocol Amendment 5) achieves a PedACR30 response 
at Week 16. 
Change #5 
Section 1, paragraph 7: 
A full interim analysis will be performed after all active subjects have completed the 
Week 24 (Visit 10) assessments. The study will continue until the approval of the marketing 
application for the polyarticular-course JIA indication in the subject’s country or region, or 
until discontinuation of the study based on the Week 16 analysis of response, or until further 
notice from UCB. 
Has been changed to: 
A full interim analysis will be performed after all active study participants have completed 
the Week 24 (Visit 10) assessments. 
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Change #6 
Section 1, paragraph 8: 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 (minimum=50mg every 2 weeks 
[Q2W], maximum=200mg Q2W) followed by a maintenance dose (minimum=50mg every 4 
weeks [Q4W], maximum=100mg Q2W). Prior to implementation of Protocol Amendments 4 
and 5, the minimum and maximum loading doses in the study were CZP 100mg Q2W and 
CZP 400mg Q2W, respectively, and the minimum and maximum maintenance doses were 
CZP 50mg Q2W and CZP 200mg Q2W, respectively. Interim analysis of PK data will 
compare plasma concentration data from this study with CZP plasma concentrations observed 
previously in adult subjects with rheumatoid arthritis (RA). Interim analysis of CZP plasma 
concentrations was started when 6 subjects in 1 of the age groups completed Week 12 (Visit 
7). Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicated that no change to the dosing algorithm was required. The protocol stated that if 
future analyses indicate that plasma concentrations of JIA subjects are outside of the 
exposure range observed in previous adult RA studies, the dosing algorithm may be changed 
via a protocol amendment. 
Has been changed to: 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4, followed by maintenance doses 
Q2W. The original minimum and maximum loading doses in the study were CZP 100mg 
Q2W and CZP 400mg Q2W, respectively, and the original minimum and maximum 
maintenance doses were CZP 50mg Q2W and CZP 200mg Q2W, respectively. Based on an 
interim PopPK analysis of RA0043 data, the minimum and maximum loading doses in the 
study were adjusted to CZP 50mg Q2W and CZP 200mg Q2W, respectively, and the 
minimum and maximum maintenance doses were adjusted to CZP 50mg Q4W and 
CZP 100mg Q2W, respectively, following implementation of Protocol Amendments 4 and 5. 
Change #7 
Section 1, Summary 
The following text was added: 
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPK analysis and 
simulations that informed the dose reduction in Protocol Amendment 4 and 5 unusable from a 
regulatory standpoint. Accordingly, PK samples were no longer collected for study 
participants on the reduced CZP dose regimen following implementation of Protocol 
Amendment 8.  
An electrochemiluminescent immuno-assay (ECLIA) method, for which selectivity had 
previously been assessed in the RA matrix, has now been validated to meet the standards set 
in the regulatory guidance for analytical procedures and methods validations for drugs and 
biologics. 
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Based on 24-week interim results from the first 163 participants enrolled in RA0043, both the 
original and reduced dose regimens showed safety profiles similar to the approved CZP dose 
regimen in the adult RA population. The overall clinical response in this analysis (taking both 
dose regimens into account) was PedACR30 and PedACR50 responses of 77.3% and 67.5%, 
respectively at Week 12. The response from the original dose regimen was 75.6% for 
PedACR30 and 64.1% for PedACR50. PedACR50 response demonstrates a highly clinically 
relevant decrease in disease activity. 
Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
JIA at both the reduced and original CZP dose regimens and also adequately support the 
safety assessment of the original CZP dosing regimen, as more of the safety data collected in 
the study to date has been on the reduced dose, 30 additional study participants will be 
enrolled on the original CZP dose regimen following Protocol Amendment 9. All study 
participants enrolled following Protocol Amendment 9 will have plasma concentrations of 
CZP and anti-CZP antibodies analyzed using the ECLIA method. In addition, PK and ADA 
samples (for which sufficient volume is available) collected in this study prior to Protocol 
Amendment 9 will be analyzed with the ECLIA method. The collective ECLIA-based PK 
data for this study will form the basis of any future CZP modeling and simulation work. 
Change #8 
Section 1, paragraph 10: 
The primary objectives of the study are to evaluate the PK and safety including the 
immunogenicity of CZP administered subcutaneously (sc) in children and adolescents with 
moderate to severe polyarticular-course JIA. The secondary objective of the study is to assess 
the effectiveness of CZP on the clinical response in children and adolescents with moderate 
to severe polyarticular-course JIA. 
Has been changed to: 
The primary objectives of the study are to evaluate the PK and safety including the 
immunogenicity of CZP administered subcutaneously (sc) in children and adolescents with 
moderate to severe polyarticular-course JIA. The primary PK and immunological variables 
are CZP plasma concentrations and anti-CZP antibody levels at Week 16 and Week 48. 
Change #9 
Section 1, paragraph 11: 
The primary safety variable is the incidence of adverse events (AEs). Other safety variables 
to be assessed are vital signs and measurements of laboratory parameters including 
hematology, biochemistry, and urinalysis. Physical examination findings (except joint 
examination) are recorded in the case report form (CRF) only at Screening. Subsequent 
physical examinations are performed to assess clinically significant changes and thus, only 
abnormal findings are recorded in the CRF as AEs. Tanner stages (except growth) and 
growth (height, weight) over the course of the study will be assessed. Autoantibody 
(antinuclear antibodies [ANA] and anti-double-stranded deoxyribonucleic acid [anti-dsDNA] 
antibodies) concentrations will be evaluated. 
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Has been changed to: 
The primary safety variables are the incidence of serious treatment-emergent adverse events 
(TEAEs) and TEAEs leading to permanent withdrawal of IMP. Other safety variables to be 
assessed are the incidence of TEAEs, vital signs and measurements of laboratory parameters 
including hematology, biochemistry, and urinalysis. Physical examination findings (except 
joint examination) are recorded in the case report form (CRF) only at Screening. Subsequent 
physical examinations are performed to assess clinically significant changes and thus, only 
abnormal findings are recorded in the CRF as AEs. Tanner stages (except growth) and 
growth (height, weight) over the course of the study will be assessed. Autoantibody 
(antinuclear antibodies [ANA] and anti-double-stranded deoxyribonucleic acid [anti-dsDNA] 
antibodies) concentrations will be evaluated. The secondary objective of the study is to assess 
the effectiveness of CZP on the clinical response in children and adolescents with moderate 
to severe polyarticular-course JIA. 
Change #10 
Section 2, paragraph 2, second sentence: 
Juvenile idiopathic arthritis is the most commonly diagnosed rheumatic disease affecting 
children less than 16 years of age with a prevalence of approximately 100 in 100,000 (Zitelli 
et al, 2012). 
Has been changed to: 
Juvenile idiopathic arthritis is the most commonly diagnosed rheumatic disease affecting 
children less than 16 years of age with a prevalence of approximately 100 in 100,000 children 
(Zitelli et al, 2012). 
Change #11 
Section 2, paragraph 12, last sentence: 
Other serious AEs that have been infrequently reported in patients treated with currently 
available TNF-antagonists including CZP include congestive heart failure, drug-induced 
lupus, new-onset psoriasis, seizures, demyelinating disorders, and pancytopenia. 
Has been changed to: 
Other serious AEs that have been infrequently reported in patients treated with currently 
available TNF-antagonists including CZP include congestive heart failure, drug-induced 
lupus, demyelinating disorders, and pancytopenia. 
Change #12 
Section 4.1.1: 
Certolizumab pegol plasma concentrations and anti-CZP antibody concentrations will be 
assessed and data will be summarized. 
Has been changed to: 
Certolizumab pegol plasma concentrations and anti-CZP antibody levels at Week 16 and 
Week 48 will be assessed and data will be summarized. 
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Change #13 
Section 4.1.2, paragraph 1: 
The primary safety variable will be the incidence of AEs. 
Has been changed to: 
The primary safety variables will be the incidence of serious TEAEs and TEAEs leading to 
permanent withdrawal of IMP. 
Change #14 
Section 4.3: 
The following text was added: 
Other PK and immunological variables are: 
 Certolizumab pegol plasma concentrations and anti-CZP antibody levels at other study 
timepoints 
Other safety variables are: 
 Incidence of TEAEs, TEAEs of interest, TEAEs by relatedness, TEAEs by severity, and 
TEAEs by duration of exposure 
Change #15 
Section 4.3, fifth bullet: 
 Assessments of subjects’ developmental stages and growth (height, weight) will be 
performed to determine Tanner stages at Baseline, every 24 weeks thereafter, and the 
Early Discontinuation/End of Treatment Visit (weight at every visit through Final Visit). 
Following Protocol Amendment 8, Tanner stages assessment will be performed every 
48 weeks, and only for those subjects who have not reached Tanner stage V. 
Has been changed to: 
 Assessments of study participant’s developmental stages and growth (height, weight) will 
be performed to determine Tanner stages at Baseline, every 24 weeks thereafter, and the 
Early Discontinuation/End of Treatment Visit (weight at every visit through Final Visit). 
For study participants enrolled prior to Protocol Amendment 9, Tanner stages assessment 
will be performed every 48 weeks following Protocol Amendment 8, and only for those 
subjects who have not reached Tanner stage V. 
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Change #16 
Section 4.3, bullet 15 and 16 under ‘other efficacy and health outcome variables’: 
 Change from Baseline in FPS-R (child-reported, ages 5 to 11 years), daily during the first 
week of treatment; Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter through 
the Early Discontinuation/End of Treatment Visit. Following Protocol Amendment 8, 
change from Baseline on FPS-R is assessed every 16 weeks. 
 Change from Baseline in JIA Pain VAS, daily during the first 7 days of the study (acute 
and standard versions); and at Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter 
through the Early Discontinuation/End of Treatment Visit (standard version) for subjects 
ages 12 to 17 years. Following Protocol Amendment 8, change from Baseline in JIA Pain 
VAS is assessed every 16 weeks. 
Has been changed to: 
 Change from Baseline in FPS-R (child-reported, ages 5 to 11 years), daily during the first 
week of treatment; Weeks 4, 12, 16, 24, and then every 8 weeks thereafter through the 
Early Discontinuation/End of Treatment Visit. For study participants enrolled prior to 
Protocol Amendment 9, visit frequency changes to every 16 weeks instead of every 
8 weeks following implementation of Protocol Amendment 8. 
 Change from Baseline in JIA Pain VAS, daily during the first 7 days of the study (acute 
and standard versions); and at Weeks 4, 12, 16, 24, and then every 8 weeks thereafter 
through the Early Discontinuation/End of Treatment Visit (standard version) for study 
participants ages 12 to 17 years. For study participants enrolled prior to Protocol 
Amendment 9, visit frequency changes to every 16 weeks instead of every 8 weeks 
following implementation of Protocol Amendment 8. 
Change #17 
Section 5.1, paragraph 4 and 5 were removed: 
An interim analysis of the PedACR30 response rate will be performed after all active subjects 
have completed the Week 16 (Visit 8) assessments. If less than 50% of the study population 
enrolled on the reduced CZP dose regimen (Protocol Amendment 5) achieves a PedACR30 
response at Week 16, the study will be discontinued. 
A full interim analysis will be performed after all active subjects have completed the 
Week 24 (Visit 10) assessments. 
Change #18 
Section 5.1, paragraph 6: 
A Screening Visit is used to initiate assessments of eligibility. Certolizumab pegol will be 
administered as a fixed dose based on weight throughout the study (see Table 7-1). At 
Baseline (Week 0, Visit 2) eligible subjects will begin with 3 loading doses of CZP at Weeks 
0, 2, and 4 (minimum=50mg Q2W, maximum=200mg Q2W) followed by a maintenance 
dose for the duration of the study (minimum=50mg Q4W, maximum=100mg Q2W). Prior to 
implementation of Protocol Amendments 4 and 5, the minimum and maximum loading doses 
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in the study were CZP 100mg Q2W and CZP 400mg Q2W, respectively, and the minimum 
and maximum maintenance doses were CZP 50mg Q2W and CZP 200mg Q2W, respectively. 
After Week 4 (Visit 5), home based CZP administration by the subject or parent/caregiver 
will be permitted between scheduled study visits. 
Has been changed to: 
A Screening Visit is used to initiate assessments of eligibility. Certolizumab pegol will be 
administered as a fixed dose based on weight throughout the study (see Table 7-1 for doses 
administered and Section 5.4.2 for the rationale for the different dose regimens). At Baseline 
(Week 0, Visit 2) eligible study participants will begin with 3 loading doses of CZP at Weeks 
0, 2, and 4 followed by a maintenance dose for the duration of the study. After Week 4 
(Visit 5), home-based CZP administration by the study participant or parent/caregiver will be 
permitted between scheduled study visits. 
Change #19 
Section 5.1, paragraph 7 was removed: 
A minimum of 10 subjects will be enrolled on the reduced CZP dose regimen (Protocol 
Amendment 5) in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), 
and ≥40kg (≥88lb). A minimum of 10 subjects will be enrolled in each age category of 2 to 
5 years, 6 to 11 years, and 12 to 17 years, irrespective of the dose regimen. A minimum of 
25 subjects will be enrolled who receive CZP as monotherapy (ie, subjects with established 
intolerability or inadequate response to MTX), irrespective of the dose regimen. A minimum 
of 10 subjects with ERA will be enrolled, irrespective of the dose regimen. Each of these 
categories is assessed independently. 
Change #20 
Section 5.1, paragraph 8: 
Interim analysis of PK data will compare CZP plasma concentration data from this study with 
plasma concentrations observed previously in adult subjects with RA. Interim analysis of 
CZP plasma concentrations was started when 6 subjects in 1 of the age groups completed 
Week 12 (Visit 7). 
Has been changed to: 
Interim analyses were performed as described in Section 13.7. A full interim analysis will be 
performed after all active study participants have completed the Week 24 (Visit 10) 
assessments.  
Change #21 
Section 5.1, paragraphs 8 and 9 were removed: 
The therapeutic plasma concentration of CZP in children and adolescents is expected to be 
similar to that required for the adult population (see Section 5.4.2). Interim CZP plasma 
concentration data available at the time of Protocol Amendment 3 indicated that no change to 
the dosing algorithm was required. The protocol stated that if future analyses indicate that 
plasma concentrations are outside of the exposure range observed in previous studies with 
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adults, the dosing algorithm may be changed via a protocol amendment. This study will 
continue during the PK analysis. All subjects assessed in this analysis will continue treatment 
after Week 12 (Visit 7). 
Results of an interim PopPK analysis conducted in Jun 2013 suggest that while observed CZP 
plasma concentrations have remained in the adult range, they have been at the upper end of 
the distribution. Simulations predict that for some subjects in RA0043 receiving the 
originally determined loading doses up to Week 4 (Visit 5), plasma concentrations are likely 
to exceed the range previously seen in adult subjects receiving CZP 400mg Q2W. 
Furthermore, plasma concentrations of subjects receiving the originally determined 
maintenance dose after Week 4 (Visit 5) are predicted to exceed the concentration range 
observed in adults receiving CZP 200mg Q2W. Based on these findings, the dosing regimen 
will be changed with Protocol Amendments 4 and 5, and the doses to be administered will be 
reduced by 50% for all weight groups. This dose change is intended to achieve plasma 
concentrations that are similar to the effective concentrations observed in previous studies in 
adult subjects with RA. Continued analysis of CZP plasma concentrations (including 
additional assessments for subjects undergoing a dose reduction with Protocol Amendment 4) 
will be performed to confirm that the 50% dose reduction will result in plasma concentrations 
within the target range of those observed in adults. 
Change #22 
Section 5.1, paragraph 10: 
Pharmacokinetic data from this study (assayed with an enzyme-linked immunosorbent assay 
[ELISA] technique) will not be used for submission to the Food and Drug Administration 
(FDA) to complete the Pediatric Research Equity Act commitment, primarily due to some 
deficiencies detected on the bioanalytical assay used. UCB determined that further collection 
of additional samples to determine CZP plasma concentrations and anti-CZP antibodies 
would be of limited utility and an undue burden on the subjects. Following Protocol 
Amendment 8, these samples will no longer be collected. 
Has been changed to: 
Pharmacokinetic data from this study that were assayed with an enzyme-linked 
immunosorbent assay (ELISA) technique will not be used for submission to the Food and 
Drug Administration (FDA) to complete the Pediatric Research Equity Act commitment, 
primarily due to deficiencies detected with the use of the bioanalytical assay within RA0043. 
All study participants enrolled following Protocol Amendment 9 will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using an ECLIA method that meets 
current regulatory standards. In addition, PK and ADA samples (for which sufficient volume 
is available) collected in this study prior to Protocol Amendment 9 will be analyzed with the 
ECLIA method. The collective ECLIA-based PK data for this study will form the basis of 
any future CZP modeling and simulation work. 
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Change #23 
Section 5.1, paragraph 11 was removed: 
For the final analysis at the end of the study, UCB will reanalyze all the available samples 
with sufficient volume with a new Meso Scale Discovery (MSD) bioanalytical assay that is 
fully validated and that meets current regulatory standards. This PK data, from the re-assayed 
samples, will be used for final study reporting and thus will not be compared to the 
previously reported RA adult concentrations, as a different bioanalytical technique was used. 
Change #24 
Section 5.1.1, paragraph 1, second sentence: 
Eligible subjects will subsequently initiate open-label treatment with CZP at Baseline (Week 
0, Visit 2) and be permitted to continue until the approval of the marketing application for the 
polyarticular-course JIA indication in the subject’s country or region, or until discontinuation 
of the study based on the Week 16 analysis of response, or until further notice from UCB. 
Has been changed to: 
Eligible study participants will subsequently initiate open-label treatment with CZP at 
Baseline (Week 0, Visit 2) and be permitted to continue until the approval of the marketing 
application for the polyarticular-course JIA indication in the study participant’s country or 
region, or until further notice from UCB.  
Change #25 
Section 5.1.1, paragraph 1, last sentence: 
Planned Last Subject, First Visit –  1Q/2Q 2015 
Has been changed to: 
Planned Last Study participant, First Visit – 3Q 2021 
Change #26 
Section 5.1.2, paragraph 1, first sentence: 
Approximately 195 subjects will be screened at about 55 centers in order to enroll 
156 subjects in this study. 
Has been changed to: 
Approximately 195 study participants are planned to be screened at about 55 centers in order 
to enroll 156 study participants in this study, as follows:  
Change #27 
Section 5.1.2, paragraph 2 was moved to paragraph 6: 
The enrollment per site is limited to a maximum of 12 subjects. 
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Change #28 
Section 5.1.2, bullet 1: 
A minimum of 10 subjects will be enrolled on the reduced CZP dose regimen (Protocol 
Amendment 5) in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), 
and ≥40kg (≥88lb) 
Has been changed to: 
A minimum of 10 study participants will be enrolled on the reduced CZP dose regimen in 
each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and ≥40kg 
(≥88lb) (See Section 7.2 for the doses administered in the study and Section 5.4.2.2 for the 
rationale for the reduced CZP dose regimen). 
Change #29 
Section 5.1.2, the following text was added: 
Recruitment based on all protocol amendments prior to Protocol Amendment 9 is complete. 
Following Protocol Amendment 9, an additional 30 study participants will be enrolled on the 
original dose regimen with the aim to enroll at least 5 study participants in each weight range 
of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and ≥40kg (≥88lb) (See Section 7.2 
for the doses administered in the study and Section 5.4.2.1 for the rationale for the original 
CZP dose regimen).  
Change #30 
Section 5.2, Schedule of study assessments, Table 5-1, CZP plasma concentrations and 
anti-CZP antibodies row 
Study period 
 
 
 
Week 
… 
4, 8, 12, 16, 
(17(u)), 20, 
24 
 
Visit (+/-3 days)(a) 
 
5 to 10 
 
… 
 
 
 
CZP plasma concentrations and anti-CZP antibodies 
 
x 
 
… 
 
 
 
Has been changed to: 
Study period 
 
 
 
Week 
… 
4, 8, 12, 16, 
(17(u)), 20, 
24 
… 
Visit (+/-3 days)(a) 
 
5 to 10 
 
… 
 
 
 
CZP plasma concentrations  
 
x 
 
Anti-CZP antibodies 
 
x 
 
… 
 
 
 
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Change #31 
Section 5.2, Schedule of study assessments, Table 5-1, footnote f 
Height and Tanner stages to be measured at Weeks 24 and 48, every 24 weeks thereafter 
(Tanner stages will be measured every 48 weeks, and only for subjects who have not reached 
Tanner stage V following Protocol Amendment 8) and at Early Discontinuation/End of 
Treatment. 
Has been changed to: 
Height stages to be measured at Week 24 and 48, every 24 weeks thereafter (for study 
participants enrolled prior to Protocol Amendment 9, Tanner stages assessment will be 
performed every 48 weeks following Protocol Amendment 8, and only for those subjects who 
have not reached Tanner stage V) and at Early Discontinuation/End of Treatment.  
Change #32 
Section 5.2, Schedule of study assessments, Table 5-1, footnote i 
TB questionnaire to be completed at Weeks 12 and 24, every 16 weeks thereafter, and Early 
Discontinuation/End of Treatment. If the Investigator suspects reactivation of latent TB or 
active TB, TB testing and/or a chest x-ray should be performed as outlined in 
Section 10.7.9.1. 
Has been changed to: 
TB questionnaire to be completed at Weeks 12 and 24 and every 16 weeks thereafter, and 
Early Discontinuation/End of Treatment. If the Investigator suspects reactivation of latent TB 
or active TB, TB testing and/or a chest x-ray should be performed as outlined in 
Section 10.7.9.  
Change #33 
Section 5.2, Schedule of study assessments, Table 5-1, footnote I, sentence 2 
If the Investigator suspects reactivation of latent TB or active TB, TB testing and/or a chest 
x-ray should be performed as outlined in Section 10.7.9. 
Has been changed to: 
If the Investigator suspects latent TB or active TB, TB testing and/or a chest x-ray should be 
performed as outlined in Section 10.7.9. 
Change #34 
Section 5.2, Schedule of study assessments, Table 5-1, footnote j 
Analyses will be performed by a central laboratory, except urine dipsticks, which will be 
done locally at the site. Subjects do not have to be fasting. 
Has been changed to: 
Hematology/biochemistry/urinalysis will be performed by a central laboratory, except urine 
dipsticks, which will be done locally at the site. Study participants do not have to be fasting. 
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Change #35 
Section 5.2, Schedule of study assessments, Table 5-1, footnote k 
At Screening, laboratory testing includes testing for HBcAb, HBsAb, HBsAg, and HCVAb. 
In addition, HBV DNA is required for subjects with only positive HBcAb (negative HBsAg 
and HBsAb) or with only positive HBsAg. Retesting on 1 additional occasion within the 
Screening Period is allowed in case of isolated exclusionary laboratory results, if, in the 
Investigator’s opinion, the value is not reflective of the subject’s previous clinical and 
laboratory pattern. In addition, retesting within the Screening Period is allowed in case of 
reporting failure of laboratory results (eg, issues with transportation of samples). 
Has been changed to: 
At Screening, laboratory testing includes testing for hepatitis B core antibody, hepatitis B 
surface antibody, hepatitis B surface antigen, hepatitis C virus antibody, and HIV 1/2. Study 
participants with a positive hepatitis B virus test will not be allowed in the study (except for 
anti-hepatitis B surface positive only, in case study participant is immune due to well-
documented hepatitis B vaccination or isolated false-positive anti-hepatitis B core test 
confirmed with a confirmatory test such as hepatitis B virus deoxyribonucleic acid [DNA]). 
A positive hepatitis C antibody test will be confirmed by a confirmatory test (such as 
hepatitis C virus ribonucleic acid [RNA]) and those with a positive confirmatory test will not 
be allowed in the study.  
Change #36 
Section 5.2, Schedule of study assessments, Table 5-1, footnote n 
TB screening if not performed within 3 months of Screening: Interferon-gamma release assay 
(IGRA) testing (QuantiFERON®) is required to be performed by the central lab for all 
subjects from 5 to 17 years of age. PPD testing is mandatory for subjects from 2 to 4 years of 
age in this study unless written documentation of BCG vaccination is available (refer to 
Section 6.2 [exclusion criterion 11] and Section 10.7.9). Following implementation of 
Protocol Amendment 7, IGRA testing (QuantiFERON) should be done once a year 
(approximately every 48 weeks) for all subjects from 5 to 17 years of age. For subjects from 
2 to 4 years of age, both IGRA and PPD testing should be performed once a year 
(approximately every 48 weeks). In cases where written documentation of BCG vaccination 
is available or previous PPD test was positive, only IGRA should be performed (Section 
10.7.9.2). 
Has been changed to: 
TB screening: Interferon-gamma release assay (IGRA) testing (QuantiFERON®) is required 
to be performed by the central lab for all study participants from 5 to 17 years of age. TST 
and IGRA testing at Screening is mandatory for study participants less than 5 years of age in 
this study unless written documentation of BCG vaccination is available (refer to Section 6.2 
[exclusion criterion 11] and Section 10.7.9). Following implementation of Protocol 
Amendment 7, IGRA testing (QuantiFERON) should be done once a year (approximately 
every 48 weeks) for all study participants. 
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Change #37 
Section 5.2, Schedule of study assessments, Table 5-1, footnote o 
A chest radiograph (anterior-posterior view at minimum, but preferably anterior-posterior and 
lateral) must be taken if the subject has a positive IGRA/PPD testing at Screening or, if 
written documentation of BCG vaccination is available for subjects ages 2 to 4 years, a TB 
questionnaire indicating an increased subject’s risk of exposure or infection with TB. If a 
subject has had a recent radiograph of the chest within approximately 3 months prior to 
Screening, it may be used in lieu of the protocol-required radiograph. All chest imaging must 
be read by a qualified radiologist/pulmonary physician who is specifically required to look 
for evidence of active TB or inactive TB. Refer to Section 10.7.9.2.2 for further information 
on chest x-rays. 
Has been changed to: 
Chest radiographic imaging is done at Screening and results must be available at Baseline 
before first drug administration unless as chest x-ray or CT is available within 2 months prior 
to Screening.  
Change #38 
Section 5.2, Schedule of study assessments, Table 5-1, footnote q 
For subjects ages 5 to 11 years. Daily assessment during the first week (Baseline and Day 1 
to Day 7, to be collected at Week 1). In addition, to be completed at Weeks 4, 12, 16, 24, and 
then every 8 weeks thereafter (every 16 weeks following Protocol Amendment 8) through the 
End of Treatment/Early Discontinuation Visit. 
Has been changed to: 
For study participants ages 5 to 11 years. Daily assessment during the first week (Baseline 
and Day 1 to Day 7, to be collected at Week 1). In addition, to be completed at Weeks 4, 12, 
16, 24, and then every 8 weeks thereafter (for study participants enrolled prior to Protocol 
Amendment 9, visit frequency changes to every 16 weeks instead of every 8 weeks following 
implementation of Protocol Amendment 8) through the End of Treatment/Early 
Discontinuation Visit. 
Change #39 
Section 5.2, Schedule of study assessments, Table 5-1, footnote r 
For subjects ages 12 to 17 years. Daily assessment of acute VAS version during the first 
week (at Baseline and Day 1 to Day 7, to be collected at Week 1). In addition, standard VAS 
version to be completed at Baseline, Weeks 4, 12, 16, 24, and then every 8 weeks thereafter 
(every 16 weeks following Protocol Amendment 8) through the End of Treatment/Early 
Discontinuation Visit for subjects ages 12 to 17 years. 
Has been changed to: 
For study participants ages 12 to 17 years. Daily assessment of acute VAS version during the 
first week (at Baseline and Day 1 to Day 7, to be collected at Week 1). In addition, standard 
VAS version to be completed at Baseline, Weeks 4, 12, 16, 24, and then every 8 weeks 
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thereafter (for study participants enrolled prior to Protocol Amendment 9, visit frequency 
changes to every 16 weeks instead of every 8 weeks following implementation of Protocol 
Amendment 8) through the End of Treatment/Early Discontinuation Visit for study 
participants ages 12 to 17 years. 
Change #40 
Section 5.2, Schedule of study assessments, Table 5-1, footnote u 
CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 4, 12, 16, and 
24. A postdose CZP plasma sample will be collected at approximately 5 to 7 days following 
the Week 16 Visit (ie, requires an additional clinic site visit for blood collection at Week 17). 
For subjects already enrolled and treated prior to the implementation of Protocol Amendment 
4 and hence undergoing a reduction of their dose, additional PK samples will be collected 
prior to dosing at the visit the dose change occurs and at the next 3 site visits following the 
dose change, ie, additional PK samples will be collected at the Unscheduled Visits or at the 
regular visits if not already planned per regular schedule. Afterwards, the regular PK 
sampling schedule applies 
Has been changed to: 
CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 4, 12, 16, and 
24. A postdose CZP plasma sample will be collected at approximately 5 to 7 days following 
the Week 16 Visit (ie, requires an additional clinic site visit for blood collection at Week 17). 
Samples for CZP plasma concentration and anti-CZP antibodies will be collected as separate 
samples.  
Change #41 
Section 5.2, Schedule of study assessments, Table 5-1, footnote v 
CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 32, 40, and 48 
and every 24 weeks thereafter. For subjects already enrolled and treated prior to the 
implementation of Protocol Amendment 4 and hence undergoing a reduction of their dose, 
additional PK samples will be collected prior to dosing at the visit the dose change occurs and 
at the next 3 site visits following the dose change, ie, additional PK samples will be collected 
at the Unscheduled Visits or at the regular visits if not already planned per regular schedule. 
Afterwards, the regular PK sampling schedule applies. Following Protocol Amendment 8, 
samples for CZP plasma concentration and anti-CZP antibodies will no longer be collected. 
Has been changed to: 
CZP plasma concentration and anti-CZP antibodies to be measured at Weeks 32, 40, 48, and 
every 24 weeks thereafter for study participants enrolled following Protocol Amendment 9. 
For study participants enrolled prior to Protocol Amendment 9, samples for CZP plasma 
concentration and anti-CZP antibodies will no longer be collected. Samples for CZP plasma 
concentration and anti-CZP antibodies will be collected as separate samples. 
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Change #42 
Section 5.2, Schedule of study assessments, Table 5-1, footnote z 
Following Protocol Amendment 8, on-site CZP administration, safety sampling, and efficacy 
assessment frequency changes to every 16 weeks instead of every 8 weeks, if administration 
at home is feasible. The option to come to the site for CZP administration between scheduled 
visits is available as needed. 
Has been changed to: 
For study participants enrolled prior to Protocol Amendment 9, on-site CZP administration, 
safety sampling, and efficacy assessment frequency changes to every 16 weeks instead of 
every 8 weeks following implementation of Protocol Amendment 8, provided that 
compliance is maintained with the CZP dosing schedule using at-home administration. The 
option to come to the site for CZP administration between scheduled visits is available as 
needed.  
Change #43 
Section 5.3, Schematic diagram, footnote a  
Following Protocol Amendment 8, visits will be every 16 weeks instead of every 8 weeks. 
Has been changed to: 
Following Week 32, visits will be every 8 weeks. For study participants enrolled prior to 
Protocol Amendment 9, visit frequency changes to every 16 weeks instead of every 8 weeks 
following implementation of Protocol Amendment 8.   
Change #44 
Section 5.3, Schematic diagram, footnote b has been added  
The futility analysis of PedACR30 after all study participants on the reduced CZP dose 
completed Week 16 has already been completed. A further futility analysis will not be 
performed using the additional study participants that will be enrolled on the original CZP 
dose regimen following the implementation of Protocol Amendment 9. 
Change #45 
Section 5.4.1, paragraph 3, sentence 3:  
In light of these results and the efficacy of CZP demonstrated in the 4 adequate and well-
controlled studies in adult RA, it is appropriate to extrapolate these efficacy data to the 
intended JIA population if similar results are obtained for PK and safety in JIA as seen for 
adult RA. The opinion within the pediatric rheumatology community supports that 
extrapolation from open-label PK/safety data is acceptable for additional members of the 
class of TNF-antagonists. 
Has been changed to: 
Through extensive interactions between the FDA and external experts, culminating in a 
collaborative workshop in October 2019 entitled “Accelerating Drug Development for 
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polyarticular Juvenile Idiopathic Arthritis (pJIA)”, a therapeutic bridging approach from RA 
to pJIA was strongly supported for TNF-α inhibitors based on the relationship between RA 
and pJIA and the extensive knowledge of TNF-α inhibitors as therapeutic agents in these two 
populations. This approach (based on "Pharmacokinetic (PK) matching") directs that the 
therapeutic effect of TNF-α inhibitors (such as CZP) in pJIA patients can be expected if the 
pediatric systemic exposure for the drug is within the therapeutic range for adult RA patients. 
Change #46 
Section 5.4.1, the following text was added:  
Study RA0043 is being undertaken in support of the pJIA Pediatric Research Equity Act 
(PREA) requirement for CZP. The pJIA development program for CZP will be based on PK 
data generated with the newly validated MSD ECLIA method for pediatric study participants 
in (Section 7.2 and Section 5.4.2). To enable this approach, an additional 30 study 
participants will be enrolled in RA0043 following Protocol Amendment 9 at the original CZP 
dosing regimen.  
Central to application of this approach is the existence of a reference systemic exposure (PK) 
range which is associated with therapeutic benefit of the drug in adult RA population. A 
supporting adult reference PK dataset for "PK matching" in the pJIA program will also need 
to be based on data generated with the ECLIA method. Accordingly, a separate study is being 
undertaken in order to generate ECLIA-based CZP PK data for CZP in adults with RA. 
Change #47 
Section 5.4.2, the following text was added:  
The original minimum and maximum loading doses in the study were CZP 100mg Q2W and 
CZP 400mg Q2W, respectively, and the original minimum and maximum maintenance doses 
were CZP 50mg Q2W and CZP 200mg Q2W, respectively (see Section 5.4.2.1 for the 
rationale for the original CZP dose regimen). Based on an interim PopPK analysis of RA0043 
data, the minimum and maximum loading doses in the study were adjusted to CZP 50mg 
Q2W and CZP 200mg Q2W, respectively, and the minimum and maximum maintenance 
doses were adjusted to CZP 50mg Q4W and CZP 100mg Q2W, respectively, following 
implementation of Protocol Amendments 4 and 5 (see Section 5.4.2.2 for the rationale for the 
reduced CZP dose regimen).  
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPK analysis and 
simulations that informed the dose reduction in Protocol Amendment 4 and 5 unusable from a 
regulatory standpoint. Accordingly, PK samples were no longer collected for study 
participants on the reduced CZP dose regimen following implementation of Protocol 
Amendment 8.  
An ECLIA method, for which selectivity had previously been assessed in the RA matrix, has 
now been validated to meet the standards set in the regulatory guidance for analytical 
procedures and methods validations for drugs and biologics (FDA, Guidance for Industry – 
Bioanalytical Method Validation, 2018). The ECLIA assay consists of a homogeneous 
bridging immunoassay on the MSD platform. 
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Based on 24-week interim results from RA0043 (Section 13.7), both the original and reduced 
dose regimens showed safety profiles similar to the approved CZP dose regimen in the adult 
RA population. The overall clinical response in the study (taking both dose regimens into 
account) was PedACR30 and PedACR50 responses of 77.3% and 67.5%, respectively at 
Week 12. The response from the original dose regimen was 75.6% for PedACR30 and 64.1% 
for PedACR50. PedACR50 response demonstrates a highly clinically relevant decrease in 
disease activity. 
Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
pJIA at both the reduced and original CZP dose regimens and also adequately support the 
safety assessment of the original CZP dosing regimen, as more of the safety data collected in 
the study to date has been on the reduced dose, 30 additional study participants will be 
enrolled on the original CZP dose regimen following Protocol Amendment 9. All study 
participants enrolled following Protocol Amendment 9 will have plasma concentrations of 
CZP and anti-CZP antibodies analyzed using the ECLIA method. In addition, PK and ADA 
samples ( for which sufficient volume is available) collected in this study prior to Protocol 
Amendment 9 will be analyzed with the ECLIA method. The collective ECLIA-based PK 
data for this study will form the basis of any future CZP modeling and simulation work. 
Change #48 
Section 5.4.2, the Section 5.4.2.1 and Section 5.4.2.2 headings were added. 
Change #49 
Section 5.4.2, paragraph 3; the following text was moved to Section 5.4.2.2:  
During the course of the study, results from the ongoing interim PK analysis and an interim 
PopPK analysis conducted in Jun 2013 indicated that plasma concentrations within the range 
previously seen in adult subjects receiving CZP 200mg Q2W would be achieved if the dose 
in RA0043 was reduced to 50% of the original dose used in the study. Therefore, the 
maintenance doses in this study will be reduced further with Protocol Amendment 4 so that 
subjects with body weights between 20 and <40kg (44 to <88lb) will receive CZP 50mg 
Q2W, and subjects with body weights of ≥40kg (≥88lb) will receive CZP 100mg Q2W (see 
Table 7-1). The optimal maintenance dose estimated in the PopPK model for the lowest 
weight group would be CZP 25mg Q2W, however, the lowest available dose size is 
CZP 50mg. Thus, subjects with body weights of 10 to <20kg (22 to <44lb) will receive 
CZP 50mg Q4W to achieve this 50% reduction. In addition, with Protocol Amendment 5, the 
loading dose in the study will be reduced by 50% for newly enrolled subjects, so that subjects 
with body weights of 10 to <20kg (22 to <44lb) will receive CZP 50mg at Weeks 0, 2, and 4, 
subjects with body weights between 20 to <40kg (44 to <88lb) will receive CZP 100mg at 
Weeks 0, 2, and 4, and subjects with body weights ≥40kg (≥88lb) will receive CZP 200mg at 
Weeks 0, 2, and 4. 
The rationale behind selecting the equivalent of the adult therapeutic dose is based on the 
following: 
 There is no metabolic rationale to expect a difference in the PK/PD of CZP in a younger 
population, particularly as there is no involvement of cytochrome P450. 
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 Evaluation of a previous anti-TNF antibody (CDP571, a whole antibody) in a pediatric 
population (administered iv) confirmed that the PK and safety were similar to that of an 
adult population. 
 Doses in excess of CZP 400mg (up to CZP 800mg) have been administered to healthy 
adult subjects and subjects with RA without any dose-limiting toxicities being identified. 
 A conservative approach to dose reduction was chosen because the body weight of 
pediatric subjects may be influenced largely by frame size while the range of body weight 
of adults may be more influenced by percent body fat. 
Change #50 
Section 5.4.2.1, paragraph 4, first sentence: 
The original choice of dose and the weight-based dose-adjustment algorithm, prior to 
Protocol Amendments 4 and 5, was supported by simulations of the PK exposure and 
response rates in children using the PopPK model and PK/PD exposure response model 
developed in adult RA subjects, corrected for pediatric demographics (C87079 addendum 
08 Oct 2008). 
Has been changed to: 
The original choice of dose and the weight-based dose-adjustment algorithm was supported 
by simulations of the PK exposure and response rates in children using the PopPK model and 
PK/PD exposure response model developed in adult RA study participants, corrected for 
pediatric demographics (C87079 addendum 08 Oct 2008).  
Change #51 
Section 5.4.2, paragraph 4, sentence 5 was removed: 
The revised dose and weight-based dose adjustment algorithm was based on a PopPK 
analysis and simulation using data from 35 subjects in this study with post-Baseline plasma 
concentrations of CZP available prior to Protocol Amendments 4 and 5. 
Change #52 
Section 5.4.2, the following text was added within Section 5.4.2.1: 
The original CZP dose regimen is the regimen that will be used for study participants 
enrolled following Protocol Amendment 9 
Change #53 
Section 5.4.2, the following text was added within Section 5.4.2.2: 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicated that no change to the dosing algorithm was required. The protocol stated that if 
future analyses indicate that plasma concentrations were outside of the exposure range of 
those observed in previous studies with adults, the dosing algorithm could have been changed 
via a protocol amendment, and if necessary additional interim analyses including PopPK, 
could have been performed. 
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Change #54 
Section 5.4.2, the following text was added within Section 5.4.2.2: 
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPK analysis and 
simulations that informed the dose reduction in Protocol Amendment 4 and 5 unusable from a 
regulatory standpoint. Study participants enrolled prior to the implementation of Protocol 
Amendment 9 can remain on the reduced CZP dose or may be switched to the original CZP 
dose at the discretion of the Investigator and in consultation with the medical monitor. 
Additional dose changes are not allowed (Section 7.2.1). 
Change #55 
Section 6.2, exclusion criterion 11: 
Subjects with known TB infection, or at high risk of acquiring TB infection, are excluded. 
Subjects with latent TB (LTB) infection that have not received a minimum of 4 weeks of 
prophylactic treatment are only eligible following prophylaxis: 
a. Known TB infection whether present or past is defined as:  
 Active TB infection or clinical signs and symptoms suspicious for TB 
(pulmonary or extra-pulmonary) 
 History of active TB infection involving any organ system or findings in other 
organ systems consistent with TB infection  
 Any evidence by radiography or other imaging modalities consistent with 
previously active TB infection that is not reported in the subject’s medical 
history 
b. High risk of acquiring TB infection is defined as: 
 Known exposure of Subject or Caregiver to another person with active TB 
infection within the 3 months prior to Screening 
 Time spent in a healthcare delivery setting or institution where individuals 
infected with TB are housed and where the risk of transmission of infection to 
Subject or Caregiver is high 
c. Latent TB infection is defined as: 
Absence of signs, symptoms (ie, evidence of organ-specific involvement), or 
physical findings suggestive of TB infection with a positive interferon-gamma 
release assay (IGRA [QuantiFERON]) test (or 2 indeterminate IGRA test results) 
or positive PPD (where the PPD skin test is approved for use by UCB; mandatory 
for ages 2 to 4 years in this study) or, if written documentation of Bacille 
Calmette-Guérin (BCG) vaccination is available for subjects ages 2 to 4 years, a 
TB questionnaire indicating an increased subject’s risk of exposure or infection 
with TB, and a chest x-ray (or other imaging) without evidence of TB infection.  
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Note: If available, respiratory or other specimens must also be smear and culture 
negative for TB (Centers of Disease Control and Prevention [CDC] diagnosis of 
LTB infection, http://www.cdc.gov/TB/topic/testing/default.htm). 
Refer to Section 10.7.9 for additional information on TB definition and clinical signs, 
diagnosis, documentation, and treatment. 
Subjects with a history of or active infection with nontuberculous mycobacteria (NTMB) 
are excluded from this study. 
Has been changed to: 
Participant has: 
a. Known active TB disease 
b. History of active TB involving any organ system  
c. History of or current latent tuberculosis infection (LTBI) 
d. High risk of exposure to TB infection 
e. Current nontuberculous mycobacterial (NTMB) infection or history of NTMB 
infection. For further information relating to definitions of known active TB, past 
history of TB, LTBI, high risk of acquiring TB infection and NTMB infection refer to 
Section 10.7.9 (Assessment and management of TB and TB risk factors). 
Change #56 
Section 6.2, exclusion criterion 13: 
Subject with known concurrent viral hepatitis or known positivity for hepatitis B surface 
antigen (HBsAg) or hepatitis C virus (HCV) antibody or known human immunodeficiency 
virus (HIV) infection. At Screening, a hepatitis panel result which indicates immunity due to 
hepatitis B vaccination is not considered an exclusion criterion.  
Has been changed to: 
Study participant has a history of or current hepatitis B or C virus or HIV 1/2 or has any of 
the following laboratory abnormalities during the screening period:  
a. Hepatitis B surface (HBs) antigen, hepatitis B core (HBc) antibody (except for isolated, 
false-positive anti-HBc confirmed with a confirmatory test such as hepatitis B virus 
[HBV]-deoxyribonucleic acid [DNA] [refer to Table 5-1 footnote k and Section 10.6 
(Clinical Laboratory Tests) table footnote c]): Positive to any of these 
b. Hepatitis C virus (HCV) positive: defined as hepatitis C antibody (anti-HCV Ab) positive 
confirmed via a confirmatory test (for example, HCV polymerase chain reaction). 
c. HIV antigen or antibody: Positive to either test 
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Change #57 
Section 6.2, exclusion criterion 17, sentence 2, 3, and 4: 
For postmenarcheal female study participants not currently sexually active, the study 
participant and parent or legal representative should agree that the study participant will 
employ an effective means of birth control should the study participant become sexually 
active. Adequate methods of birth control are: oral/parenteral/implantable hormonal 
contraceptives (stable at least 2 months prior to Screening (Visit 1) if initiated prior to 
entering the study) or a combination of barrier and spermicide. Study participants must agree 
to use adequate contraception during the study and for 12 weeks after their last dose of study 
medication (or longer if required by local regulations).   
Has been changed to: 
For postmenarcheal female study participants not currently sexually active, the study 
participant and parent or legal representative should agree that the study participant will 
employ an effective means of birth control consistently and correctly should the study 
participant become sexually active. Effective methods of birth control are: 
oral/parenteral/implantable hormonal contraceptives (stable at least 2 months prior to 
Screening (Visit 1) if initiated prior to entering the study) or a combination of barrier and 
spermicide. Study participants must agree to use effective contraception during the study and 
for 12 weeks after their last dose of study medication (or longer if required by local 
regulations). 
Change #59 
Section 6.3, paragraph 2, bullet 3 was removed: 
Subjects with LTB infection, indicated by positive PPD skin test or positive IGRA test result 
(or TB questionnaire indicating an increased risk of exposure or infection with TB for 
subjects ages 2 to 4 years with documented BCG vaccination) and a chest imaging without 
evidence of TB infection at Screening, may be rescreened after initiation of treatment for 
latent TB. Prior to first study medication administration, TB treatment must have been 
ongoing for at least 4 weeks before enrollment will be allowed and after approval of the 
Medical Monitor. Treatment for TB must be continued until completion of 9 months of 
therapy (refer to Section 10.7.9). 
Change #60 
Section 6.4, the following text for Liver Chemistry Stopping Criteria was added: 
Participants with potential drug-induced liver injury (PDILI) must be assessed to determine if 
IMP must be discontinued. In addition, all concomitant medications and herbal supplements 
that are not medically necessary should be discontinued. The PDILI criteria below require 
immediate and permanent discontinuation of IMP:  
 Participants with either of the following:  
- 
ALT or AST ≥5xULN 
- 
ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
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The PDILI criterion below requires immediate discontinuation of IMP:  
 Participants with ALT or AST ≥3xULN who exhibit temporally associated symptoms 
of hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, 
and right upper quadrant pain or tenderness. Hypersensitivity symptoms include fever 
(without clear alternative cause), rash, and eosinophilia (ie, >5%).  
The PDILI criterion below allows participants to continue on IMP at the discretion of the 
investigator:  
 Participants with ALT or AST ≥3xULN (and ≥2x baseline) and <5xULN, total 
bilirubin <2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of 
hepatitis (eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness).  
Evaluation of PDILI must be initiated as described in Section 17.10. If participants are unable 
to comply with the applicable monitoring schedule, IMP must be discontinued immediately.  
Investigators should attempt to obtain information on participants in the case of IMP 
discontinuation to complete the final evaluation. Participants with PDILI should not be 
withdrawn from the study until investigation and monitoring are complete. All results of 
these evaluations and observations, as well as the reason(s) for IMP discontinuation and 
participant withdrawal (if applicable), must be recorded in the source documents. The eCRF 
must document the primary reason for IMP discontinuation. 
Change #61 
Section 6.5, Withdrawal criteria, the following text was added: 
Study participants are free to withdraw from the study at any time, without prejudice to their 
continued care. Where possible, study participants discontinuing study medication should be 
encouraged to remain in the study. 
A study participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
If the study participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
If a study participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
See the Schedule of Activities for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
Change #62 
Section 6.5, withdrawal criteria 3 and 4: 
3) Subject who develops active TB or NTMB infection during the study must be withdrawn 
(refer to Section 10.7.9). 
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4) Subject who prematurely discontinues treatment for LTB, or, in the opinion of the 
Investigator or Sponsor, is noncompliant with anti-TB therapy must be withdrawn. 
Has been changed to: 
A study participant considered as having either a suspected new LTBI or who develops active 
TB or NTMB infection during the study (including but not limited to, conversion 
demonstrated by interferon-gamma release assay (IGRA) or other diagnostic means) must be 
immediately discontinued from IMP (refer to Section 10.7.9.8 for further details). 
a. The study participant must be permanently withdrawn from the study if further 
examinations result in a diagnosis of active TB, NTMB infection or if the study 
participant is diagnosed with LTBI. An Early Discontinuation visit must be scheduled as 
soon as possible, but not later than the next regular visit.  
b. Any confirmed diagnosis or suspicion of a latent or active TB infection is a reportable 
event. Either type of infection must be reported as an adverse event of special interest 
(AESI) and must be captured on an AE report form, ticking the appropriate AESI and, if 
applicable, serious adverse event (SAE) field(s) on the form to clearly indicate the level 
of seriousness. A UCB TB follow-up form also must be completed. 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 requirements until such time as the TB 
infection resolves. 
Change #63 
Section 6.5, withdrawal criteria 2, 3, 4, and 6: 
Subjects should be withdrawn from the study if any of the following events occur: 
2) Subject/caregiver is noncompliant with the study procedures or medications in the 
opinion of the Investigator or Sponsor. 
3) Subject who develops active TB or NTMB infection during the study must be 
withdrawn (refer to Section 10.7.9).  
4) Subject who prematurely discontinues treatment for LTB, or, in the opinion of the 
Investigator or Sponsor, is noncompliant with anti-TB therapy must be withdrawn. 
5) Subject is found to be persistently noncompliant (missing 2 or more consecutive 
scheduled CZP doses or missing 3 or more doses over a 12-month period), the 
Sponsor in conjunction with the Investigator will make a decision as to whether the 
subject should be withdrawn from the study (see Section 7.7).  
This rule does not apply when CZP is discontinued if the subject is in CRM or if CZP 
is temporarily discontinued due to an AE. In the case of temporary discontinuation 
due to an AE, the Sponsor in conjunction with the Investigator will make a decision as 
to whether the subject should be withdrawn from the study. 
6) Subject takes prohibited concomitant medications as defined in this protocol (see 
Section 7.8.3). 
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Has been changed to: 
Study participants must be permanently discontinued from study medication (but not 
necessarily from the study) if any of the following occurs: 
1. Study participant/caregiver is noncompliant with the study procedures or medications in 
the opinion of the Investigator or Sponsor. 
2. A study participant considered as having either a suspected new LTBI or who develops 
active TB or NTMB infection during the study (including but not limited to, conversion 
demonstrated by interferon-gamma release assay (IGRA) or other diagnostic means) must 
be immediately discontinued from IMP (refer to Section 10.7.9.8 for further details). 
a) The study participant must be permanently withdrawn from the study if further 
examinations result in a diagnosis of active TB, NTMB infection or if the study 
participant is diagnosed with LTBI. An Early Discontinuation visit must be scheduled 
as soon as possible, but not later than the next regular visit. 
3. Study participant is found to be persistently noncompliant (missing 2 or more consecutive 
scheduled CZP doses or missing 3 or more doses over a 12-month period), the Sponsor in 
conjunction with the Investigator will make a decision as to whether the study participant 
should be withdrawn from the study (see Section 7.7).  
This rule does not apply when CZP is discontinued if the study participant is in CRM or if 
CZP is temporarily discontinued due to an AE. In the case of temporary discontinuation 
due to an AE, the Sponsor in conjunction with the Investigator will make a decision as to 
whether the study participant should be withdrawn from the study. 
4. Study participant takes prohibited concomitant medications as defined in this protocol 
(see Section 7.8.3). 
Change #64 
Section 6.5, withdrawal criteria 1 and 8: 
Subjects should be withdrawn from the study if any of the following events occur: 
1. Subject develops an illness that would interfere with continued participation (eg, 
malignancies). 
8. There is confirmation of a pregnancy during the study, as evidenced by a positive 
pregnancy test. 
Has been changed to: 
Study participants may be discontinued from study medication (but not necessarily from the 
study) if any of the following occurs, but may be restarted after consultation with the Medical 
Monitor: 
1. Study participant develops an illness that would interfere with continued participation (eg, 
malignancies). 
2. If there is a positive pregnancy test, study medication will be held. If there is confirmed 
pregnancy, study medication must be discontinued until end of the pregnancy. In case the 
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study participant intends to breastfeed after a pregnancy study medication must be further 
discontinued until end of breastfeeding. 
Change #65 
Section 6.5, withdrawal criteria 7 and 9: 
Subjects should be withdrawn from the study if any of the following events occur: 
7. Subject/legal representative withdraws consent. 
9. The Sponsor or a regulatory agency requests withdrawal of the subject.. 
Has been changed to: 
Study participants should be withdrawn from the study if any of the following events occur: 
1. Study participant or legal representative withdraws his/her consent. 
2. The sponsor or a regulatory agency requests withdrawal of the study participant. 
Change #66 
Section 7.2, paragraph 1, sentence 1 and 2: 
Throughout the study, CZP dosing is fixed dose based on weight and given Q2W, with 
exception of the lowest weight group, who will receive the maintenance dose Q4W following 
implementation of Protocol Amendment 4. The range of exposures in each weight category is 
presented in Table 7-1. Subjects start with 3 loading doses of CZP at Weeks 0, 2, and 4 
(minimum=50mg Q2W, maximum=200mg Q2W) followed by a maintenance dose for the 
duration of the study (minimum=50mg Q4W, maximum=100mg Q2W). 
Has been changed to: 
Throughout the study, CZP dosing is fixed dose based on weight and given Q2W, with 
exception of the lowest weight group on the reduced CZP regimen who will receive the 
maintenance dose Q4W. The loading dose, maintenance dose, and range of exposures in each 
weight category for both the original and reduced CZP regimens are presented in Table 7-1. 
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Change #67 
Section 7.2, Table 7-1, the following was added: 
Table 17-1 
Dosing administration of CZPa  
Weight range 
Loading dose – Weeks 0, 2, and 4 
(mg/kg dose range) 
IMP Description 
Maintenance – Week 6 and onwards 
(mg/kg dose range) 
IMP Description 
Original CZP regimen 
10 to <20kg 
(22 to <44lb) 
100mg Q2W 
(5-10mg/kg) 
1 x 0.5mL inj 
50mg Q2W 
(2.5-5mg/kg) 
1 x 0.25 mL inj 
20 to <40kg 
(44 to <88lb) 
200mg Q2W 
(5-10mg/kg) 
1 x 1mL inj 
100mg Q2W 
(2.5-5mg/kg) 
1 x 0.5mL inj 
≥40kg 
(≥88lb) 
400mg Q2W 
(<10mg/kg) 
2 x 1mL inj 
200mg Q2W 
(<5mg/kg) 
1 x 1mL inj 
Change #68 
Section 7.2, Table 7-1, footnote a: 
Note that Table 7-1 describes the dosing administration of CZP after implementation of 
Protocol Amendments 4 and 5. Refer to Section 7.2.1 for the procedure to be taken for 
subjects already enrolled and treated prior to the implementation of Protocol Amendment 4, 
and who are undergoing a dose change 
Has been changed to: 
Note that the original CZP regimen describes the dosing administration of CZP prior to the 
implementation of Protocol Amendments 4 and 5 and for study participants enrolled 
following the implementation of Protocol Amendment 9. The reduced CZP regimen describes 
the dosing administration of CZP after implementation of Protocol Amendments 4 and 5. 
Refer to Section 7.2.1 for the procedure to be taken for study participants who are undergoing 
a dose change.  
Change #69 
Section 7.2, paragraph 5, sentence 1 has been moved to the 4th sentence position: 
Prior to CZP administration at home, study participants/caregivers will be trained by the site 
staff and provided written instructions on the fixed dose for injection and the correct sc 
injection technique including 0.25mL, 0.5mL, and 1mL injections, as appropriate. 
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Change #70 
Section 7.2, paragraph 7, last sentence: 
Subjects not maintaining persistent CID following achievement of CRM and resuming 
treatment will restart the fixed-dose CZP dosing based on their current weight with 3 loading 
doses of CZP administered Q2W over 6 weeks, followed by a maintenance dose administered 
Q2W, or Q4W for the lowest weight group after implementation of Protocol Amendment 4, 
for the duration of the study. 
Has been changed to: 
Study participants not maintaining persistent CID following achievement of CRM and 
resuming treatment will restart the fixed-dose CZP dosing based on their current weight with 
3 loading doses of CZP administered Q2W over 6 weeks, followed by a maintenance dose 
administered Q2W, or Q4W for the lowest weight group on the reduced CZP regimen for the 
duration of the study. 
Change #71 
Section 7.2.1, paragraph 1: 
With Protocol Amendment 4, the maintenance dose in the study will be reduced by 50% for 
all weight groups (not applicable for subjects enrolled on the reduced CZP dose regimen per 
Protocol Amendment 5). 
Has been changed to: 
Following Protocol Amendment 9, study participants will only be enrolled on the original 
CZP dose regimen. With Protocol Amendment 4, the maintenance dose in the study was 
reduced by 50% for all weight groups (not applicable for study participants enrolled on the 
reduced CZP dose regimen per Protocol Amendment 5). Participants on the reduced CZP 
dose regimen can remain on the reduced CZP dose or may be switched to the original CZP 
dose regimen at the discretion of the Investigator and in consultation with the medical 
monitor. Additional dose changes are not allowed. The procedure for dose change is as 
follows. 
Change #72 
Section 7.2.1, bullet 2, sub-bullets 1 and 2 have been deleted: 
 For subjects undergoing a dose change prior to or at Week 12 (Visit 8), and who 
return for regularly scheduled visits every 4 weeks for a period of 12 weeks after the 
dose change, no additional Unscheduled Visits will be required. 
 For subjects undergoing a dose change after Week 12 (Visit 8), 1 or 2 additional 
Unscheduled Visits will be required. For example, a subject undergoing a dose change 
at Week 20 (Visit 9) will return for a regularly scheduled visit at Week 24 (Visit 10), 
will require an additional Unscheduled Visit at Week 28, and will return for the next 
regularly scheduled visit at Week 32 (Visit 11). A subject who is undergoing a dose 
change at Week 40 (Visit 12) will require an Unscheduled Visit at Week 44, will 
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return for a regularly scheduled visit at Week 48 (Visit 13), and will require another 
Unscheduled Visit at Week 52. 
Change #73 
Section 7.2.1, bullet 2, sub-bullet 3, sentence 3 has been deleted: 
 For example, a subject undergoing the dose change at Week 42 at the clinic will 
return for an Unscheduled Visit at Week 46, then continue with the regular visit at 
Week 48 (Visit 13), and return for an additional Unscheduled Visit at Week 52 before 
continuing with the regular Week 56 visit (Visit 14). 
Change #74 
Section 7.2.1, bullet 4 has been deleted: 
 A predose PK sample will be collected prior to administration of CZP at the visit the dose 
change occurs. Additional predose PK sampling after the change in dose will be 
performed at the next 3 site visits, ie, additional PK samples will be collected at the 
Unscheduled Visits or at the regular visit if not already planned per regular schedule. 
Change #75 
Section 7.8.3, paragraph 1 bullet 1: 
 Nonbiologic DMARDs (other than MTX; see Section 7.8.1) and biologic DMARDs (eg, 
anakinra, rilonacept, etanercept, adalimumab, infliximab, golimumab, rituximab, 
abatacept, tocilizumab, CZP other than study medication) 
Has been changed to: 
 Nonbiologic DMARDs (other than MTX; see Section 7.8.1) and biologic DMARDs  
Change #76 
Section 7.9 (Lost to Follow up) was added: 
Change #77 
Section 8.1, paragraph 1 sentence 1: 
Prior to any study activities and 4 days prior to the Baseline Visit (Visit 2), subjects and 
parent(s)/legal representative, as applicable, will be asked to read and sign an Informed 
Consent/Assent Form that has been approved by an IRB/IEC and which complies with 
regulatory requirements. 
Has been changed to: 
Prior to any study activities and at least 4 days prior to the Baseline Visit (Visit 2), study 
participants and parent(s)/legal representative, as applicable, will be asked to read and sign an 
Informed Consent/Assent Form that has been approved by an IRB/IEC and which complies 
with regulatory requirements.  
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Change #78 
Section 8.1, paragraph 2 bullet 15: 
Chest x-ray (only for subjects with positive IGRA or PPD testing)** 
Has been changed to: 
Chest radiographic imaging and results must be available at Baseline before first IMP 
administration unless a chest X-ray or CT scan is available from 2 months prior to Screening.   
Change #79 
Section 8.1, paragraph 2 bullet 16: 
TB screening if not performed within 3 months of Screening: PPD skin test for subjects from 
2 to 4 years of age (unless written documentation for BCG vaccination is available) or IGRA 
(to be performed by the central lab) for subjects from 5 to 17 years of age** 
Has been changed to: 
TB screening: TST and IGRA for study participants from 2 to 4 years of age (unless the study 
participant is located in a country with high TST positivity and/or written documentation for 
BCG vaccination is available) or IGRA (to be performed by the central lab) for study 
participants from 5 to 17 years of age. Note that the TST may be positive due to BCG 
vaccination, however, UCB will not permit enrollment of pediatric study participants <5 
years old into the study without written approval from a physician with expertise in pediatric 
TB** 
Change #80 
Section 8.2  
 CZP plasma concentrations and anti-CZP antibodies 
Has been changed to: 
 CZP plasma concentrations  
 Anti-CZP antibodies 
Change #81 
Section 8.3  
 CZP plasma concentrations and anti-CZP antibodies(Week 1 only) 
Has been changed to: 
 CZP plasma concentrations (Week 1 only) 
 Anti-CZP antibodies (Week 1 only) 
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Change #82 
Section 8.4  
 CZP plasma concentrations and anti-CZP antibodies (Weeks 4, 12, 16, and 24 only, OR if 
a dose change is performed at the current visit OR if the subject’s dose was changed 
during 1 of the last 3 visits following Protocol Amendment 4; predose.  
Subjects will return to the clinic site for a postdose CZP plasma sample approximately 
5 to 7 days following the Week 16 visit.) 
Has been changed to: 
 CZP plasma concentrations (predose at Weeks 4, 12, 16, and 24.  
Study participants will return to the clinic site for a postdose CZP plasma sample 
approximately 5 to 7 days following the Week 16 visit.) 
 Anti-CZP antibodies (predose at Weeks 4, 12, 16, and 24) 
Change #83 
Section 8.4, last paragraph 
Documentation of the Week 16 and Week 24 assessment of all 6 core set measures of 
PedACR response (PRINTO/PRCSG standard joint examination, Physician’s Global 
Assessment of Disease Activity [VAS], CHAQ-parent reported, Parent’s Assessment of 
Arthritis Pain [VAS], Parent’s Global Assessment of Overall Well-Being [VAS] and CRP) 
will be submitted to UCB or designee for immediate review of completeness, while the 
subject is still on site. 
Has been changed to: 
Documentation of the Week 24 assessment of all 6 core set measures of PedACR response 
(PRINTO/PRCSG standard joint examination, Physician’s Global Assessment of Disease 
Activity [VAS], CHAQ-parent reported, Parent’s Assessment of Arthritis Pain [VAS], 
Parent’s Global Assessment of Overall Well-Being [VAS] and CRP) will be submitted to 
UCB or designee for immediate review of completeness, while the study participant is 
still on site. 
Change #84 
Section 8.5, heading 
Visits 11 and continuing (Week 32 and every 8 weeks thereafter [every 16 weeks following 
Protocol Amendment 8]) 
Has been changed to: 
Visits 11 and continuing (Week 32 and every 8 weeks thereafter)  
Change #85 
Section 8.5, the following paragraph has been added 
For study participants enrolled prior to Protocol Amendment 9, visit frequency changes to 
every 16 weeks instead of every 8 weeks following implementation of Protocol 
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Amendment 8, provided that compliance is maintained with the CZP dosing schedule using 
at-home administration. 
Change #86 
Section 8.5, bullet 2 
Height (Week 48 and every 24 weeks thereafter [every 48 weeks following Protocol 
Amendment 8]) 
Has been changed to: 
Height (Week 48 and every 24 weeks thereafter; for study participants enrolled prior to 
Protocol Amendment 9, height assessment will be performed every 48 weeks following 
Protocol Amendment 8) 
Change #87 
Section 8.5, bullet 4 
Tanner stages (except growth; Week 48 and every 24 weeks thereafter [every 48 weeks and 
only for subjects who have not reached Tanner stage V following Protocol Amendment 8]) 
Has been changed to: 
Tanner stages (except growth; for study participants enrolled prior to Protocol Amendment 9, 
Tanner stages assessment will be performed every 48 weeks following Protocol Amendment 
8, and only for those subjects who have not reached Tanner stage V) 
Change #88 
Section 8.5, bullet 6 
TB screening once a year (approximately every 48 weeks) 
Has been changed to: 
TB screening once a year (at least every 48 weeks) 
Change #89 
Section 8.5, bullet 28 
 CZP plasma concentrations and anti-CZP antibodies (Weeks 32, 40, and 48 and every 
24 weeks thereafter, OR if a dose change is performed at the current visit OR if the 
subject’s dose was changed during 1 of the last 3 visits following Protocol Amendment 4; 
following Protocol Amendment 8, these samples will no longer be collected) 
Has been changed to: 
 CZP plasma concentrations (for study participants enrolled following Protocol 
Amendment 9 only; Weeks 32, 40, and 48 and every 24 weeks thereafter) 
 Anti-CZP antibodies (for study participants enrolled following Protocol Amendment 9 
only; Weeks 32, 40, and 48 and every 24 weeks thereafter)  
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Change #90 
Section 8.6.1, the following paragraph has been removed: 
Documentation of the Week 56 assessment of all 6 core set measures of PedACR response 
(PRINTO/PRCSG standard joint examination, Physician’s Global Assessment of Disease 
Activity [VAS], CHAQ-parent reported, Parent’s Assessment of Arthritis Pain [VAS], 
Parent’s Global Assessment of Overall Well-Being [VAS] and CRP) will be submitted to 
UCB or designee for immediate review of completeness, while the subject is still on site. 
Change #91 
Section 8.6.1, the following sentence has been added: 
If required, study participants will return for an Unscheduled Visit to undergo the dose 
change. 
Change #92 
Section 8.6.1, the following assessment has been removed: 
 CZP plasma concentrations and anti-CZP antibodies (predose) 
Change #93 
Section 8.7, bullet 27: 
 CZP plasma concentrations and anti-CZP antibodies (following Protocol Amendment 8, 
these samples will no longer be collected) 
Has been changed to: 
 CZP plasma concentrations (for study participants enrolled following Protocol 
Amendment 9 only  
 Anti-CZP antibodies (for study participants enrolled following Protocol Amendment 9 
only) 
Change #94 
Section 8.8, bullet 11: 
 CZP plasma concentrations and anti-CZP antibodies (following Protocol Amendment 8, 
these samples will no longer be collected) 
Has been changed to: 
 CZP plasma concentrations (for study participants enrolled following Protocol 
Amendment 9 only) 
 Anti-CZP antibodies (for study participants enrolled following Protocol Amendment 9 
only) 
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Change #95 
Section 9, the following paragraph has been deleted: 
Following Protocol Amendment 8, blood samples for determination of CZP plasma 
concentrations and anti-CZP antibodies will not be collected throughout the remainder of the 
study. 
Change #96 
Section 9, paragraph 1, the following sentence has been added: 
For study participants enrolled prior to Protocol Amendment 9, samples for CZP plasma 
concentration and anti-CZP antibodies will no longer be collected. 
Change #97 
Section 9, paragraph 3, has been deleted: 
For subjects already enrolled and treated prior to the implementation of Protocol 
Amendment 4 and hence undergoing a reduction of their dose, additional PK samples will be 
collected prior to dosing at the visit the dose change occurs and at the next 3 site visits 
following the dose change, ie, additional PK samples will be collected at either Unscheduled 
Visits or regular visits if not already planned per regular schedule. Afterwards, the regular PK 
sampling schedule applies. 
Change #98 
Section 9, paragraph 5, 6, 7, and 8, have been deleted: 
Plasma concentration data for CZP from this study will be compared with plasma 
concentrations observed previously in adult subjects with RA, as described in Section 13.7. 
This plasma concentration analysis will be done on an ongoing basis throughout the study, 
starting when 6 subjects in 1 of the age groups have completed Week 12 (Visit 7). 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicated that no change to the dosing algorithm was required. The protocol stated that if 
future analyses indicate that plasma concentrations are outside of the exposure range of those 
observed in previous studies with adults, the dosing algorithm may be changed via a protocol 
amendment, and if necessary additional interim analyses including PopPK, may be 
performed. This study will continue during the PK analysis. All subjects assessed in this 
analysis will continue treatment after Week 12 (Visit 7). 
Results of an interim PopPK analysis conducted in Jun 2013 suggest that while observed CZP 
plasma concentrations have remained in the adult range, they have been at the upper end of 
the distribution. Simulations predict that for some subjects in RA0043 receiving the 
originally determined loading doses up to Week 4 (Visit 5), plasma concentrations are likely 
to exceed the range previously seen in adult subjects receiving CZP 400mg Q2W. 
Furthermore, plasma concentrations of subjects receiving the originally determined 
maintenance dose after Week 4 (Visit 5) are predicted to exceed the concentration range 
observed in adults receiving CZP 200mg Q2W. Based on these findings, the dosing regimen 
will be changed with Protocol Amendments 4 and 5, and the doses to be administered will be 
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reduced by 50% for all weight groups. This dose change is intended to achieve plasma 
concentrations that are similar to the effective concentrations observed in previous studies in 
adult subjects with RA. Continued analysis of CZP plasma concentrations (including 
additional assessments for subjects undergoing a dose reduction with Protocol Amendment 4) 
will be performed to confirm that the 50% dose reduction will result in plasma concentrations 
within the target range of those observed in adults.  
The final pediatric PopPK model will be combined with PD data (PedACR) and if the data 
allow, an exposure-response relationship will be derived. 
Change #99 
Section 9, paragraph 9, sentence 1: 
Blood samples to determine plasma concentrations of CZP and anti-CZP antibodies will be 
analyzed by the central laboratory.  
Has been changed to: 
Blood samples to determine plasma concentrations of CZP and anti-CZP antibodies will be 
analyzed by a specialty laboratory. 
Change #100 
Section 9, paragraph 9, the following text has been added: 
All study participants enrolled following Protocol Amendment 9 will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using an ECLIA method that meets 
current regulatory standards. In addition, PK and ADA samples (for which sufficient volume 
is available) collected in this study prior to Protocol Amendment 9 will be analyzed with the 
ECLIA method. The collective ECLIA-based PK data for this study will form the basis of 
any future CZP modeling and simulation work. 
Change #101 
Section 10.1.6 (Reporting requirements for events relating to TB) was added. 
Change #102 
Section 10.1.7, paragraph 1, sentence 2: 
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. If pregnancy is determined 
at a study visit, the subject is withdrawn from the study and all Early Discontinuation 
Visit assessments should be completed at that visit. 
 The subject should immediately stop receiving the IMP at the first confirmation of the 
pregnancy but no later than as instructed at the Early Discontinuation Visit. 
 A Final Visit should be scheduled 12 weeks after the subject has discontinued their IMP..  
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Has been changed to: 
Study medication must be discontinued as soon as pregnancy is known (by positive 
pregnancy test). Study participants can remain in the study under observation and should 
attend to scheduled visits regularly as their condition allows.  
Change #103 
Section 10.3, heading: 
AEs of interest  
Has been changed to: 
AEs of special interest 
Change #104 
Section 10.3, paragraph 1, sentence 1: 
An AE of 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 not 
fulfill the expedited reporting criteria of “serious,” “unexpected,” and “associated with the 
use of the drug.”  
Has been changed to: 
An AESI 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 not 
fulfill the expedited reporting criteria of “serious,” “unexpected,” and “associated with the 
use of the drug.”  
Change #105 
Section 10.3, paragraph 2: 
Adverse events of interest include: 
Has been changed to: 
Adverse events of special interest include: 
Change #106 
Section 10.3, paragraph 2, the following text has been added: 
 Potential Hy’s Law 
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin 
in the absence of ≥2xULN ALP, with no alternative explanation for the biochemical 
abnormality (ie, without waiting for any additional etiologic investigations to have been 
concluded). Follow-up information should be reported if an alternative etiology is identified 
during investigation and monitoring of the participant. 
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Change #107 
Section 10.5, Table 10-1: 
Preferred Term 
Juvenile arthritis 
Has been changed to: 
Preferred Term 
Juvenile idiopathic arthritis 
Change #108 
Section 10.6, paragraph 1, sentence 1: 
Hematology, biochemistry, and urinalysis samples will be collected at Screening, Baseline, 
Weeks 4, 8, 12, 16, 20, 24, 32, every 8 weeks thereafter (every 16 weeks following Protocol 
Amendment 8), the Early Discontinuation/End of Treatment Visit, and the Final Visit 
12 weeks after the last dose of study medication. 
Has been changed to: 
Hematology, biochemistry, and urinalysis samples will be collected at Screening, Baseline, 
Weeks 4, 8, 12, 16, 20, 24, 32 and every 8 weeks thereafter (for study participants enrolled 
prior to Protocol Amendment 9, visit frequency changes to every 16 weeks instead of every 8 
weeks following implementation of Protocol Amendment 8), the Early Discontinuation/End 
of Treatment Visit, and the Final Visit 12 weeks after the last dose of study medication. At 
Week 1, only CRP and PK samples will be collected and at Week 2, only CRP samples will 
be collected. In addition, hematology, biochemistry, and CRP samples will be collected at 
Unscheduled Visits for study participants undergoing a dose change (Section 7.2.1 and 
Section 8.6.1). 
Change #109 
Section 10.6, paragraph 1, sentence 3: 
In addition, hematology, biochemistry, and CRP samples will be collected at Unscheduled 
Visits related to the dose change implemented with Protocol Amendment 4. 
Has been changed to: 
In addition, hematology, biochemistry, and CRP samples will be collected at Unscheduled 
Visits for study participants undergoing a dose change (Section 7.2.1 and Section 8.6.1). 
Change #110 
Section 10.6, paragraph 9: 
If IGRA testing is required to be performed by the central lab (for all subjects from 5 to 17 
years of age, see Section 6.2) additional blood sampling of approximately 3mL will be 
required at Screening. 
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Has been changed to: 
The TB assessment by IGRA testing is required to be performed by the central lab; additional 
blood sampling of approximately 3mL will be required at Screening.  
Change #111 
Section 10.6, paragraph 10: 
If the result of the IGRA is indeterminate, the test may be repeated once. The retest must be 
conducted in the allowable Screening window. Subjects with IGRA (performed ≤3 months 
prior to Screening) positive or indeterminate and a chest x-ray confirmative of TB infection 
are excluded (see Section 10.7.9.2). 
Has been changed to: 
If the result of the IGRA test is indeterminate, the test may be repeated once. If positive or 
indeterminate on retest, the study participant must not be enrolled (Section 10.7.9.5).  
Change #112 
Section 10.6, paragraph 11 and 12 
For subjects from 2 to 4 years of age, PPD testing will be performed locally (except for 
subjects with documented BCG vaccination) as described in Section 10.7.9.2.4. 
During the study and upon implementation of Protocol Amendment 7, IGRA testing should 
be done once a year (approximately every 48 weeks) for all subjects from 5 to 17 years of 
age. For subjects from 2 to 4 years of age, both IGRA and PPD testing should be performed 
once a year (approximately every 48 weeks). In cases where written documentation of BCG 
vaccination is available or previous PPD test was positive, only IGRA should be performed. 
Has been changed to: 
For study participants from 2 to 4 years of age, TST and IGRA testing will be performed 
(except for study participants with documented BCG vaccination) as described in Section 
10.7.9.8.2. In countries with high BCG vaccination or high TST positivity, only IGRA should 
be performed (Section 10.7.9.8.2). The TST may be positive due to BCG vaccination, 
however, UCB will not permit enrollment of pediatric study participants <5 years old into the 
study with written approval from a physician with expertise in pediatric TB. IGRA testing 
should be done once a year (approximately every 48 weeks) for all study participants.   
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Change #113 
Section 10.6, Table 10-2: 
Hepatitis screening(c) 
HBcAb 
HBsAb 
HBsAg 
HCVAb 
HBV DNA, if applicable 
TB screening(d) 
IGRA,  
PPD 
Has been changed to: 
Hepatitis screening(c) 
HBcAb 
HBsAb 
HBsAg 
HCVAb 
HBV DNA, if applicable 
HCV RNA, if applicable 
TB screening(d) 
IGRA,  
TST 
HIV Screening 
HIV antigen or antibody 
Change #114 
Section 10.6, Table 10-2, footnote C: 
Subjects will be tested for hepatitis at Screening. HBV DNA is required for subjects with 
only positive HBcAb (negative HBsAg and HBsAb) or only positive HBsAg. A hepatitis 
panel result which indicates immunity due to hepatitis B vaccination is not considered an 
exclusion criterion. 
Has been changed to: 
At Screening, laboratory testing includes testing for hepatitis B core antibody, hepatitis B 
surface antibody, hepatitis B surface antigen, hepatitis C virus antibody, and HIV 1/2. Study 
participants with a positive HBV test will not be allowed in the study (except for anti-
hepatitis B positive only, in case study participant is immune due to well-documented 
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hepatitis B vaccination or isolated false-positive anti-HBc test confirmed with a confirmatory 
test such as hepatitis B virus deoxyribonucleic acid [HBV-DNA]). A positive hepatitis C 
antibody test will be confirmed by a confirmatory test (such as HCV RNA) and those with a 
positive confirmatory test will not be allowed in the study. 
Change #115 
Section 10.7.2, paragraph 1, sentence 1: 
Height will be recorded at Screening, Baseline, every 24 weeks thereafter (every 48 weeks 
following Protocol Amendment 8), and the Early Discontinuation/End of Treatment Visit.  
Has been changed to: 
Height will be recorded at Screening, Baseline, every 24 weeks thereafter (for study 
participants enrolled prior to Protocol Amendment 9, the height assessment will be performed 
every 48 weeks following Protocol Amendment 8), and the Early Discontinuation/End of 
Treatment Visit. 
Change #116 
Section 10.7.3, sentence 2: 
These assessments will be performed at Baseline, every 24 weeks thereafter, and the Early 
Discontinuation/End of Treatment Visit. Following Protocol Amendment 8, the assessments 
will be performed every 48 weeks, and only for subjects who have not reached Tanner stage 
V.  
Has been changed to: 
These assessments will be performed at Baseline and every 24 weeks thereafter, and the 
Early Discontinuation/End of Treatment Visit. For study participants enrolled prior to 
Protocol Amendment 9, Tanner stages assessment will be performed every 48 weeks 
following Protocol Amendment 8, and only for those subjects who have not reached Tanner 
stage V. 
Change #117 
Section 10.7.6, sentence 2: 
If the subject is of reproductive potential and is sexually active, the method of birth control 
used will be recorded. Sexually active subjects (male and female) must use adequate 
contraceptive measures (see Section 6.2, Exclusion Criterion 17). 
Has been changed to: 
If the study participant is of reproductive potential and is sexually active, the method of birth 
control used will be recorded. Sexually active study participants (male and female) must use 
effective contraceptive measures (see Section 6.2, Exclusion Criterion 17). 
Change #118 
Section 10.7.9, heading: 
Tuberculosis guidance, testing, and screening 
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Has been changed to: 
Assessment and management of TB and TB risk factors  
Change #119 
Section 10.7.9, the following text has been added: 
As TNF inhibitors are known to be associated with significant risk of reactivation of LTBI or 
previously treated active TB, appropriate rigorous precautions are being taken within the 
protocol (see Section 6.2 [Exclusion Criterion 11] and Section 6.4  [Withdrawal Criterion 2]). 
Study participants with known active TB disease, at high risk of acquiring TB infection, or 
with past or current LTBI or current or history of NTMB infection are excluded from the 
study. 
a. Known TB infection whether present or past is defined as: 
 Active TB infection or clinical signs and symptoms strongly suggestive of TB 
(pulmonary or extra pulmonary). 
 History of active TB infection involving any organ system or findings in other organ 
systems consistent with TB infection. 
 Any evidence by radiography or other imaging modalities consistent with previously 
active TB infection that is not reported in the participant 's medical history. 
b. High risk of acquiring TB infection is defined as: 
 Known close exposure (eg, sleeping in the same room) to another person with active 
TB infection within 3 months prior to Screening. 
 Time spent within 3 months prior to Screening in a healthcare delivery setting or 
institution where individuals infected with TB are housed or where the risk of 
transmission of infection is high. 
c. LTBI is defined as an infection by mycobacteria tuberculosis with: 
 A positive IGRA (or 2 indeterminate IGRAs), AND 
 Chest imaging (or other imaging) negative for TB infection, AND 
 Absence of signs, symptoms (eg, evidence of organ-specific involvement), or physical 
findings suggestive of TB infection. 
d. Pulmonary NTMB infection is defined as a group of lung infections caused by 
mycobacteria different from mycobacterium tuberculosis infections. 
Change #120 
Section 10.7.9.1, Section 10.7.9.2, Section 10.7.9.3 have been removed 
Change #121 
Section 10.7.9.1, Section 10.7.9.2, Section 10.7.9.3, Section 10.7.9.4, Section 10.7.9.5, 
Section 10.7.9.6, Section 10.7.9.7 have been added. 
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Change #122 
Section 11.1, last paragraph: 
Documentation of the assessment of all 6 core set measures will be submitted to UCB or 
designee for immediate review of completeness at Week 0 (Baseline), Week 16, Week 24, 
and Week 56, while the subject is still on site. 
Has been changed to: 
Documentation of the assessment of all 6 core set measures will be submitted to UCB or 
designee for immediate review of completeness at Week 0 (Baseline) and Week 24, while the 
study participant is still on site. 
Change #123 
Section 11.2, last paragraph: 
These assessments are completed at Screening, Baseline, and every visit (including 
Unscheduled Visits that are related to the dose change implemented with Protocol 
Amendment 4) through the Early Discontinuation/End of Treatment Visit. 
Has been changed to: 
These assessments are completed at Screening, Baseline, and every visit (including 
Unscheduled Visits that are related to dose change) through the Early Discontinuation/End of 
Treatment Visit. 
Change #124 
Section 11.4, paragraph 2: 
The Physician’s Global Assessment of Disease Activity (VAS) will be completed at 
Screening, Baseline, and every visit (including Unscheduled Visits that are related to the dose 
change implemented with Protocol Amendment 4) through the Early Discontinuation/End of 
Treatment Visit. 
Has been changed to: 
The Physician’s Global Assessment of Disease Activity (VAS) will be completed at 
Screening, Baseline, and every visit (including Unscheduled Visits that are related to dose 
change) through the Early Discontinuation/End of Treatment Visit. 
Change #125 
Section 11.5, paragraph 3, sentence 2: 
The CHAQ will be completed by the parents/caregivers at Screening, Baseline, and every 
visit (including Unscheduled Visits that are related to the dose change implemented with 
Protocol Amendment 4) through the Early Discontinuation/End of Treatment Visit.. 
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Has been changed to: 
The CHAQ will be completed by the parents/caregivers at Screening, Baseline, and every 
visit (including Unscheduled Visits that are related to dose change) through the Early 
Discontinuation/End of Treatment Visit. 
Change #126 
Section 11.7, paragraph 2, sentence 2: 
The Parent’s Global Assessment of Overall Well-Being (VAS) will be completed at 
Screening, Baseline, and every visit (including Unscheduled Visits that are related to the dose 
change implemented with Protocol Amendment 4) through the Early Discontinuation/End of 
Treatment Visit. 
Has been changed to: 
The Parent’s Global Assessment of Overall Well-Being (VAS) will be completed at 
Screening, Baseline, and every visit (including Unscheduled Visits that are related to dose 
change) through the Early Discontinuation/End of Treatment Visit. 
Change #127 
Section 11.8, sentence 2: 
Samples will be collected at Screening, Baseline, and every visit (including Unscheduled 
Visits that are related to the dose change implemented with Protocol Amendment 4) through 
the Early Discontinuation/End of Treatment Visit. 
Has been changed to: 
Samples will be collected at Screening, Baseline, and every visit (including Unscheduled 
Visits that are related to dose change) through the Early Discontinuation/End of Treatment 
Visit. 
Change #128 
Section 11.10, last paragraph, last sentence: 
Subjects not maintaining persistent CID following achievement of CRM and resuming 
treatment will restart the fixed-dose CZP dosing based on their current weight with 3 loading 
doses of CZP administered Q2W over 6 weeks, followed by a maintenance dose administered 
Q2W for the duration of the study, with exception of the lowest weight group, who will 
receive the maintenance dose Q4W following implementation of Protocol Amendment 4.  
Has been changed to: 
Study participants not maintaining persistent CID following achievement of CRM and 
resuming treatment will restart the fixed-dose CZP dosing based on their current weight with 
3 loading doses of CZP administered Q2W over 6 weeks, followed by a maintenance dose 
administered Q2W for the duration of the study, with exception of the lowest weight group 
on the reduced dose regimen, who will receive the maintenance dose Q4W.  
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Change #129 
Section 11.12, last paragraph, second sentence: 
The FPS-R will be administered at Baseline and then daily during the first week of the study; 
at Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter (every 16 weeks following 
Protocol Amendment 8) through the Early Discontinuation/End of Treatment Visit. 
Has been changed to: 
The FPS-R will be administered at Baseline and then daily during the first week of the study; 
at Weeks 4, 12, 16, 24, and then every 8 weeks thereafter (for study participants enrolled 
prior to Protocol Amendment 9, visit frequency changes to every 16 weeks instead of every 8 
weeks following implementation of Protocol Amendment 8) through the Early 
Discontinuation/End of Treatment Visit. 
Change #130 
Section 11.13, second paragraph, second sentence: 
The Pain (VAS) will be completed at Baseline (acute and standard versions), daily during the 
first week of treatment (acute version); Weeks 4, 12, 16, and 24; and then every 8 weeks 
thereafter (every 16 weeks following Protocol Amendment 8) through the Early 
Discontinuation/End of Treatment Visit (standard version). 
Has been changed to: 
The Pain (VAS) will be completed at Baseline (acute and standard versions), daily during the 
first week of treatment (acute version); Weeks 4, 12, 16, 24, and then every 8 weeks 
thereafter (for study participants enrolled prior to Protocol Amendment 9, visit frequency 
changes to every 16 weeks instead of every 8 weeks following implementation of Protocol 
Amendment 8) through the Early Discontinuation/End of Treatment Visit (standard version). 
Change #131 
Section 11.14, fourth paragraph, second sentence: 
The Fatigue Assessment Scale will be assessed at Baseline, Weeks 1, 2, 4, 8, 16, 24, 32, then 
every 8 weeks thereafter (every 16 weeks following Protocol Amendment 8), and the Early 
Discontinuation/End of Treatment Visit. Preferably, the same parent/caregiver should 
complete the scale for each visit. 
Has been changed to: 
The Fatigue Assessment Scale will be assessed at Baseline, Weeks 1, 2, 4, 8, and then every 
8 weeks thereafter (for study participants enrolled prior to Protocol Amendment 9, visit 
frequency changes to every 16 weeks instead of every 8 weeks following implementation of 
Protocol Amendment 8) and the Early Discontinuation/End of Treatment Visit. 
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Change #132 
Section 12.4, the following text has been added: 
A futility analysis of the PedACR30 response rate was performed after all active study 
participants on the reduced CZP dose had completed the Week 16 (Visit 8) assessments. If 
less than 50% of the study population enrolled on the reduced CZP dose regimen (Protocol 
Amendment 5) achieved a PedACR30 response at Week 16, the study was to be 
discontinued. The futility analysis confirmed that ≥50% of the study population enrolled on 
the reduced CZP dose regimen achieved a PedACR30 response at Week 16. A further futility 
analysis will not be performed using the additional participants that will be enrolled on the 
original CZP dose regimen following the implementation of Protocol Amendment 9.  
Change #133 
Section 13.2.1, paragraph 1, bullet 2: 
Reduced CZP dose regimen: includes all subjects in the SS who began treatment in 
accordance with the reduced dosing regimen defined for the study (3 loading doses of CZP at 
Weeks 0, 2, and 4 [minimum=50mg Q2W, maximum=200mg Q2W] followed by a 
maintenance dose for the duration of the study [minimum=50mg Q4W, maximum=100mg 
Q2W]). 
Has been changed to: 
Reduced CZP dose regimen: includes all study participants in the SS who began treatment in 
accordance with the reduced dosing regimen defined for the study (3 loading doses of CZP at 
Weeks 0, 2, and 4 [minimum=50mg Q2W, maximum=200mg Q2W] followed by a 
maintenance dose for the duration of the study [minimum=50mg Q4W, maximum=100mg 
Q2W]). This subgroup includes all study participants who began the study with this CZP 
dose regimen and received 1 or more doses of this regimen, regardless of any subsequent 
switch to the original CZP dose regimen. 
Change #134 
Section 13.2.2: 
Approximately 55 centers are planned to enroll 156 subjects into this study. The enrollment 
per site is limited to a maximum of 12 subjects. 
Has been changed to: 
Approximately 55 centers are planned to enroll the original 156 study participants into this 
study. A subset of these centers will be used to enroll the additional 30 study participants 
following Protocol Amendment 9. The enrollment per site is limited to a maximum of 
12 study participants.  
Change #135 
Section 13.3, paragraph 1, sentence 1: 
The incidence of AEs will be assessed as primary safety variable in this study. 
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Has been changed to: 
The incidence of serious TEAEs and TEAEs leading to permanent withdrawal of IMP will be 
assessed as primary safety variables in this study. Other safety variables include the incidence 
of TEAEs, TEAEs of interest, TEAEs by relatedness, TEAEs by severity, and TEAEs by 
duration of exposure. 
Change #136 
Section 13.3, paragraph 4, sentence 1 and 2: 
For the original CZP dose regimen subgroup, in addition to the overall presentation of AEs, 
AEs will be summarized separately for the periods of exposure to original and reduced CZP 
dose regimens. Additionally, the frequency and percentage of AEs reported during the first 
16 weeks of study medication exposure will be summarized separately for the 2 CZP dose 
regimens (original CZP dose regimen, reduced CZP dose regimen). 
Has been changed to: 
For the original CZP dose regimen subgroup, in addition to the overall presentation of AEs, 
AEs will be summarized separately for the periods of exposure to original CZP dose regimen 
and the reduced CZP dose regimen, in addition to exposure for study participants that 
switched from the reduced CZP dose regimen to the original CZP dose regimen following 
Protocol Amendment 9. 
Change #137 
Section 13.4, paragraph 1: 
Certolizumab pegol plasma concentrations and anti-CZP antibody concentrations will be 
assessed as primary variables in this study. 
Has been changed to: 
Certolizumab pegol plasma concentrations levels at Week 16 and Week 48 will be assessed 
as primary variables in this study. Other PK and immunological variables include CZP 
plasma concentrations at other study timepoints and anti-CZP antibody levels throughout the 
study. 
Change #138 
Section 13.4, paragraph 2: 
Plasma concentrations will be used to build a PopPK model with the nonlinear mixed-effect 
modeling (NONMEM) software. 
Has been changed to: 
Plasma CZP concentrations will be used to build a PopPK model with the nonlinear mixed-
effect modeling (NONMEM) software. The model will be parameterized in terms of 
clearance, volume of distribution, and absorption rate constant. Details of the PopPK 
modeling procedures will be described in a separate data analysis plan. The pediatric PopPK 
model will be combined with PD data (PedACR) and if the data allow, an exposure response 
relationship will be derived. These modeling analyses and results will be reported separately. 
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Change #139 
Section 13.4, paragraph 3, 4, 5, 6, and 7: 
A meta-analysis was previously performed by adding the pediatric data to the adult data in a 
PopPK analysis within NONMEM (C87068 and CL0153) for the Week 24 interim analysis 
(with ELISA data). 
For the final analysis, UCB will be re-assaying all available PK samples (ie, for which 
sufficient volume is available) with a newly developed MSD bioanalytical assay. The data 
from the re-assayed RA0043 PK samples will be used to build a PopPK model. 
The model will be parameterized in terms of clearance, volume of distribution, and 
absorption rate constant. Details of the PopPK modeling procedures will be described in a 
separate data analysis plan. Analyses and results will be reported in a separate report. 
The pediatric PopPK model will be combined with PD data (PedACR) and if the data allow, 
an exposure-response relationship will be derived. 
Individual anti-CZP antibody concentrations will be listed and the incidence of anti-CZP 
positive (>2.4units/mL) subjects will be summarized by study visit and overall incidence by 
Baseline age stratum (all subjects, 2 to 5 years, 6 to 11 years, and 12 to 17 years). In addition 
safety and efficacy profiles by antibody status will be investigated. 
Certolizumab pegol plasma concentration data will be tabulated and summarized by dose 
regimen (original CZP dose regimen or reduced CZP dose regimen) for each visit on which 
samples were taken (geometric mean, arithmetic mean, minimum, maximum, standard 
deviation and % coefficient of variation). Plasma concentration time curves will be plotted 
separately for subjects who began treatment according to the original CZP dose regimen or 
the reduced CZP dose regimen, overall, by Baseline age stratum, and by anti-CZP antibody 
status. Subgroup analyses will include an analysis of the subjects enrolled and treated up to 
the Week 16 timepoint under the original maintenance dosing regimen. 
Has been changed to: 
All study participants enrolled following Protocol Amendment 9 will have plasma CZP 
concentrations and anti-CZP antibodies analyzed using the ECLIA method. In addition, PK 
and ADA samples (for which sufficient volume is available) collected in this study prior to 
Protocol Amendment 9 will be analyzed with the ECLIA method.  
Data from the ECLIA method will constitute the study's main PK and anti-CZP antibody 
evaluations. As such, PK and anti-CZP antibody data generated with the original ELSIA 
method will be reported as Listings. Plasma CZP concentration data generated by the ECLIA 
method will be tabulated and summarized (geometric mean, arithmetic mean, minimum, 
maximum, standard deviation and % coefficient of variation) by study dose regimen (original 
CZP dose regimen or reduced CZP dose regimen) for each PK sampling visit. Plasma 
concentration time curves will be plotted, along with respective individual anti-CZP antibody 
titers where available, separately for study participants who began treatment according to the 
original CZP dose regimen or the reduced CZP dose regimen, overall, and by Baseline age 
stratum. Subgroup analyses will include study participants enrolled with Protocol 
Amendment 9 and those treated up to the Week 16 timepoint under the original maintenance 
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dosing regimen. Where available, individual ECLIA-based anti-CZP antibody data will be 
tabulated by study visit and Baseline age stratum (all study participants, 2 to 5 years, 6 to 
11 years, and 12 to 17 years). In addition, safety and efficacy profiles by antibody titers (or 
titer categories) may be investigated.  
Change #140 
Section 13.5, paragraph 5, bullets 14 and 15: 
 Change from Baseline on FPS-R (child-reported, for subjects ages 5 to 11 years), daily 
during the first 7 days of treatment; Weeks 4, 12, 16, and 24; and then every 8 weeks 
thereafter through the Early Discontinuation/End of Treatment Visit. Following Protocol 
Amendment 8, change from Baseline on FPS-R is assessed every 16 weeks. 
 Change from Baseline in JIA Pain VAS, daily during the first week of the study (acute 
and standard versions); Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter 
through the Early Discontinuation/End of Treatment Visit (standard version) for subjects 
ages 12 to 17 years. Following Protocol Amendment 8, change from Baseline in JIA Pain 
VAS is assessed every 16 weeks. 
Has been changed to: 
 Change from Baseline on FPS-R (child-reported, for study participants ages 5 to 11 
years), daily during the first 7 days of treatment; Weeks 4, 12, 16, 24, and then every 
8 weeks thereafter (for study participants enrolled prior to Protocol Amendment 9, visit 
frequency changes to every 16 weeks instead of every 8 weeks following implementation 
of Protocol Amendment 8) through the Early Discontinuation/End of Treatment Visit.  
 Change from Baseline in JIA Pain VAS, daily during the first week of the study (acute 
and standard versions); Weeks 4, 12, 16, 24, and then every 8 weeks thereafter (for study 
participants enrolled prior to Protocol Amendment 9, visit frequency changes to every 16 
weeks instead of every 8 weeks following implementation of Protocol Amendment 8) 
through the Early Discontinuation/End of Treatment Visit (standard version) for study 
participants ages 12 to 17 years. 
Change #141 
Section 13.7, the following text was added: 
A futility analysis of the PedACR30 response rate was performed after all active study 
participants enrolled on the reduced CZP dose had completed the Week 16 (Visit 8) 
assessments. If less than 50% of the study population enrolled on the reduced CZP dose 
regimen (Protocol Amendment 5) achieved a PedACR30 response at Week 16, the study was 
to be discontinued. The futility analysis confirmed that ≥50% of the study population enrolled 
on the reduced CZP dose regimen achieved a PedACR30 response at Week 16. Given the 
descriptive nature of the data presentations, there were no statistical implications of this 
interim analysis. A further futility analysis will not be performed using the additional subjects 
that will be enrolled on the original CZP dose regimen following the implementation of 
Protocol Amendment 9.  
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In addition to the futility analysis, several interim analyses were planned, including interim 
analyses of PK data, and full interim analyses of PK, immunogenicity, safety, and efficacy 
endpoints, as described below. 
Change #142 
Section 13.7, paragraph 1 and 2, the following text was removed: 
Interim analysis of PK data will compare CZP plasma concentration data from this study with 
CZP plasma concentrations observed previously in adult subjects with RA. Interim analysis 
of CZP plasma concentrations was started when 6 subjects in 1 of the age groups completed 
Week 12 (Visit 7).  
Comparisons will be made between the Week 12 geometric mean and median values for the 
pediatric and adult subjects, as well as between the individual pediatric data and the adult 5th 
and 95th percentile and minimum and maximum observed values. 
Change #143 
Section 13.7, paragraph 3: 
If the pediatric plasma concentrations demonstrate that the geometric mean and median 
concentrations are below the adult 5th percentile or above the 95th percentile, the PK data 
will be used to re-evaluate the weight-based dose adjustment algorithm for pediatric subjects. 
Interim CZP plasma concentration data available at the time of Protocol Amendment 3 
indicated that no change to the dosing algorithm was required. The protocol stated that if 
future interim analyses, which may include PopPK, indicate that plasma concentrations of 
JIA subjects are outside of the exposure range observed in previous adult RA studies, a 
revised pediatric dose algorithm will be derived. Any change in dose regimen will require a 
protocol amendment prior to implementation. 
Based on results of an interim PopPK analysis conducted in Jun 2013 described in Section 
5.1, the dosing regimen will be changed with Protocol Amendments 4 and 5, and the doses to 
be administered will be reduced by 50% for all weight groups. This change is intended to 
achieve plasma concentrations similar to the effective concentrations observed in previous 
studies in adult subjects with RA. 
Has been changed to: 
Per original protocol, if the pediatric plasma concentrations demonstrate that the geometric 
mean and median concentrations are below the adult 5th percentile or above the 95th 
percentile, the PK data will be used to re-evaluate the weight-based dose adjustment 
algorithm for pediatric study participants. Interim CZP plasma concentration data available at 
the time of Protocol Amendment 3 indicated that no change to the dosing algorithm was 
required. The protocol stated that if future interim analyses, which may include PopPK, 
indicate that plasma concentrations of JIA study participants are outside of the exposure 
range observed in previous adult RA studies, a revised pediatric dose algorithm will be 
derived. Any change in dose regimen will require a protocol amendment prior to 
implementation. 
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An interim analysis of PK data conducted following Protocol Amendment 3 compared CZP 
plasma concentration data from this study with CZP plasma concentrations observed 
previously in adult study participants with RA. Interim analysis of CZP plasma 
concentrations was started when 6 study participants in 1 of the age groups completed 
Week 12 (Visit 7). Comparisons were made between the Week 12 geometric mean and 
median values for the pediatric and adult study participants, as well as between the individual 
pediatric data and the adult 5th and 95th percentile and minimum and maximum observed 
values. 
Based on results of this interim PopPK analysis (also described in Section 5.1), the dosing 
regimen was changed with Protocol Amendments 4 and 5, and the doses to be administered 
were reduced by 50% for all weight groups. This change was intended to achieve plasma 
concentrations similar to the effective concentrations observed in previous studies in adult 
study participants with RA. 
Change #144 
Section 13.7, paragraph 5, 6, 7: 
For the Week 24 interim clinical study report, the CZP plasma concentrations were monitored 
following the change in dose regimen to confirm they were within the targeted adult range. 
Following Protocol Amendment 8, no more interim PK analyses will be performed, and the 
final PK data to be reported will use a new MSD assay, and consequently no further 
comparison will be performed with respect to the adult RA concentrations range. 
After all active subjects have completed the Week 16 (Visit 8) assessments, an interim 
analysis of PedACR30 response rates will be performed and the study will be discontinued if 
less than 50% of the study population enrolled on the reduced CZP dose regimen (Protocol 
Amendment 5) achieves a PedACR30 response at Week 16. Given the descriptive nature of 
the data presentations, there are no statistical implications of this interim analysis. 
After the last subject has reached the Week 24 Visit (Visit 10), the database will be cut and a 
full interim analysis of all safety and efficacy endpoints will be performed based upon 
24 weeks of exposure for each individual (or all data for those cases who withdrew before 
this timepoint).  
Has been changed to: 
An interim analysis of PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants that were enrolled and treated prior to implementation of 
Protocol Amendment 9 had completed the Week 24 (Visit 10) assessments, and the results 
were reported separately. An interim analysis, including all enrolled participants, for all PK, 
immunogenicity, safety, and efficacy endpoints will be performed after all active study 
participants, including those enrolled following the implementation of Protocol 
Amendment 9, have completed the Week 24 (Visit 10) assessments. 
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Change #145 
Section 13.8, paragraph 1: 
Based upon the ICH guideline for the assessment of safety, it is planned to enroll a sufficient 
number of subjects to this study to have a minimum of 100 with at least 12 months 
continuous exposure to CZP. Assuming a dropout rate of approximately 20%, it was 
originally determined that 125 subjects would need to be enrolled. At the time of Protocol 
Amendment 5, 78 subjects had been enrolled according to the original CZP dose regimen, 
and it is planned to enroll a further 78 subjects on the reduced CZP dose regimen, so that a 
comparable number of subjects on the reduced CZP dose regimens can be analyzed. Thus, the 
total number of subjects planned to be enrolled will be increased to 156 subjects. Assuming a 
Screening failure rate of 25%, it is planned to screen 195 subjects in total. 
Has been changed to: 
Based upon the ICH guideline for the assessment of safety, it is planned to enroll a sufficient 
number of study participants to this study to have a minimum of 100 with at least 12 months 
continuous exposure to CZP. Assuming a dropout rate of approximately 20%, it was 
originally determined that 125 study participants would need to be enrolled. At the time of 
Protocol Amendment 5, 78 study participants had been enrolled according to the original 
CZP dose regimen, and it was planned to enroll a further 78 study participants on the reduced 
CZP dose regimen, so that a comparable number of study participants on the reduced CZP 
dose regimens could be analyzed. Thus, the total number of study participants planned to be 
enrolled was increased to 156 study participants. Assuming a Screening failure rate of 25%, it 
is planned to screen 195 study participants in total.  
Change #146 
Section 13.8, the following text has been added: 
With Protocol Amendment 9, an additional 30 study participants will be enrolled on the 
original dose regimen with the aim to enroll at least 5 study participants in each weight range 
of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and ≥40kg (≥88lb). 
Change #147 
Section 16, the following reference has been added: 
FDA Guidance for Industry – Bioanalytical Method Validation. 2018. 
 
 
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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 
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19 
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. 
 
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Approval Signatures
Name:
ra0043-protocol-amend-9
Version:
1. 0
Document Number:
CLIN-000151233
Title:
RA0043 - Protocol Amendment 9 - Phase 3 - Open-label
Approved Date:
27 Apr 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Medical
Date of Signature: 27-Apr-2020 17:14:30 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 27-Apr-2020 17:57:24 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 27-Apr-2020 18:03:16 GMT+0000
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SAP_001.pdf: 
UCB 
 
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Statistical Analysis Plan 
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   STATISTICAL ANALYSIS PLAN (SAP) 
Study: RA0043 
Product: Certolizumab pegol (CZP) 
A MULTICENTER, OPEN-LABEL STUDY TO ASSESS THE 
PHARMACOKINETICS, SAFETY, AND EFFICACY OF 
CERTOLIZUMAB PEGOL IN CHILDREN AND 
ADOLESCENTS WITH MODERATELY TO SEVERELY 
ACTIVE POLYARTICULAR-COURSE JUVENILE IDIOPATHIC 
ARTHRITIS 
PASCAL (Pediatric Arthritis Study of CertolizumAb pegoL) 
 
SAP/Amendment  
Date 
Final SAP 
23 Jun 2015 
SAP Amendment 1 
29 Sep 2015 
SAP Amendment 2 
24 Jun 2016 
SAP Amendment 3 
30 Jun 2021 
SAP Amendment 4 
8 Dec 2022 
SAP Amendment 5 
21 Jun 2023 
SAP Amendment 6 
23 May 2024 
Confidentiality Statement 
Confidential 
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Statistical Analysis Plan 
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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. 
 
TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 7 
LIST OF ABBREVIATIONS .................................................................................................... 8 
1 
INTRODUCTION ........................................................................................................... 11 
2 
PROTOCOL SUMMARY ............................................................................................... 11 
2.1 
Study objectives ........................................................................................................... 16 
2.1.1 
Primary objective ................................................................................................. 16 
2.1.2 
Secondary objective ............................................................................................. 16 
2.1.3 
Other objectives ................................................................................................... 16 
2.2 
Study variables ............................................................................................................. 16 
2.2.1 
Primary variables ................................................................................................. 16 
2.2.1.1 
Pharmacokinetic and immunological variables ......................................... 16 
2.2.1.2 
Safety variables ......................................................................................... 16 
2.2.2 
Secondary variables ............................................................................................. 16 
2.2.3 
Other variables ..................................................................................................... 16 
2.2.3.1 
Other PK and immunological variables .................................................... 16 
2.2.3.2 
Other safety variables ................................................................................ 16 
2.2.3.3 
Other efficacy and health outcomes variables ........................................... 17 
2.2.3.4 
Additional other variables ......................................................................... 18 
2.3 
Study design and conduct ............................................................................................ 18 
2.4 
Determination of sample size ....................................................................................... 22 
2.5 
Study RA0138 .............................................................................................................. 23 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 23 
3.1 
General presentation of summaries and analyses ........................................................ 23 
3.2 
General study level definitions .................................................................................... 26 
3.2.1 
Analysis time points ............................................................................................ 26 
3.2.2 
Relative day ......................................................................................................... 26 
3.2.3 
Medications .......................................................................................................... 26 
3.2.4 
Final Visit ............................................................................................................ 26 
3.2.5 
Week 24 ............................................................................................................... 27 
3.2.6 
Entire treatment period ........................................................................................ 27 
3.3 
Definition of Baseline values ....................................................................................... 27 
3.4 
Protocol deviations....................................................................................................... 27 
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3.5 
Exclusion of PK data points ......................................................................................... 27 
3.5.1.1 
Rules for exclusions of specific PK samples ............................................. 28 
3.6 
Analysis sets................................................................................................................. 29 
3.6.1 
Enrolled Set ......................................................................................................... 29 
3.6.2 
Safety Set ............................................................................................................. 29 
3.6.3 
Full Analysis Set .................................................................................................. 29 
3.6.4 
Pharmacokinetic Per-Protocol (PK-PP) Set ......................................................... 29 
3.7 
Treatment assignment and treatment groups ............................................................... 29 
3.8 
Center pooling strategy ................................................................................................ 30 
3.9 
Coding dictionaries ...................................................................................................... 30 
3.10 
Changes to protocol-defined analyses ......................................................................... 30 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 32 
4.1 
Adjustments for covariates .......................................................................................... 32 
4.2 
Handling of dropouts or missing data .......................................................................... 33 
4.2.1 
Incomplete dates for adverse events and concomitant medications .................... 33 
4.2.2 
Incomplete date for the last administration of study medication ......................... 34 
4.2.3 
Handling of questionnaire data ............................................................................ 35 
4.2.4 
Missing adverse event intensity ........................................................................... 35 
4.2.5 
Missing adverse event relationship to study medication ..................................... 36 
4.3 
Interim analyses and data monitoring .......................................................................... 36 
4.4 
Multicenter studies ....................................................................................................... 37 
4.5 
Multiple comparisons/multiplicity ............................................................................... 37 
4.6 
Use of an efficacy subset of study participants ............................................................ 37 
4.7 
Examination of subgroups ........................................................................................... 38 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 39 
5.1 
Study participant disposition........................................................................................ 39 
5.2 
Protocol deviations....................................................................................................... 39 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 39 
6.1 
Demographics .............................................................................................................. 39 
6.2 
Other baseline characteristics ...................................................................................... 40 
6.3 
Medical history and concomitant diseases ................................................................... 40 
6.4 
Prior and concomitant medications .............................................................................. 40 
6.5 
Prohibited medications................................................................................................. 41 
6.6 
Rescue medications ...................................................................................................... 42 
6.7 
Short-acting medications ............................................................................................. 43 
6.8 
Medical procedure history and concomitant medical procedures ................................ 44 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 44 
8 
PHARMACOKINETICS AND IMMUNOLOGICAL PROCEDURES ........................ 45 
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8.1 
CZP plasma concentrations.......................................................................................... 45 
8.1.1 
ECLIA vs ELISA samples ................................................................................... 46 
8.2 
Anti-CZP antibodies .................................................................................................... 47 
8.2.1 
Participant ADAb classification .......................................................................... 48 
8.2.2 
ADAb Titer Classification ................................................................................... 50 
8.2.3 
Time to first occurrence of treatment-emergent ADAb positivity ...................... 51 
8.2.4 
ECLIA vs ELISA samples ................................................................................... 52 
8.3 
CZP plasma concentrations, anti-CZP antibody titers, and PedACR response ............. 53 
8.4 
PopPK analyses ............................................................................................................ 53 
9 
SAFETY ANALYSES ..................................................................................................... 53 
9.1 
Extent of exposure ....................................................................................................... 54 
9.1.1 
Subject time at risk .............................................................................................. 55 
9.1.2 
Updated Week 24 Interim Analysis and other interim analyses .......................... 57 
9.2 
Adverse events ............................................................................................................. 58 
9.2.1 
TEAEs of interest ................................................................................................ 61 
9.2.2 
AE of special interest ........................................................................................... 62 
9.2.3 
Covid vaccine sensitivity analysis ....................................................................... 62 
9.3 
Clinical laboratory evaluations .................................................................................... 63 
9.4 
Vital signs, physical findings, and other observations related to safety ...................... 66 
9.4.1 
Vital Signs ........................................................................................................... 66 
9.4.2 
Other safety variables .......................................................................................... 68 
9.4.2.1 
Height and weight ..................................................................................... 68 
9.4.2.2 
Tanner stages ............................................................................................. 68 
9.4.2.3 
Physical examination ................................................................................. 68 
9.4.2.4 
Reproductive potential and birth control ................................................... 68 
9.4.2.5 
Autoantibodies ........................................................................................... 69 
9.4.2.6 
Tuberculosis assessments .......................................................................... 69 
10 EFFICACY ANALYSES ................................................................................................ 69 
10.1 
Statistical analysis of the primary efficacy variable .................................................... 70 
10.2 
Statistical analysis of the secondary efficacy variables ............................................... 70 
10.3 
Analysis of other efficacy variables ............................................................................. 71 
10.3.1 
PedACR30, PedACR50, PedACR70, and PedACR90 ........................................ 71 
10.3.2 
PRINTO/PRCSG standard joint examination ..................................................... 72 
10.3.2.1 
Joints with active arthritis .......................................................................... 72 
10.3.2.2 
Joints with limitation of range of motion .................................................. 73 
10.3.3 
Physician’s Global Assessment of Disease Activity VAS .................................. 74 
10.3.4 
Childhood Health Assessment Questionnaire ..................................................... 74 
10.3.5 
Parent’s Assessment of Arthritis Pain VAS ........................................................ 75 
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10.3.5.1 
Updated Week 24 Interim Analysis .......................................................... 75 
10.3.5.2 
Final Analysis ............................................................................................ 75 
10.3.6 
Parent’s Global Assessment of Overall Well-Being VAS .................................. 76 
10.3.7 
C-reactive protein ................................................................................................ 76 
10.3.8 
Juvenile Arthritis Disease Activity Score 71-joint .............................................. 76 
10.3.9 
Clinically Inactive Disease .................................................................................. 77 
10.3.9.1 
Updated Week 24 Interim Analysis .......................................................... 77 
10.3.9.2 
Final Analysis ............................................................................................ 77 
10.3.10 
Clinical Remission ............................................................................................... 78 
10.3.10.1 
Updated Week 24 Interim Analysis .......................................................... 78 
10.3.10.2 
Final Analysis ............................................................................................ 78 
10.3.11 
Duration of morning stiffness .............................................................................. 79 
10.3.11.1 
Updated Week 24 Interim Analysis .......................................................... 79 
10.3.11.2 
Final Analysis ............................................................................................ 79 
10.3.12 
Faces Pain Scale-Revised .................................................................................... 79 
10.3.12.1 
Updated Week 24 Interim Analysis .......................................................... 79 
10.3.12.2 
Final Analysis ............................................................................................ 79 
10.3.13 
Patient’s Assessment of Arthritis Pain ................................................................ 80 
10.3.13.1 
Updated Week 24 Interim Analysis .......................................................... 80 
10.3.13.2 
Final Analysis ............................................................................................ 80 
10.3.14 
FASCA – Fatigue Assessment Scale ................................................................... 80 
10.3.14.1 
Updated Week 24 Interim Analysis .......................................................... 80 
10.3.14.2 
Final Analysis ............................................................................................ 80 
10.3.15 
Juvenile Arthritis School Attendance and Caregiver Work Productivity 
Survey .................................................................................................................. 81 
10.3.15.1 
Updated Week 24 Interim Analysis .......................................................... 81 
10.3.15.2 
Final Analysis ............................................................................................ 81 
11 REFERENCES ................................................................................................................ 82 
12 APPENDIX ...................................................................................................................... 82 
12.1 
Comparisons with RA0138 data .................................................................................. 82 
13 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) ...................... 83 
13.1 
AMENDMENT 1......................................................................................................... 83 
13.2 
AMENDMENT 2......................................................................................................... 90 
13.3 
AMENDMENT 3....................................................................................................... 105 
13.4 
AMENDMENT 4....................................................................................................... 138 
13.5 
AMENDMENT 5....................................................................................................... 189 
13.5.1 
Subject time at risk ............................................................................................ 218 
13.6 
AMENDMENT 6....................................................................................................... 224 
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LIST OF TABLES 
Table 2‒1: 
Protocol, Amendments, Dates and Rationales ................................................. 11 
Table 2‒2: 
Visit Schedule .................................................................................................. 19 
Table 2‒3: 
Dosing administration of CZPa ........................................................................ 21 
Table 8‒1: 
ADAb status at sample level ............................................................................ 47 
Table 8‒2: 
ADAb status classification at participant level ................................................ 48 
Table 8‒3: 
Aid to Programming ADAb participant status category .................................. 50 
Table 9‒1: 
Dosing periods ................................................................................................. 54 
Table 9‒2: 
Covid vaccination related adverse events for sensitivity analysis ................... 62 
Table 9‒3: 
Definitions of Markedly Abnormal Hematology Values ................................. 64 
Table 9‒4: 
Definitions of Markedly Abnormal Biochemistry Values ............................... 64 
Table 9‒5: 
Definitions of Markedly Abnormal Vital Signs Values .................................. 67 
Table 10‒1: 
CHAQ Aids and Devices ................................................................................. 74 
Table 13‒1: 
Protocol, Amendments, Dates and Rationales ............................................... 139 
Table 13‒2: 
Dosing administration of CZPa ...................................................................... 145 
Table 13‒3: 
ADAb status at sample level .......................................................................... 168 
Table 13‒4: 
ADAb status classification at participant level .............................................. 169 
Table 13‒5: 
Covid vaccination related adverse events for sensitivity analysis ................. 183 
Table 13‒6: 
Definitions of Markedly Abnormal Vital Signs Values ................................ 185 
Table 13‒7: 
ADAb status classification at participant level .............................................. 207 
Table 13‒8: 
ADAb status classification at participant level .............................................. 208 
Table 13‒9: 
Aid to Programming ADAb participant status category ................................ 210 
Table 13‒10: Dosing periods ............................................................................................... 216 
 
 
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LIST OF ABBREVIATIONS 
 
ADAb 
Anti-CZP antibody 
ADAB- 
anti-CZP antibody-negative 
ADAB+ 
anti-CZP antibody-positive 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
BSA 
body surface area 
CHAQ 
Childhood Health Assessment Questionnaire 
CI 
confidence interval  
CID 
Clinically Inactive Disease 
COVID-19 
Coronavirus disease 2019 
COX-2 
cyclooxygenase-2 
CRF 
case report form 
CRM 
derived clinical remission (previously referred to as 
clinical remission on medication)  
CRP 
C-reactive protein 
CSR 
clinical study report  
CV 
coefficient of variation 
CZP 
certolizumab pegol  
DMARD 
disease-modifying antirheumatic drug 
DMS 
duration of morning stiffness 
ds-DNA 
double-stranded deoxyribonucleic acid  
DSMB 
Data and Safety Monitoring Board 
EAER 
exposure-adjusted event rate 
EAIR 
exposure-adjusted incidence rate 
ECG 
electrocardiogram 
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ECLIA 
electrochemiluminescence immunoassay 
ED 
early discontinuation 
ELISA 
enzyme-linked immunosorbent assay 
EOT 
end of treatment 
ERA 
enthesitis-related arthritis 
ES 
Enrolled Set 
FAS 
Full Analysis Set 
FASCA 
Fatigue Assessment Scale 
FPS-R 
Faces Pain Scale - Revised 
HLT 
High -Level Term 
ia 
intra-articular 
im 
intramuscular 
IMP 
investigational medicinal product 
iv 
intravenous 
IXRS 
interactive voice/web response system 
JADAS 
Juvenile Arthritis Disease Activity Score  
JIA 
juvenile idiopathic arthritis 
LOCF 
last observation carried forward 
LOM 
limitation of motion 
LoQ 
limit of quantification 
MAR 
missing at random 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MRD 
Minimum required dilution 
MTX 
NRI 
Methotrexate 
Nonresponder Imputation 
NRS 
numeric rating scale 
NSAID 
OC 
nonsteroidal anti-inflammatory drug 
observed case 
PD 
Pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
PedACR30, 50, 70, 90 
American College of Rheumatology Pediatric 30%, 
50%, 70%, 90% 
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pcJIA 
Polyarticular-course juvenile idiopathic arthritis 
PK 
pharmacokinetic 
PK-PD 
Pharmacokinetic-Pharmacodynamic 
PK-PP 
Pharmacokinetic Per-Protocol  
POM  
pain on motion 
PopPK 
population pharmacokinetic 
PRN 
as needed 
PT 
Preferred Term 
Q2W, Q4W 
every 2 weeks, every 4 weeks 
RA 
rheumatoid arthritis 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
sc 
subcutaneously  
SOC 
system organ class 
SRC 
Safety Review Committee 
SS 
Safety Set  
TE 
Treatment-emergent 
TEAE 
treatment-emergent adverse event 
VAS 
visual analog scale 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
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1 
INTRODUCTION 
This document describes the planned analyses and summary tables, figures, and listings to be 
included in the final clinical study report (CSR) for RA0043 as well as for the Updated Week 
24 Interim Analysis and other analyses supporting marketing applications; specific analyses 
added just for the Updated Week 24 Interim Analysis have been updated to say that they were 
only generated for that analysis Note that the Week 16 interim analysis and the 2016 Week 
24 interim analyses were completed as specified in SAP Amendment 1 and text about these 
analyses will be kept as is. 
If, after the final database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, those unplanned analyses will not be described in an 
amended SAP, but they will be identified in the CSR. Any deviations from this SAP will be 
documented in the CSR. 
2 
PROTOCOL SUMMARY 
This is a Phase 3, multicenter, open-label study to assess the pharmacokinetics (PK), safety, 
and efficacy of certolizumab pegol (CDP870, CZP, Cimzia®) in children and adolescents 
with moderately to severely active polyarticular-course juvenile idiopathic arthritis (pcJIA). 
The primary objectives of the study are to evaluate the PK and safety including the 
immunogenicity of CZP administered subcutaneously (sc) in children and adolescents with 
moderate to severe pcJIA.  The primary PK and immunological variables are CZP plasma 
concentration and anti-CZP antibody (ADAb) levels at Week 16 and Week 48. 
Below is the list of protocol amendments, dates and rationales for key updates: 
 
Table 2‒1: 
Protocol, Amendments, Dates and Rationales 
RA0043 
Protocol/Amendment 
Number 
Date 
Rationale for Key Updates 
Protocol 
10 Jan 2010 
NA 
Amendment 1 
26 Aug 2011 
The primary purpose of this substantial protocol amendment is 
to revise the protocol in line with change requests from health 
authorities following discussions on the CZP pediatric arthritis 
development program. Key updates include adding 
effectiveness as a secondary objective, defining the study 
population as polyarticular-course JIA, setting minimum 
number of enrolled participants by body weight and age and 
adding the study stopping rule. 
Amendment 2 
02 Jul 2012 
The primary purpose of this non-substantial amendment is to 
change in the participating countries, including removal of 
Western Europe. RA0043 will not be included in the European 
Paediatric Investigational Plan and will therefore not be 
conducted in Western Europe. 
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Table 2‒1: 
Protocol, Amendments, Dates and Rationales 
Amendment 2.1  
21 Aug 2012 
Amendment 2 adapted for Russia. The primary purpose of this 
substantial amendment is to change the age range for 
enrollment from 2-17 years to 6-17 years of age which is in 
response to comments received from the Ministry of Health 
and Social Development of the Russian Federation. 
Amendment 3 
06 May 2013 
The primary purpose of this substantial amendment is to update 
the exclusion criteria and guidelines related to TB detection 
and monitoring in order to comply with the revised UCB TB 
Task Force policy. 
Amendment 3.1 
06 May 2013 
Amendment 3 adapted for Russia as per Amendment 2.1. 
Amendment 4 
01 Aug 2013 
The primary purpose of this substantial amendment is for the 
dose for study participants already enrolled in RA0043 to be 
reduced (enrollment into RA0043 was suspended, effective 17 
Jul 2013). An overall dose reduction for pediatric study 
participants of 50% of the dose currently used in RA0043 is 
proposed to provide a pragmatic dosing regimen that will yield 
a closer match to the adult plasma concentration range 
achieved in adults with the approved label for RA (CZP 400mg 
at Weeks 0, 2, and 4 followed by CZP 200mg Q2W thereafter).  
Amendment 4.1 
01 Aug 2013 
Amendment 4 adapted for Russia as per Amendment 2.1. 
Amendment 5 
20 Jan 2014 
The primary purpose of this substantial amendment is to 
reopen enrollment under the new reduced CZP dose regimen 
and to update the statistical analysis to account for the changes 
in the CZP dose regimen. 
Amendment 5.1 
20 Jan 2014 
Amendment 5 adapted for Russia as per Amendment 2.1. 
Amendment 5.2 
23 Feb 2015 
The primary purpose of this non-substantial amendment is to 
lift the enrollment cap per site in Russia to allow further 
enrollment in the weight group of 15 to <20kg for sites that 
have enrolled the maximum number of 12 study participants.  
Amendment 6 
17 Sep 2015 
The primary purpose of this administrative amendment is to 
update the packaging and labeling sections of the protocol to 
account for a new presentation of the prefilled syringe (PFS). 
Amendment 6.1 
17 Sep 2015 
Amendment 6 adapted for Russia as per Amendment 2.1. 
Amendment 7 
22 Sep 2016 
The primary purpose of this substantial amendment is to update 
the protocol in accordance with current UCB TB detection 
procedures, including the introduction of yearly TB testing and 
the extension of the prophylactic TB treatment duration from 
4 to 8 weeks. Furthermore, it has been clarified that long-term 
efficacy data from study participants who withdraw from the 
study after Week 56 or initiate any rescue medication use after 
Week 56 will be analyzed “as observed” and will no longer be 
imputed as nonresponse or missing. 
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Table 2‒1: 
Protocol, Amendments, Dates and Rationales 
Amendment 7.1 
22 Sep 2016 
Amendment 7 adapted for Russia as per Amendment 2.1. 
Amendment 8 
24 Jun 2019 
The primary purpose of this substantial amendment is to reduce 
the study participants’ burden by limiting the frequency of on-
site visits, safety sampling, and efficacy assessments.  
The frequency of on-site visits will be reduced from every 8 
weeks to every 16 weeks in this long-term study. At the time of 
implementing Protocol Amendment 8, all ongoing study 
participants have at least completed the visit for Week 180. As 
before, on-site CZP administration between scheduled visits is 
offered as needed. 
Amendment 8.1 
18 Jul 2019 
Amendment 8 adapted for Russia as per Amendment 2.1 
Amendment 9 
27 Apr 2020 
The primary purpose of this substantial amendment is to enroll 
an additional 30 study participants on the original CZP dose 
regimen in order to adequately assess the exposure levels and 
clinical experience of CZP in pcJIA at both the reduced and 
original CZP dose regimens and also adequately support the 
safety assessment of the original CZP dosing regimen. More of 
the safety data collected in the study to date has been on the 
reduced dose, and which of these dose regimens to be included 
in the marketing application for CZP in pcJIA is still to be 
determined.  
Amendment 9.1 
28 Jul 2020 
Amendment 9 adapted for Russia as per Amendment 2.1 
Amendment 9.2 
30 Jul 2021 
The primary purpose of this non-substantial amendment is to 
increase the enrollment cap per site in Russia to allow further 
enrollment on the original dose regimen for sites that have 
enrolled the maximum number of 16 study participants. 
 
Study participants, prior to Protocol Amendment 4, were enrolled on the Original CZP Dose. 
Results of a planned interim PopPK analysis conducted suggested that while observed CZP 
plasma concentrations with the Original Dose administration remained in the adult range, 
they were at the upper end of the distribution. Based on these findings, the dosing was 
changed with Protocol Amendments 4 and 5, and the doses to be administered were reduced 
by 50% for all weight groups, Reduced CZP Dose, see Table 2‒3. This dose change was 
intended to achieve plasma concentrations that were similar to the effective concentrations 
observed in previous studies in adult study participants with RA. Based on interactions with 
FDA, Amendment 9 allowed 30 new participants to be enrolled taking Original CZP Dose; 
for the study participants who were taking Reduced CZP Dose, it introduced the option to 
increase to the Original CZP Dose. 
Study participants will be summarized by the following 3 dose groups:  
• Any CZP Dose – includes all data from all study participants while being treated in the 
study 
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• Original CZP Dose – includes all data for study participants enrolled on Original CZP 
Dose prior to the first change in dosage 
• Reduced CZP Dose – includes all data for study participants enrolled on Reduced CZP 
Dose prior to the first change in dosage 
For the Updated Week 24 Interim Analysis only, study participants were also summarized by 
the following 2 dose groups: 
• Complete Original CZP Dose – includes all data for study participants who took Original 
CZP Dose prior to the first change in dosage as well as the data from when study 
participants increased their dosage to Original CZP after taking Reduced CZP Dose 
• Complete Reduced CZP Dose – includes all data for study participants who took Reduced 
CZP Dose prior to the first change in dosage as well as the data from when study 
participants took Reduced CZP Dose after taking Original CZP Dose  
The following graphic illustrates the study conduct once study participants taking original 
dose regimen were allowed to reduce their dose: 
 
 
 
 
OD=Original CZP Dose, RD=Reduced CZP Dose, PA=protocol amendment 
The following graphic illustrates the time course of the study as well and analysis timepoints: 
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An interim analysis of the American College of Rheumatology Pediatric 30% (PedACR30) 
response rate was performed after all active study participants who enrolled prior to Protocol 
Amendment 9 completed the Week 16 (Visit 8) assessments. The study would have been 
discontinued if less than 50% of the study population enrolled on the Reduced CZP Dose 
(Protocol Amendment 5) achieved a PedACR30 response at Week 16. A further futility 
analysis will not be performed using the additional study participants that will be enrolled 
after Protocol Amendment 9.  
A full interim analysis was performed in 2016 for all active study participants that had 
completed the Week 24 (Visit 10) assessments. After Protocol Amendment 9 which enrolls 
30 new study participants, interim analyses will be performed after all active study 
participants have completed the Week 24 (Visit 10) assessments and at other timepoints to 
support marketing applications.  
In order to adequately assess the exposure levels and clinical experience of CZP in pcJIA at 
both the Reduced and Original CZP Dose and also to further support the safety assessment of 
the Original CZP Dose, 30 additional study participants will be enrolled on the Original CZP 
Dose following Protocol Amendment 9. 
All study participants enrolled under Protocol Amendment 9 or later will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using electrochemiluminescence 
immunoassay (ECLIA) methods that meets current regulatory standards (versus those 
previously analyzed using ELISA methods for the prior Week 24 interim analysis). In 
addition, PK and ADAb samples (for which sufficient volume is available) collected in this 
study for participants enrolled prior to Protocol Amendment 9 will be re-analyzed with the 
ECLIA methods. The collective ECLIA-based PK data for this study will form the basis of 
any future CZP modeling and simulation work. 
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2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objectives of the study are to evaluate the PK and safety, including the 
immunogenicity, of CZP administered subcutaneously (sc) in children and adolescents with 
moderate to severe pcJIA. 
2.1.2 
Secondary objective 
The secondary objective is to assess the effectiveness of CZP on the clinical response in 
children and adolescents with moderate to severe pcJIA. 
2.1.3 
Other objectives 
Other objectives of the study are to further assess safety as well as efficacy and health 
outcomes. 
2.2 
Study variables 
2.2.1 
Primary variables 
2.2.1.1 
Pharmacokinetic and immunological variables 
• CZP plasma concentrations at Weeks 16 and 48 
• Anti-CZP antibody levels at Weeks 16 and 48 
2.2.1.2 
Safety variables 
The primary safety variables are the incidence of serious treatment-emergent adverse events 
(TEAEs) and TEAEs leading to permanent withdrawal of investigational medicinal product 
(IMP). 
Adverse events will be solicited at every visit, recorded and coded according to Medical 
Dictionary for Regulatory Activities (MedDRA®) criteria. 
2.2.2 
Secondary variables 
Efficacy will be assessed by the PedACR30, PedACR50, PedACR70 and PedACR90 
response rates at Week 16 as compared to Baseline. 
2.2.3 
Other variables 
2.2.3.1 
Other PK and immunological variables 
• CZP plasma concentrations and anti-CZP antibody levels at other study timepoints 
2.2.3.2 
Other safety variables 
• Incidence of TEAEs, TEAEs of interest, TEAEs by relatedness, TEAEs by severity, and 
TEAEs by duration of exposure 
• Clinical laboratory values (hematology, biochemistry, urinalysis) at every visit except 
Visits 3 and 4 (Week 1 and Week 2) and Unscheduled Visits 
• Vital sign abnormalities at every visit 
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• Developmental stages and growth (Tanner stages, height, weight) at Baseline, every 
protocol-specified visit thereafter, and the Early Discontinuation/End of Treatment Visit 
(weight at every visit through Final Visit).  
• Autoantibody concentrations (antinuclear antibodies (ANA) and anti-double-stranded 
desoxyribonucleic acid (anti-dsDNA) antibodies) at Baseline (testing for anti-dsDNA 
antibodies only if ANA is positive), Weeks 16 and 48, and at the Early 
Discontinuation/End of Treatment Visit 
2.2.3.3 
Other efficacy and health outcomes variables 
Other efficacy and health outcomes variables are: 
• PedACR30, PedACR50, PedACR70, and PedACR90 response rates at every post-
Baseline visit, except Week 16 and Final Visit, as compared to Baseline. 
• Change from Baseline in number of joints with active arthritis at every post-Baseline visit 
except Final Visit.  
• Change from Baseline in number of joints with limitation of range of motion at every 
post-Baseline visit except Final Visit. 
• Change from Baseline in Physician’s Global Assessment of Disease Activity (visual 
analog scale (VAS)) at every post-Baseline visit except Final Visit. 
• Change from Baseline in Childhood Health Assessment Questionnaire (CHAQ) at every 
post-Baseline visit except Final Visit. 
• Change from Baseline in Parent’s Assessment of Arthritis Pain (VAS) at every post-
Baseline visit except Final Visit. 
• Change from Baseline in Parent’s Global Assessment of Overall Well-Being (VAS) at 
every post-Baseline visit except Final Visit. 
• Percent Change from Baseline in C-reactive protein (CRP) at every post-Baseline visit 
except Final Visit. 
• Change from Baseline in Juvenile Arthritis Disease Activity Score 71-joint (JADAS-71) 
at every post-Baseline visit except Final Visit. 
• Percentage of study participants with Clinically Inactive Disease (CID) at every post-
Baseline visit except Final Visit. 
• Percentage of study participants with clinical remission on medication (CRM) at every 
post-Baseline visit from Week 24 onwards except Final Visit. 
• Time (in days) to CID calculated from first dose of study medication. 
• Time (in days) to CRM calculated from first dose of study medication. 
• Change from Baseline in duration of morning stiffness (DMS) at every post-Baseline visit 
except Final Visit. 
• Change from Baseline in Faces Pain Scale-Revised (FPS-R) (child-reported, ages 5 to 11 
years), at every post-Baseline visit except Final Visit.  
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• Change from Baseline in JIA Pain VAS (acute and standard versions); at every post-
Baseline visit except Final Visit 
• Change from Baseline in Fatigue Assessment Scale (FASCA) at every post-Baseline visit 
except Weeks 12 and 20, and Final Visit. 
• Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey responses 
at Baseline, Week 4, and every post-Baseline visit except Final Visit.   
2.2.3.4 
Additional other variables  
Additional variables that were covered under other variables that were specifically analyzed 
in the Updated Week 24 Interim Analysis only and were used for comparison purposes to 
support the regulatory submission include: 
• CZP plasma concentrations at Weeks 12 and 24 
• Anti-CZP antibody levels up to and including Week 24 
• CZP plasma concentration from study RA0138 at Weeks 12 and 24 
• Anti-CZP antibody levels from study RA0138 up to and including Week 24 
2.3 
Study design and conduct 
This is a Phase 3, multicenter, open-label study to assess the PK, safety, and efficacy of CZP 
in children and adolescents with moderately to severely active pcJIA. 
The study population will consist of study participants 2 to 17 years of age upon enrollment 
with a minimum weight of 10kg (22lb) (except in Russia, where the study population will 
consist of study participants 6 to 17 years of age upon enrollment with a minimum weight of 
15kg [33lb]). Study participants must have had onset of signs and symptoms consistent with 
pcJIA and initiation of pcJIA treatment for at least 6 months prior to Baseline. Active pcJIA 
disease is defined as ≥5 joints with active arthritis including: polyarthritis rheumatoid factor-
positive, polyarthritis rheumatoid factor-negative, extended oligoarthritis, juvenile psoriatic 
arthritis, and enthesitis-related arthritis (ERA). Study participants cannot have had active 
uveitis within the last 6 months prior to Baseline. In addition, study participants must have 
had an inadequate response to, or intolerance to, at least 1 disease-modifying antirheumatic 
drug (DMARD). 
The study consists of a Screening Period of up to 4 weeks; eligible study participants will 
then enter an open-label Treatment Period which will continue until the approval of the 
marketing application for the indication of pcJIA in the study participant’s country or region 
or closing the study by UCB.  A Final Visit will be conducted 12 weeks after last dose of 
study medication. 
The table below shows the data collection schedule prior to Protocol Amendment 8 and after 
implementing Protocol Amendment 8. For the study participants who switch to the 16-week 
schedule, the date of the first visit of this schedule will be captured on the “Study 
Participation” CRF module. Of note, the participants enrolled after Protocol Amendment 9 
(the new 30 study participants on Original CZP Dose) will remain on the original visit 
schedule throughout the study. 
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Table 2‒2: 
Visit Schedule  
Collected/ Assessed/ 
Administered at 
Prior to Protocol Amendment 8a 
Following Protocol Amendment 8 
Most parameters  
Screening, Baseline, Weeks 4, 8, 12, 16, 
20, 24, 32 and every 8 weeks thereafter, 
the Early Discontinuation/End of 
Treatment Visit, and the Final Visit 
Screening, Baseline, Weeks 4, 8, 12, 16, 
20, 24, 32 and every 16 weeks thereafter, 
the Early Discontinuation/End of 
Treatment Visit, and the Final Visit 
Height 
Screening, Baseline, every 24 weeks 
thereafter and Early 
Discontinuation/End of Treatment Visit 
Screening, Baseline, every 48 weeks 
thereafter and Early Discontinuation/End 
of Treatment Visit; assessed study 
participants who have not reached Tanner 
stage V 
Tanner 
Screening, Baseline, every 24 weeks 
thereafter and Early 
Discontinuation/End of Treatment Visit 
Screening, Baseline, every 48 weeks 
thereafter and Early Discontinuation/End 
of Treatment Visit; assessed study 
participants who have not reached Tanner 
stage V 
FPS-R and pcJIA 
Pain VAS 
Baseline and then daily during the first 
week of the study; at Weeks 4, 12, 16, 
24 and 32; and then every 8 weeks 
thereafter through the Early 
Discontinuation/End of Treatment 
Baseline and then daily during the first 
week of the study; at Weeks 4, 12, 16, 24 
and 32; and then every 16 weeks 
thereafter through the Early 
Discontinuation/End of Treatment 
NRS 
Baseline, Weeks 1, 2, 4, 8, and then 
every 8 weeks thereafter through the 
Early Discontinuation/End of Treatment 
Baseline, Weeks 1, 2, 4, 8, 16, 24, 32 and 
then every 16 weeks thereafter through 
the Early Discontinuation/End of 
Treatment 
a Participants enrolled after Protocol Amendment 9 (the new 30 study participants on Original CZP Dose) will 
remain on the original visit schedule throughout the study.  
Prior to Protocol Amendment 9, approximately 195 study participants are planned to be 
screened to enroll 156 study participants in this study, as follows: 
• A minimum of 10 study participants will be enrolled on the Reduced CZP Dose (Protocol 
Amendment 5) in each weight range of 10 < 20kg (22 to <44lb), 20 to <40kg (44 to 
<88lb), and >40kg (>88lb). 
• A minimum of 10 study participants will be enrolled in each age category of 2 to 5 years, 
6 to 11 years, and 12 to 17 years, irrespective of the dose. 
• A minimum of 25 study participants will be enrolled who receive CZP as monotherapy 
(ie, study participants with established intolerability or inadequate response to MTX), 
irrespective of the dose. 
• A minimum of 10 study participants with ERA will be enrolled, irrespective of the dose. 
Each of these categories is assessed independently.  
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In order to further support the safety assessment of the Original CZP Dose, as more of the 
safety data collected in the study to date has been on the reduced dose, an additional 30 study 
participants are intended to be enrolled on the Original CZP Dose with the aim to enroll at 
least 5 study participants in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 
to <88lb), and >40kg (>88lb) following Protocol Amendment 9. 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 followed by maintenance doses 
Q2W (except the 10 to < 20kg group on the Reduced CZP Dose will be administered 50mg 
Q4W). The doses are explained in the following table:  
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Table 2‒3: 
Dosing administration of CZPa  
Weight range 
Loading dose – Weeks 0, 2, and 
4 
(mg/kg dose range) 
IMP Description 
Maintenance – Week 6b and 
onwards 
(mg/kg dose range) 
IMP Description 
Original CZP Dose 
10 to <20kg 
(22 to <44lb) 
100mg Q2W 
(5-10mg/kg) 
1 x 0.5mL inj 
50mg Q2W 
(2.5-5mg/kg) 
1 x 0.25 mL inj 
20 to <40kg 
(44 to <88lb) 
200mg Q2W 
(5-10mg/kg) 
1 x 1mL inj 
100mg Q2W 
(2.5-5mg/kg) 
1 x 0.5mL inj 
≥40kg 
(≥88lb) 
400mg Q2W 
(<10mg/kg) 
2 x 1mL inj 
200mg Q2W 
(<5mg/kg) 
1 x 1mL inj 
Reduced CZP Dose 
10 to <20kg 
(22 to <44lb) 
50mg Q2W 
(2.5-5mg/kg) 
1 x 0.25mL inj  
50mg Q4W 
(2.5-5mg/kg) 
1 x 0.25mL inj  
20 to <40kg 
(44 to <88lb) 
100mg Q2W 
(2.5-5mg/kg) 
1 x 0.5mL inj  
50mg Q2W 
(1.25-2.5mg/kg) 
1 x 0.25mL inj  
≥40kg 
(≥88lb) 
200mg Q2W 
(<5mg/kg) 
1 x 1mL inj  
100mg Q2W 
(<2.5mg/kg) 
1 x 0.5mL inj  
CZP=certolizumab pegol; inj=injection; Q2W=every 2 weeks; Q4W=every 4 weeks 
Note: A study participant should change dosing category during the course of the study if their weight crosses 
the 40kg/88lb boundary or crosses the 20kg/44lb boundary. 
a Note that the Original CZP Dose describes the dosing administration of CZP prior to the implementation of 
Protocol Amendments 4 and 5 and for study participants enrolled following the implementation of Protocol 
Amendment 9. The Reduced CZP Dose describes the dosing administration of CZP after implementation of 
Protocol Amendments 4 and 5.  
bNote that for Reduced Dose, 10 to <20kg study participants, maintenance dosing started at Week 8. 
Based on interim PopPK analysis of RA0043 data, the minimum and maximum loading doses 
in the study were adjusted to CZP 50mg Q2W and CZP 200mg Q2W, respectively, and the 
minimum and maximum maintenance doses were adjusted to CZP 50mg Q4W and CZP 
100mg Q2W, respectively, following implementation of Protocol Amendments 4 and 5. 
However, it was later determined that there were deficiencies with the bioanalytical assays 
used for RA0043, which rendered the PK data unreliable. Accordingly, PK samples were no 
longer collected for study participants on the Reduced CZP Dose following implementation 
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of Protocol Amendment 8, in addition to reducing the burden on participants who had already 
been in the study for a number of years. 
A validated ECLIA method that meets the standards set in the regulatory guidance for 
analytical procedures and methods validations for drugs and biologics was introduced after 
Protocol Amendment 9, it has been used for all new analyses, including re-analysis of 
archived samples collected before Protocol Amendment 9 and for the analysis of bio-samples 
collected from the additional 30 study participants after Protocol Amendment 9. 
Based on 24-week interim results from the first 163 study participants enrolled in RA0043, 
both the Original CZP Dose and Reduced CZP Dose showed safety profiles similar to the 
approved CZP dose in the adult RA population.  The overall clinical response in this analysis 
(taking both doses into account) was PedACR30 and PedACR50 responses of 77.3% and 
67.5%, respectively at Week 12. The response from the original dose was 75.6% for 
PedACR30 and 64.1% for PedACR50; the response from the reduced dose was 78.8% for 
PedACR30 and 70.6% for PedACR50.  PedACR50 response demonstrates a highly clinically 
relevant decrease in disease activity. 
Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
pcJIA at both the Reduced and Original CZP Doses and support the safety for the Original 
CZP Dose, as more of the safety data collected in the study prior to Amendment 9 were on 
the reduced dose, 30 additional study participants have been enrolled on the Original CZP 
Dose following Protocol Amendment 9.  
All study participants enrolled following Protocol Amendment 9 will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using the ECLIA method. In 
addition, PK and ADAb samples (for which sufficient volume is available) collected in this 
study prior to Protocol Amendment 9 will be analyzed with the ECLIA method. The 
collective ECLIA-based PK data for this study will form the basis of any future CZP PK 
analysis, and was the basis for the modeling and simulation work that supported the interim 
PK analysis in 2023 and the 2024 submission. 
Full interim analyses were performed in 2016 after all active study participants completed the 
Week 24 (Visit 10) assessments.  Week 24 full interim analyses were completed as described 
in SAP Amendment 1. An Updated Week 24 (Visit 10) interim analysis, including the 30 
new study participants enrolled after Protocol Amendment 9, was completed as described in 
SAP Amendments 4, 5, and 6. The final analysis will be completed as described in SAP 
Amendment 6. 
 
2.4 
Determination of sample size 
Based upon the ICH guideline for the assessment of safety, it is planned to enroll a sufficient 
number of study participants to this study to have a minimum of 100 with at least 12 months 
continuous exposure to CZP. Assuming a dropout rate of approximately 20%, it was 
originally determined that 125 study participants would need to be enrolled. At the time of 
Protocol Amendment 5, 78 study participants had been enrolled according to the Original 
CZP Dose, and it was planned to enroll a further 78 study participants on the Reduced CZP 
Dose, so that a comparable number of study participants on the Reduced CZP Dose could be 
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analyzed. Thus, the total number of study participants planned to be enrolled was increased to 
156 study participants. Assuming a Screening failure rate of 25%, it was planned to screen 
195 study participants in total. 
With Protocol Amendment 9, an additional 30 study participants were enrolled with the aim 
to enroll at least 5 study participants in each weight range of 10 to <20kg (22 to <44lb), 20 to 
<40kg (44 to <88lb), and >40kg (>88lb). 
Prior to the start of study conduct, simulations using the adult population PK model in 
pediatric study participants with pcJIA suggested that the planned sample size of 125 study 
participants would also be adequate for PK assessment purposes. Individual apparent 
clearance (CL/F) and volume of distribution (V/F) were simulated for a total of 125 study 
participants (using the same approach presented in C87079 report addendum 08 Oct 2008 
performed for 190 study participants). In all age groups, the standard errors of both PK 
parameters, CL/F and V/F, relative to their mean were substantially <20%, with values 
ranging from 5.5 to 7.0% for CL/F and from 4.6 to 7.5% for V/F. 
Available ECLIA-based data from all study participants were included in the final PopPK 
analysis as described in a separate Data Analysis Plan and reported separately for the 
Updated Week 24 Interim Analysis only.  
2.5 
Study RA0138 
RA0138 is an open-label study in 33 adult study participants with RA who took 400mg 
loading dose (Weeks 0, 2, and 4), followed by 200mg CZP Q2W.  This study was conducted 
to generate PK and ADAb data using the same ECLIA assay as used in RA0043 to form the 
basis of “PK-matching” for CZP approval. For Updated Week 24 Interim Analysis, the PK 
and ADAb data from RA0138 was analyzed and displayed in the same manner as data from 
RA0043; comparisons and conclusions were made.  Those details are presented in the 
Appendix, Section 12.1. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
SAS® Version 9.3 (or later) will be used to perform all summaries and analyses, unless 
specified otherwise. 
All study participants received CZP and in most cases, are grouped by their Baseline weight 
group in the summary tables.  Generally, data summaries will be organized by CZP dose, and 
will include the following CZP dose groups: 
• Original CZP Dose: includes all study participants who began treatment in accordance 
with the Original CZP Dose defined for the study (3 loading doses of CZP at Weeks 0, 2, 
and 4 [minimum=100mg Q2W, maximum=400mg Q2W] followed by a maintenance 
dose for the duration of the study [minimum=50mg Q2W, maximum=200mg Q2W]). 
Only data obtained prior to their first change in dosage will be included in summaries of 
the Original CZP Dose. 
• Reduced CZP Dose: includes all study participants who began treatment in accordance 
with the Reduced CZP Dose defined for the study (3 loading doses of CZP at Weeks 0, 2, 
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and 4 [minimum=50mg Q2W, maximum=200mg Q2W] followed by a maintenance dose 
for the duration of the study [minimum=50mg Q4W, maximum=100mg Q2W]). Only 
data obtained prior to their first change in dosage will be included in summaries of the 
Reduced CZP Dose. 
• Any CZP Dose: includes all data from all study participants while being treated with the 
Original CZP Dose or the Reduced CZP Dose at any time in the study, regardless of dose 
switching.  
The planned data summaries using dose groups of Original CZP Dose and Reduced CZP 
Dose are designed to allow for the most relevant comparison of PK data and PK extrapolation 
using only data collected from study participants while receiving one consistent dosing 
regimen of CZP. This assignment of treatment groups will allow for a pure comparison of PK 
of the Original CZP Dose and the Reduced CZP Dose between pediatrics and adults without 
the potential of confounding differences in CZP plasma concentrations due to dose switching. 
Additionally, these dose groupings allow for the continuity of safety, immunogenicity, and 
open label efficacy analyses for the Original CZP Dose and Reduced CZP Dose. 
 
Generally, data will be summarized by the Original CZP Dose, Reduced CZP Dose, and Any 
CZP Dose groups.  For PK and ADAb analyses, data will be summarized by Original CZP 
Dose and Reduced CZP Dose only. For the Juvenile Arthritis School Attendance and 
Caregiver Work Productivity Survey, data will be summarized by Any CZP Dose group only. 
Following recommendations received from 
 
, a few data summaries were organized for the Updated Week 24 Interim Analysis 
only, by "Complete" CZP dose groups defined below, which allowed assessment of exposure 
and safety for all time that study participants were receiving the specified dose regardless of 
dose switching: 
• Complete Original CZP Dose: included all study participants who began treatment in 
accordance with the Original CZP Dose, as well as study participants who began 
treatment in accordance with the Reduced CZP Dose and then later dose escalated to the 
Original CZP Dose. 
 
Only data obtained while the study participant was receiving the Original CZP Dose was 
included in summaries of the Complete Original CZP Dose. For study participants who 
began treatment with the Original CZP Dose, this included time on the Original CZP 
Dose prior to first change in dosage, as well as time after returning to Original CZP Dose 
after a previous dose reduction. For study participants who began treatment with the 
Reduced CZP Dose, this included only time after dose escalation to the Original CZP 
Dose. 
• Complete Reduced CZP Dose: included all study participants who began treatment in 
accordance with the Reduced CZP Dose, as well as study participants who began 
treatment in accordance with the Original CZP Dose and later dose reduced to the 
Reduced CZP Dose. 
 
Only data obtained while the study participant was receiving the Reduced CZP Dose was 
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included in summaries of the Complete Reduced CZP Dose. For study participants who 
began treatment with the Reduced CZP Dose, this included time on the Reduced CZP 
Dose prior to first change in dosage. For study participants who began treatment with the 
Original CZP Dose, this included only time after dose reduction to the Reduced CZP 
Dose, and prior to any potential later dose escalation back to the Original CZP Dose. 
 
Selected exposure and TEAE summaries were produced on Complete Original CZP Dose and 
Complete Reduced CZP Dose in order to answer specific agency questions. Similarly, 
summaries of the proportion of PK and ADAb samples and participants that have been 
reanalyzed with the ECLIA assay were also produced with this treatment association. 
Further details regarding these displays based upon dose groups can be found in the 
respective PK, safety and efficacy analysis sections below. 
Categorical data will be presented as summary tables. A missing category will be included as 
applicable.   
Continuous variables will be summarized with the mean, standard deviation, median, 
minimum, and maximum. For CZP plasma concentrations and CRP, the geometric mean and 
geometric coefficient of variation (CV) will be presented.     
Due to shifts in visit schedules per protocol amendments that were adopted at different times 
for different sites and study participants, some visits/ time points had very few study 
participants assessed. For categorical and continuous efficacy variables presented by 
visit/time point, if the visit/time point for the Any CZP Dose group contains 19 or fewer 
study participants with non-missing data, those visits/ time points will not be displayed in the 
efficacy tables or plotted in figures for Reduced CZP Dose, Original CZP Dose and Any CZP 
Dose groups.  All information will appear in the listings. 
Mean, standard deviation, and median will be displayed to 1 more decimal place than 
collected in the case report form (CRF). Minimum and maximum values will be displayed to 
the same level of precision as collected in the CRF. Percentages will be calculated using the 
number of study participants in the relevant population or subgroup as the denominator. 
Presentation of percentages will be to 1 decimal place. Percentages will not be presented if 
the frequency count is 0. 
No formal statistical hypothesis testing will be performed. Ninety-five percent confidence 
intervals (CIs) for the percentage of responders will be calculated using the exact binomial 
method. 
For certain laboratory parameter results that are collected as either “<XX.X” or “>XX.X”, if 
descriptive statistics are calculated for the parameter, the XX.X will be used in the calculation 
but the data listing will reflect the actual reported result. 
The classification of AEs occurring on the same date as a dose change will belong to the 
period of the dose change. 
In addition, for other subgroup analyses (e.g. Baseline age group, concomitant MTX use, 
etc.), data will be generally presented by the specified subgroups pooling across all weight 
groups (with the exception of PK analyses which are specified in the corresponding sections).  
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3.2 
General study level definitions 
3.2.1 
Analysis time points 
The analysis time points of interest are detailed in Table 2‒2. Safety assessments will also be 
done at the Final Visit 12 weeks after the final dose of CZP. 
For study participants who withdraw prior to the last time point for the particular analysis 
being conducted (ie, Week 16, Week 24, other interim analysis, Final), data recorded at the 
Early Discontinuation/EOT Visit will be assigned to what would have been the next 
scheduled visit, unless unavailable or otherwise specified, dependent on which visit schedule 
the study participant is following. This re-assignment should be based upon the study day 
(relative to the baseline visit date) and also keeping in mind the +/- 3-day window into which 
visits fall. These data will be included in the summaries of the assigned visit and the “Early 
Discontinuation/EOT” Visit if applicable. For efficacy data, the Early Discontinuation/EOT 
Visit will not be summarized and only the re-assigned visit will be included in the summary 
tables. Note that data from the Early Discontinuation Visit or EOT will be listed as “Visit X 
(Week Y)/ED” or “Visit X (Week Y)/EOT” where the X was the re-assigned visit number 
and Y was the re-assigned week number in all safety and efficacy data listings as applicable. 
3.2.2 
Relative day 
Relative day of an event or assessment will be included in data listings and will be calculated 
as follows: 
Relative day 1 is the date of first CZP administration. 
Relative day of date X = date X - Date of first CZP administration+1 day if date X is on or 
after date of first CZP administration. 
Relative day of date X = date X - Date of first CZP administration if date X is before date of 
first CZP administration. 
Relative days before first administration of CZP will have the prefix “-“. 
Relative day after last dose will have the prefix “+”,and will be calculated from the date of 
last CZP administration (date X - date of last CZP administration). Relative day will not be 
calculated when any part of a corresponding date is missing,and will not be included in 
corresponding tables and listings. 
3.2.3 
Medications 
The UCB study physician will review a listing of all medications and flag those which are 
steroids, DMARDs, anti-TNFs, NSAIDs, Cox 2 inhibitors, analgesics, opioids, experimental 
medications, vaccines, etc. This flagging is then used to generate various medication tables. 
3.2.4 
Final Visit 
Final visit is defined as the visit conducted 12 weeks after the last dose of study medication. 
Most efficacy variables state that the Final Visit data will not be included in table summaries; 
the data will be included in study participant data listings. 
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3.2.5 
Week 24 
Week 24 is defined as the visit labeled as Week 24 or Visit 10 in the data. 
3.2.6 
Entire treatment period 
The entire treatment period is the same as the entire exposure period which includes all data 
while the study participant is taking study medication. 
3.3 
Definition of Baseline values 
The Baseline value for all variables will be the last non-missing pre-treatment measurement. 
The last non-missing pretreatment measurement will generally be the Baseline (Week 0) 
visit, but could be the Screening Visit if no Baseline value was obtained or an unscheduled 
Visit that occurs prior to first dose.  For study participants enrolled on the Original CZP Dose 
or Reduced CZP Dose, Baseline is the last non-missing pre-treatment measurement prior to 
the initial dose on the Original CZP Dose or Reduced CZP Dose. 
The change from Baseline will be calculated as the difference between the post-Baseline 
value and last non-missing pre-treatment measurement. Change from Baseline will only be 
calculated if a valid Baseline value is available. 
3.4 
Protocol deviations 
Important protocol deviations will be pre-defined and data cleaning meetings will be held on 
an ongoing basis to review the important protocol deviations.  At these data cleaning 
meetings, protocol deviations from the Clinical Trial Management System (CTMS) as well as 
those generated programmatically will be reviewed by the study team in order to flag those 
that are important. 
In addition, protocol deviations related to the impact of the global pandemic of coronavirus 
disease 2019 (COVID-19) will be documented.   
Study participants, if taking CZP Q2W, should be dosed 9 to 19 days from the previous 
dosing; if taking CZP Q4W, study participants should be dosed 23 to 33 days from the 
previous dosing. Study participants who are taking CZP Q2W, if they have instances where 
they take their study medication > 42 days from the last dosing, or for those who are taking 
CZP Q4W, if they have instances where they take their study medication > 84 days from the 
last dosing, these instances will be flagged as important protocol deviations.  For study 
participants not in derived CRM and taking CZP Q2W, gaps less than 9 days or >19 to 42 
days will be considered as protocol deviations. For study participants not in derived CRM 
and taking CZP Q4W, gaps less than 23 days or >33 to 84 days will be considered as protocol 
deviations. 
3.5 
Exclusion of PK data points 
Exclusion of specific PK data points will be done for that CZP plasma concentration data 
presented in the subset of tables and figures where geometric means are calculated and 
displayed.  These exclusions will not occur in the CZP plasma concentration data presented 
in spaghetti plots or individual profile figures.  The reasons why CZP plasma concentration 
data points may be excluded are the following:  
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• Study participant taking an incorrect treatment or dose, 
• Study participant’s discontinuation of CZP, 
• Study participant being in derived CRM (and not taking CZP), 
• Study participant having deviations where CZP dosings occur outside the scheduled CZP 
dosing window, and 
• Study participant is procedurally non-compliant, in not having plasma concentration 
samples taken at the appropriate time points. 
 CZP plasma concentration data that is excluded due to the above reasons will be flagged on 
the analysis PK dataset.  The flagging will allow the data to be excluded from geometric 
mean calculations which could be more affected by instances of treatment and procedure 
non-compliance.   
3.5.1.1 
Rules for exclusions of specific PK samples 
The PK sample results taken at a specific visit will be excluded from analysis for the 
following reasons: 
• If the study participant’s CZP plasma concentration sample was taken at a visit where the 
prior 2 consecutive CZP doses were missed, then the study participant’s CZP plasma 
concentration sample is excluded, 
− For study participants returning to CZP dosing, a study participant’s CZP plasma 
concentration result will be included in summaries if the prior 3 consecutive CZP 
doses are present. 
• If in the 168 days prior to the study participant’s CZP plasma concentration sample, there 
were >3 CZP doses missed, then that study participant’s CZP plasma concentration 
sample is excluded, 
− For study participants returning to CZP dosing, a study participant’s CZP plasma 
concentration result will be included in summaries if the prior 3 consecutive CZP 
doses are present. 
• If a study participant is on a Q2W CZP dosing interval, and the study participant’s CZP 
plasma concentration sample is taken <9 days or >19 days from the last CZP dosing, then 
it is excluded, 
• If a study participant is on a Q4W CZP dosing interval, and the study participant’s CZP 
plasma concentration sample is taken <23 days or >33 days from the last CZP dosing, 
then it is excluded, 
• For the Week 1 CZP plasma concentration sample, if a study participant’s sample is taken 
(too soon) <4 days after or (too late) >10 days after the Week 0 CZP dose, it is excluded, 
or 
• For the Week 17 CZP plasma concentration sample, if a study participant’s sample is 
taken (too soon) <4 days after or (too late) >10 days after the Week 16 CZP dose, it is 
excluded. 
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In addition, CZP plasma concentrations that have been analyzed outside the stability 
coverage of the ECLIA assay have also been excluded. In this latter case from all tables 
and figures and only will appear in the listings with a flag for out of stability.  
3.6 
Analysis sets 
The efficacy variables will be summarized using the Full Analysis Set (FAS). All safety and 
immunogenicity analyses will be based on the Safety Set (SS). Plasma concentration data will 
be summarized using the Pharmacokinetic Per-Protocol Set (PK-PP).   
3.6.1 
Enrolled Set 
The Enrolled Set (ES) will consist of all study participants who have given informed consent. 
3.6.2 
Safety Set 
The Safety Set (SS) will consist of all study participants in the ES who have received at least 
1 dose of study medication. 
3.6.3 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all study participants in the SS who have no more 
than one of the 6 core components missing at baseline (count of joints with active arthritis, 
count of joints with limitation of range of motion, Physician’s Global Assessment of Disease 
Activity score, CHAQ score, Parent’s Global Assessment of Overall Well-Being score and 
CRP result) for calculating PedACR30/50/70/90. 
3.6.4 
Pharmacokinetic Per-Protocol (PK-PP) Set 
The Pharmacokinetic Per-Protocol (PK-PP) Set is a subset of the SS consisting of those study 
participants who took at least 1 dose of study medication, provided measurable plasma CZP 
concentration samples (with recorded sampling date/time or for which date/time can be 
reasonably assumed and it was analyzed using the ECLIA method) on at least 1 occasion. 
The PK-PP Set will be used for presentations of plasma concentration. The PK-PP Set was 
used for the PopPK model that was described in a separate data analysis plan (DAP) to 
support the marketing application in 2024. 
3.7 
Treatment assignment and treatment groups 
All study participants received CZP as a fixed dose based on weight (Table 2‒3). Prior to 
implementation of Protocol Amendments 4 and 5 (where study participants switched to the 
reduced dose), and after Protocol Amendment 9, the Original CZP Dose was followed; study 
participants in the 10 to <20kg weight group received CZP loading doses of 100mg and a 
maintenance dose of 50mg, study participants in the 20 to <40kg weight group received CZP 
loading doses of 200mg and a maintenance dose of 100mg, and study participants in the 
>40kg weight group received CZP loading doses of 400mg and a maintenance dose of 
200mg, all Q2W.  Following implementation of Protocol Amendments 4 and 5, all CZP 
doses were reduced by 50% (Reduced CZP Dose); study participants in the 10 to <20kg 
weight group received a CZP loading dose of 50mg Q2W and a maintenance dose of 50mg 
Q4W, study participants in the 20 to <40kg weight group received a CZP loading dose of 
100mg Q2W and a maintenance dose of 50mg Q2W, and study participants in the >40kg 
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weight group received a loading dose of 200mg Q2W and a maintenance dose of 100mg 
Q2W.   
A study participant’s dosing category will only be changed after the confirmation of a weight 
change by the Investigator at a scheduled clinic visit. The study participant will receive the 
dose of the next weight category once their weight crosses the 40kg/88lb boundary or crosses 
the 20kg/44lb boundary, at a scheduled clinic visit. The study participant will continue on the 
dose of the new weight category regardless of potential decrease of the weight below the 
boundary. 
Prior to the implementation of Protocol Amendment 5, study participants were required to 
meet additional criteria prior to moving to a higher dosing category.  Specifically, the 
following changes in weight were required prior to dose increases:  (1) weight crosses the 
40kg/88lb boundary due to a weight change of >5kg (11lb) compared to their last weight 
measurement of the lower weight category (eg, a 39.0kg study participant becomes 44.1kg) 
or (2) weight crosses the 20kg/44lb boundary due to a weight change of >2.5kg (5.5lb) (eg, a 
19.0kg study participant becomes 21.6kg). 
For PK, safety and efficacy analyses, study participants will be grouped by their Baseline 
weight group. Selected analyses will also group study participants by their Baseline age 
group, concomitant MTX use, and ADAb titer (as defined in Section 8.2 ).   
Regardless of specific prescribed doses dictated by weight change during study conduct, 
study participants will be analyzed by the CZP dose group stated in Section 3.1. 
3.8 
Center pooling strategy 
For analyses, all centers will be pooled together. 
3.9 
Coding dictionaries 
Adverse events and medical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA® version 23.1) according to UCB standard operating 
procedures (SOP). Medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD version dated Sep 2020 B3) according to UCB SOPs.  
3.10 
Changes to protocol-defined analyses 
The definition for the FAS has been clarified to the following: The Full Analysis Set (FAS) 
will consist of all study participants in the SS who have no more than one of the 6 core 
components (count of joints with active arthritis, count of joints with limitation of range of 
motion, Physician’s Global Assessment of Disease Activity score, CHAQ score, Parent’s 
Global Assessment of Overall Well-Being score and CRP result) for calculating improvement 
in PedACR30/50/70/90 missing at baseline. 
The definition for the PK-PP has been clarified such that study participants in this set must 
have PK data analyzed using the ECLIA method. 
In line with 
 response, 
for the Updated Week 24 Interim Analysis only, additional analyses were added to:  
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• summarize exposure and treatment-emergent adverse events for when study participants 
were taking Complete Original CZP Dose and Complete Reduced CZP Dose.  
− Complete Original CZP Dose included all data for study participants who took 
Original CZP Dose prior to the first change in dosage as well as the data from when 
study participants increased their dosage to Original CZP after taking Reduced CZP 
Dose.  
− Complete Reduced CZP Dose included all data for study participants who took 
Reduced CZP Dose prior to the first change in dosage as well as the data from when 
study participants took Reduced CZP Dose after taking Original CZP Dose. 
• summarize the proportion of study participants and the proportion of PK samples with 
sufficient volume for re-analysis with the ECLIA method out of all PK samples initially 
analyzed with the ELISA method were summarized by Original CZP Dose, Reduced CZP 
Dose, Complete Original CZP Dose, and Complete Reduced CZP Dose. 
• summarize the proportion of study participants and the proportion of PK samples with 
sufficient volume for re-analysis with the ECLIA method out of all PK samples analyzed 
with the ECLIA method (either originally or via re-analysis) will be summarized by 
Original CZP Dose, Reduced CZP Dose, Complete Original CZP Dose, and Complete 
Reduced CZP Dose. 
• summarize the proportion of study participants and the proportion of ADAb samples with 
sufficient volume for re-analysis with the ECLIA method out of all ADAb samples 
initially analyzed with the ELISA method will be summarized by Original CZP Dose, 
Reduced CZP Dose, Complete Original CZP Dose, and Complete Reduced CZP Dose.   
• Additionally, to summarize the proportion of study participants and the proportion of 
ADAb samples with sufficient volume for re-analysis with the ECLIA method out of all 
ADAb samples analyzed with the ECLIA method (either originally or vis re-analysis) will 
be summarized by Original CZP Dose, Reduced CZP Dose, Complete Original CZP 
Dose, and Complete Reduced CZP Dose. 
In the statistical section of the protocol, it is stated that the AEs will be summarized 
separately for the periods of exposure to Original CZP Dose and the Reduced CZP Dose, in 
addition to exposure for study participants that switched from the Reduced CZP Dose to the 
Original CZP Dose following Protocol Amendment 9.  The analysis of AEs after a study 
participant changes doses will not be separately identified and presented in the Updated 
Week 24 Interim Analysis or the final analysis although the AEs that occur after dose 
changes will be summarized in the Any CZP Dose group. 
In the statistical section of the protocol, it is stated that the frequency and percentage of AEs 
reported during the first 16 weeks of study medication exposure will be summarized 
separately for the 2 CZP doses (the Original CZP Dose, the Reduced CZP Dose), and that this 
analysis will be repeated, excluding any study participants who switched from the original to 
the reduced CZP dose prior to Week 16.  The protocol-specified safety Week 16 analyses 
generated for prior interim analyses will not be included in the Updated Week 24 Interim 
Analysis or any later analyses. 
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Exposure-adjusted event rates (EAER) are added to selected TEAE tables. 
This analysis plan, for the Updated Week 24 Interim Analysis only, includes plots of CZP 
plasma concentrations, ADAb titers, and maximum PedACR response for individual study 
participants by visit. Box plots of the PK distribution at Weeks 12 and 24 stratified by 
Baseline weight group, Baseline age group, concomitant MTX use and participant ADAb 
classification will be performed as a basis of the comparison with the adult RA PK exposures 
in RA0138; this comparison of observed PK data will be covered in Appendix Section 12.1. 
Plots of PK and ADAb data were not pre-specified in the study protocol.   
It is not planned to perform a population PKPD modeling analysis of RA0043 data to explore 
the exposure-response relationship in pcJIA pediatric population for the following reasons: i) 
the purpose of the RA0043 study is to support the efficacy extrapolation to the pediatric 
population by PK matching with respect to RA adult PK, and thus the main aim of the 
analysis that will be performed by nonlinear mixed effect modeling is to characterize the PK 
in pcJIA pediatrics with precise parameter estimates; and ii) the W24 interim analyses 
performed and submitted in 2016 (BLA 125160-275) included PedACR and JADAS-71 
graphical explorations by dose which concluded that a substantial improvement of the 
PedACR and JADAS-71 responses across both doses investigated in Study RA0043 was 
observed, with no differences between these, that would support a pop-PKPD analysis. Hence 
the PK-PD Set was removed as no analyses are planned for this population. 
In the protocol it was stated that continuous efficacy endpoints would be presented using both 
last observation carried forward (LOCF) and observed case (OC) analyses. Instead, only 
observed case summaries of continuous efficacy endpoints will be presented since efficacy is 
not the primary objective of this study and little difference is expected between the two 
different analyses. 
For the Updated Week 24 Interim Analysis, the efficacy data were summarized and plotted 
up to and including Week 24; all efficacy data were included in listings. For the Final 
Analysis, all data will be summarized and plotted, by visit (week) when there are 20 or more 
study participants with non-missing data, as applicable; all efficacy data will be included in 
listings. 
For joints with limitation of motion (LOM), it was stated in the protocol that the assessment 
of LOM would be made using 69 of the 75 joints from the standard PRINTO/PRCSG 
standard joint examination. In all SAPs since SAP Amendment 2, the assessment now utilizes 
67 joints and this was according to an updated definition of LOM in the PRINTO/PRCSG 
assessment that was not available prior to the finalization of the protocol. 
For CRP, summaries present the percent change from Baseline instead of the ratio to Baseline 
to aid in interpretation. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
No adjustment for covariates will be performed. 
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4.2 
Handling of dropouts or missing data 
For all binary efficacy endpoints assessing response (PedACR30, PedACR50, PedACR70, 
PedACR90, CID, CRM), a study participant having missing data for the time point assessed 
will be conservatively counted as a non-remitter or non-responder. This will be done whether 
the data is missing, the study participant discontinued the study prior to the time point 
assessed, or the data is considered missing due to use of prohibited or rescue medication.  
For all non-missed visits, if any of the PedACR core set measures are missing then those 
scores will be considered as not having met the criteria for improvement in the PedACR30, 
PedACR50, PedACR70 and PedACR90 response analyses. PedACR30, PedACR50, 
PedACR70, and PedACR90 responses will be derived if a single core set measure is missing.  
However, if 2 or more core set measures are missing, the corresponding PedACR30, 
PedACR50, PedACR70 and PedACR90 responses will in general be treated as missing. 
Derived binary efficacy endpoints at visits affected by the use of rescue medications, or 
prohibited medications, will be treated as non-response.  See Section 6.7 for a list of 
medications which would result in all efficacy data at only the next scheduled visit (and not 
all subsequent visits) being treated as missing/non-response. Any joint receiving intra-
articular corticosteroids will be treated as missing with respect to assessments of that joint for 
3 months (91 days).   
For continuous efficacy endpoints, missing assessments will not be imputed.  
For the non-responder imputation (NRI) calculations for binary efficacy outcomes,  
• the study participants who discontinued up to and including Week 56, NRI will be 
imputed up to Week 56, 
• the study participants who discontinued after Week 56, no imputation will be performed 
after the last visit,  
• for study participants who take rescue and prohibited medications (see Section 6.6 ),  
− for visits up to and including Week 56, the outcomes are imputed as NRI up to Week 
56 
− for visits after Week 56, the outcomes are imputed as NRI if medication initiation is 
before or on Week 56 
• for the initiation of rescue, short-acting or prohibited medications after Week 56, then the 
NRI imputation is not applied. 
No further imputations of any other missing data are planned (eg, efficacy data missing at 
random). 
4.2.1 
Incomplete dates for adverse events and concomitant 
medications 
Partial adverse event (AE), medical procedures, and concomitant medication start dates will 
be imputed as follows: 
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1. If the year is unknown, the date will be imputed as the date of first intake of study 
medication if this is possible (ie, the AE end date is not prior to treatment start date). 
2. If the month is unknown, then: 
a) If the year matches the first dose date, then impute the month and day of the first dose 
date. 
b) Otherwise, assign January. 
3. If the day is unknown, then: 
a) If the month and year match the first dose date, then impute the day of the first dose 
date. 
b) Otherwise, assign ‘01’. 
Partial AE and concomitant medication stop dates will be imputed as follows: 
1. If the year is unknown, the date will not be imputed and will be assigned a missing value. 
2. If the month is unknown, then assign December. 
3. If the day is unknown, then assign the last day of the month. 
If the date of diagnosis of pcJIA is partial, it should be imputed to the most recent feasible 
date (ie, last day of the month if only day is missing, or the last day of the year if day and 
month are missing).  Duration of pcJIA will not be imputed if the year of diagnosis is 
missing. 
 
4.2.2 
Incomplete date for the last administration of study medication 
No imputation should be performed for missing study medication start dates. This field on the 
CRF should not be partial or missing. 
For partial or missing date of last dose of study medication, the following imputation rules 
will be applied for the purpose of calculating overall exposure: 
If the day is missing (but month and year available), impute the last dose date as the 
minimum of the last day of the month or the date of last contact reported on the Study 
Termination CRF; if day and month are both missing (only year available), impute the last 
dose date as the minimum of the last day of the year or the date of last contact on the Study 
Termination CRF. 
If a study participant died and has a partial or missing last administration date, the date is to 
set to the date of death. If there is a partial date of last dose and the month/year are prior to 
the month and year of the date of death, follow partial date imputation rules. 
If the last dose date is completely missing and no information could be obtained from data 
cleaning exercises, the last dose date should be imputed as the date of last contact according 
to the Study Termination CRF. A review of the data for study participants with completely 
missing last dose dates should be performed to ensure that the imputation does not result in 
an unrealistic value for duration of exposure.  
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Imputed date of last dose dates should only be used for calculation of the duration of 
exposure. The date as recorded on the CRF should be presented in study participant data 
listings (no imputed dates should be included in study participant data listings). 
4.2.3 
Handling of questionnaire data 
When relevant, the following rules will apply for analysis of (1) out of range and (2) 
ambiguous answers (i.e. invalid or unable to interpret answers) to questionnaires completed 
by study participants or parents/caregivers: 
1. In case of an out-of-range answer (i.e., an answer that does not correspond to any possible 
response proposed in the questionnaire, e. g. “?”, “I don’t know” or any value superior or 
inferior to the ones specified in the response options): the answer will be scored 
“missing”. 
However, in case the study participant or parent/caregiver selected one of the 
proposed responses but added a comment (for instance “6 +++” or “5?”), the response 
(i.e., "6" or "5") will be retained for scoring but not the comment (i.e., "+++" or "?").  
In the same way, if the study participant or parent/caregiver selected one of the 
proposed responses but added a value superior or inferior to the ones specified in the 
response options (for instance “4/5” or “-1/2” on a 5-point scale ranging from 0 to 4), 
the response corresponding to the possible responses options (i.e., "4" or "2") will be 
retained for scoring but not the values superior or inferior to the responses options 
(i.e., "5" or "-1"). 
2. In case of an ambiguous answer (i.e., multiple responses to a question allowing only a 
single response, a response marked between two allowed responses): 
a) Multiple responses to a question allowing only a single response: 
i) If half or more responses are marked (i.e., 4 responses marked on a seven-point 
scale, 3 responses marked on a 5-point scale, 2 responses to a Yes/No item…): the 
answer will be scored “missing”. 
ii) If less than half of the responses are marked: 
(1) if the responses are NOT adjacent to each other: the answer will be scored 
“missing”, 
(2) if the responses are adjacent to each other (“2/3” or “2/3/4”, for instance), the 
more severe score will be retained. 
b) If a response is marked between two allowed responses (for instance, the study 
participant marked his/her response between 2 and 3 on a 4-point scale allowing only 
responses 1, 2, 3 and 4): the nearest more severe score will be retained. 
4.2.4 
Missing adverse event intensity 
If the intensity of an AE is missing, then it will be counted as severe for analysis purposes. 
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4.2.5 
Missing adverse event relationship to study medication 
If the AE relationship to study medication is missing, then it will be counted as related for 
analysis purposes. 
4.3 
Interim analyses and data monitoring 
A futility analysis of the PedACR30 response rate was performed after all active study 
participants who enrolled prior to Protocol Amendment 9 had completed the Week 16 (Visit 
8) assessments. If less than 50% of the study population enrolled on the Reduced CZP Dose 
(Protocol Amendment 5) achieved a PedACR30 response at Week 16, the study was to be 
discontinued. The futility analysis confirmed that ≥50% of the study population enrolled on 
the Reduced CZP Dose achieved a PedACR30 response at Week 16. Given the descriptive 
nature of the data presentations, there were no statistical implications of this interim analysis. 
A further futility analysis will not be performed using the additional study participants that 
will be enrolled on the Original CZP Dose following the implementation of Protocol 
Amendment 9.  
In addition to the futility analysis, several interim analyses were planned, including interim 
analyses of PK data, and full interim analyses of PK, immunogenicity, safety, and efficacy 
endpoints, as described below. 
Interim analyses of PK data 
Per original protocol, if the pediatric plasma concentrations demonstrate that the geometric 
mean and median concentrations are below the adult 5th percentile or above the 95th 
percentile, the PK data will be used to re-evaluate the weight-based dose adjustment 
algorithm for pediatric study participants. Interim CZP plasma concentration data available at 
the time of Protocol Amendment 3 indicated that no change to the dosing algorithm was 
required. The protocol stated that if future interim analyses, which may include PopPK, 
indicate that plasma concentrations of pcJIA study participants are outside of the exposure 
range observed in previous adult RA studies, a revised pediatric dose algorithm will be 
derived. Any change in doses will require a protocol amendment prior to implementation. 
An interim analysis of PK data conducted following Protocol Amendment 3 compared CZP 
plasma concentration data from RA0043 with CZP plasma concentrations observed 
previously in adult study participants with RA. Interim analysis of CZP plasma 
concentrations was started when 6 study participants in 1 of the age groups completed 
Week 12 (Visit 7). Comparisons were made between the Week 12 geometric mean and 
median values for the pediatric and adult study participants, as well as between the individual 
pediatric data and the adult 5th and 95th percentile and minimum and maximum observed 
values. 
Based on results of this interim PopPK analysis, the doses were changed with Protocol 
Amendments 4 and 5, and the doses to be administered were reduced by 50% for all weight 
groups. This change was intended to achieve plasma concentrations similar to the effective 
concentrations observed in the previous study in adult study participants with RA (study  
C87050).  
Interim analyses of PK, immunogenicity, safety, and efficacy endpoints 
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An interim analysis of PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants that were enrolled and treated prior to implementation of 
Protocol Amendment 9 had completed the Week 24 (Visit 10) assessments, and the results 
were reported separately; this is referred to as the 2016 Week 24 interim analysis. However, 
it was then determined that there were deficiencies with the bioanalytical assay used within 
RA0043, which rendered the PK data for the PopPK analysis and simulations not up to 
current standards and FDA guidelines; therefore those data were not able to support the 
regulatory filing. 
At the time of Protocol Amendment 9, a new assay had been developed and was used to 
analyze samples from the 30 new study participants enrolled on the original dose as well as 
any old samples with sufficient volume remaining. An interim analysis, including all enrolled 
study participants, for all PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants, including those enrolled following the implementation of 
Protocol Amendment 9, completed the Week 24 (Visit 10) assessments; this is referred to as 
the Updated Week 24 Interim analysis that was used in support of the re-submission of BLA 
125160-275.   
All statistical tables, listings and figures comprising this SAP will be produced for all future 
interim and final analyses. Interim data from RA0043 may be summarized to support 
regulatory submissions, regular safety signal detection monitoring, publications and annual 
reports to regulatory agencies.  For any interim data summary, all available data as of the 
time of the clinical cut-off date will be included.  Study participants ongoing at the time of an 
interim data summary will be assumed to be treated (ie exposed) up to and including the date 
of the clinical data cut-off; efficacy data will not be imputed for the closest visit to the 
clinical snapshot date if the visit is not currently in the clinical database; composite variables 
will not be calculated if one or more components are unavailable for the visit closest to the 
clinical snapshot date. 
A Data and Safety Monitoring Board (DSMB) will periodically review all emerging safety 
data. The DSMB consists of 3 external pediatric experts and an external pharmacometrician 
and is independent of the Sponsor and Investigators. The DSMB members will be informed 
by the Drug Safety representative (or designee) of all serious adverse events (SAEs) at the 
time of expedited reporting and will review periodically all emerging safety data (eg, SAEs, 
AEs, safety laboratory data). Based on the safety data, the DSMB can recommend 
modifying/stopping the study. 
Further interim analyses may be performed at the Sponsor’s discretion as required. 
4.4 
Multicenter studies 
All centers will be pooled and no analysis by center will be performed. 
4.5 
Multiple comparisons/multiplicity 
There will be no formal hypothesis testing in this study; therefore, adjustments for 
multiplicity are not required. 
4.6 
Use of an efficacy subset of study participants 
No efficacy subset will be defined for this study. 
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4.7 
Examination of subgroups 
Most PK, safety and efficacy summaries will be presented by Baseline weight group (10 to 
<20kg, 20 to <40kg, and ≥40kg). For some safety and efficacy endpoints, such as 
PedACR30, PedACR50, PedACR70, PedACR90 and incidence of treatment-emergent AEs 
(TEAEs), results will also be presented by the subgroups as listed below (at times, pooling 
across all baseline weight groups): 
• Baseline age group:  
− 2-<6 years 
− 6-<12 years 
− 12-17 years 
• ADAb titer classification (defined in Section 8.2 using RA0043 data): ):  
− >= 0 to <= Quartile 1 
− > Quartile 1 to <= Quartile 2 (Median) 
− > Quartile 2 (Median) to <= Quartile 3 
− > Quartile 3 
− Missing 
• Concomitant MTX use (distinct from Baseline MTX use presented in Section 6.1 and 
defined as any concomitant MTX use during the Treatment Period):  
− With Concomitant MTX Use 
− Without Concomitant MTX Use 
• Gender 
− Female 
− Male 
• Race 
− White 
− Non-white 
For subgroup analyses of incidence of ADAb formation and CZP plasma concentrations, 
results will also be presented by Baseline age group. In addition, summaries will be provided 
by ADAb titer classification, ADAb participant status classification (defined in Section 8.2), 
and concomitant MTX use group in combination with Baseline weight group.  
As specified in Section 3.3, Baseline for all subgroup analyses will always be the original 
Baseline (ie, prior to the 1st CZP Dose in this study). 
In addition, selected outputs will only be summarized for the Any CZP Dose as specified in 
each relevant section. 
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5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Study participant disposition 
The number of screened study participants, and reasons for screen failure, will be 
summarized for all screened study participants. 
The number and percentage of study participants who were treated, and who discontinued 
from the study, along with the discontinuation reasons, will be summarized for the Safety Set 
by CZP Dose (Reduced, Original and Any) and Baseline weight group as well as by CZP 
Dose and ADAb titer classification; because the study was closed, every ongoing study 
participant is discontinued from the study.  For the Week 16, the number of study participants 
completing Week 16 was added. For the Updated Week 24 Interim Analysis, the number of 
study participants completing Week 24 was added. For the Final Analysis, the number of 
study participants completing Week 24 and Week 48, respectively, will be added. The 
disposition of study participants in their initial dosing phase, reduction phase and escalation 
dosing phase of the study will also be presented. The number of study participants in each 
analysis set will be presented.  
Discontinuations due to AEs will be summarized separately for the SS, and will be provided 
for the Reduced CZP Dose, Original CZP Dose, and Any CZP Dose groups. 
The number and percentages of study participants impacted by COVID-19 will be presented 
for overall and by impact visit, for any reason for all study participants in the SS.  This data 
will be presented in study participant data listings. 
Study participant disposition details will be listed, along with a listing of visit dates per study 
participant. A listing of analysis sets per study participant will also be presented.   
5.2 
Protocol deviations 
The number and percentage of study participants with important protocol deviations will be 
summarized by type for the SS for the Reduced CZP Dose, Original CZP Dose, and Any CZP 
Dose. All important protocol deviations will also be listed. 
Note that PK sample exclusion will be implemented due to certain protocol deviations; see 
Section 3.5. Study participants with at least one PK data exclusion from scheduled visits are 
summarized and listed. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
All summaries of demographics and Baseline characteristics will be provided for the SS; 
selected summaries as specified below will also be summarized for the PK-PP set.  
6.1 
Demographics 
Demographics will be summarized for the SS and the PK-PP Set for the Reduced CZP Dose, 
Original CZP Dose, and Any CZP Dose groups. The following continuous variables will be 
summarized by Baseline weight group and ADAb titer classification: age (years), weight 
(kg), height (cm), body surface area (BSA) and body mass index (BMI) (kg/m2) at Baseline. 
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The following categorical variables will be summarized by Baseline weight group and ADAb 
titer classification: gender (male, female), racial group (American Indian/Alaskan Native, 
Asian, Black, Native Hawaiian or Other Pacific Islander, White, Other/Mixed), ethnicity 
(Hispanic or Latino, Not Hispanic or Latino), Country (Argentina, Brazil, Canada, Chile, 
Mexico, Russia, and USA), Baseline age group (2 to 5 years, 6 to 11 years, and 12 to 17 
years), Baseline MTX use group (with, without) and Concomitant MTX Use (with, without). 
Demographics information will be listed. 
6.2 
Other baseline characteristics 
Baseline characteristics described in this section will be summarized for the SS and the PK-
PP Set for the Reduced CZP Dose, Original CZP Dose, and Any CZP Dose groups. Time 
since first diagnosis of pcJIA (or onset of signs and symptoms consistent with a diagnosis of 
pcJIA for those enrolled after Protocol Amendment 3) will be summarized in years. The time 
will be calculated as the duration from the date of first diagnosis of pcJIA to Baseline (Week 
0 [Visit2]); time since diagnosis will not be calculated when date of diagnosis is missing. The 
number and percentage of study participants with a history of each of the following pcJIA 
categories will also be summarized: 
• Polyarthritis rheumatoid factor-positive 
• Polyarthritis rheumatoid factor-negative 
• Extended oligoarthritis 
• Juvenile psoriatic arthritis 
• Enthesitis-related arthritis 
Other baseline characteristics information will be listed. 
6.3 
Medical history and concomitant diseases 
Medical history excluding pcJIA will be summarized by MedDRA® System Organ Class 
(SOC) and Preferred Term (PT) for Reduced CZP Dose, Original CZP Dose, and Any CZP 
Dose, and will include the number and percentage of study participants with each PT present.  
Medical history, JIA history and a glossary of medical history conditions will be listed. 
6.4 
Prior and concomitant medications 
Prior medications include any medications that started prior to the start date of study 
medication, and also include any medications that continue post-Baseline. Past medications 
are a subset of prior medications and include prior medications with a stop date before the 
date of first study medication administration. Concomitant medications are medications taken 
at least one day in common with the study medication dosing period. For Cimzia, the dosing 
period is from the date of first dose up to (but not including) 14 days Q2W (or 28 days if 
Q4W) post last dose if a study participant discontinued early or at end of treatment per 
protocol. For ongoing study participants, the dosing period is from the date of first dose up to 
the data cutoff date in interim analyses.  Thus a concomitant medication is any medication 
whose start date is prior to the date of last study medication administration + 14 days Q2W 
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(or +28 days if Q4W) or data cutoff date, and whose stop date is either missing, or on or after 
the date of first study medication administration. 
All prior medications will be summarized by anatomical therapeutic chemical (ATC) 
classification level 3 (Pharmacological Subgroup) and WHO-DD generic name. The number 
of DMARDs stopped prior to Baseline and not re-initiated during the study will be assessed 
and summarized. For those study participants with these stopped DMARDs, the WHO-DD 
generic name will be summarized.  These summaries will be provided for the SS for the 
Reduced CZP Dose, the Original CZP Dose and the Any CZP Dose. 
Concomitant medications will be summarized for all medications, and separately for 
DMARDs, systemic corticosteroids, and intra-articular corticosteroid injections. DMARDs 
and corticosteroids will be identified through ATC codes and medical review. Concomitant 
medications will be summarized by ATC level 3 and WHO-DD generic name. All summaries 
of concomitant medications will be provided for the SS for the Reduced CZP Dose, Original 
CZP Dose, and Any CZP Dose groups. 
Listings of all prior and concomitant medications will be provided as well as a glossary of the 
concomitant medications. 
 
Medications related to triamcinolone with the following WHO-DD generic names will be 
grouped and appear in summaries as "Triamcinolone" with the ATC3 level label of "UCB 
Triamcinolone ATC3": triamcinolone, triamcinolone acetonide, triamcinolone hexacetonide, 
triamcinolone acetate, triamcinolone diacetate, triamcinolone acetonide dipotassium 
phosphate. 
 
Medications related to prednisone with the following WHO-DD generic names will be 
grouped and appear in summaries as "Prednisone" with the ATC3 level label of "UCB 
Prednisone ATC3": prednisone, prednisolone, prednisolone acetate, prednisolone sodium 
phosphate, methylprednisolone, methylprednisolone acetate. 
 
Medications related methotrexate with the following WHO-DD generic names will be 
grouped and appear in summaries as "Methotrexate" with the ATC3 level label of "UCB 
Methotrexate ATC3": methotrexate, methotrexate sodium. 
6.5 
Prohibited medications 
The following medications are prohibited at any time during the study: 
• 
Nonbiologic DMARDs (other than MTX) and biologic DMARDs (eg, anakinra, 
rilonacept, etanercept, adalimumab, infliximab, golimumab, rituximab, abatacept, 
tocilizumab, CZP other than study medication). 
• 
Any experimental (biological or non-biological) therapy (within or outside a clinical 
study). 
• 
Live and live attenuated vaccinations including, but not limited to, oral polio, chicken pox 
(varicella), measles-mumps-rubella (MMR), nasal influenza, and rotavirus. No data are 
available on the response to live vaccinations or the secondary transmission of infection by 
live vaccines in study participants receiving CZP. 
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All efficacy data collected at any assessments after the use of prohibited medications that 
could impact efficacy will be treated as non-response for binary endpoints in all analyses 
except where specifically stated otherwise.  Prohibited medication use and date of first usage 
will be determined and documented during the data cleaning meetings prior to the database 
lock. The number and percentage of study participants who used prohibited medication will 
be summarized. Prohibited medication use will also be listed.  
The +1 day rule was applied to the first usage date when considering its impact on efficacy 
endpoints. Therefore, only efficacy data with dates after the first usage date of the prohibited 
medication were impacted (using the non-responder imputation (NRI) method). 
All summaries of prohibited medications will be provided for the SS for the Reduced CZP 
Dose, the Original CZP Dose and the Any CZP Dose. Prohibited medication usage will be 
listed. 
6.6 
 Rescue medications 
Rescue medication use is defined as any initiation of treatment or increase in dose of a 
medication used to treat pcJIA (in addition to the study drug) that is considered to impact the 
efficacy analyses. In general, a study participant requiring rescue medication after first 
administration of study drug is considered as a treatment failure from that time point forward 
for the purpose of efficacy analyses. Use of some short-acting medications (detailed below) 
may result in efficacy data at the next scheduled visit being treated as non-response (for 
categorical data).   
A study participant requiring rescue medication may remain on study medication if the 
benefit/risk assessment of the study participant’s continued participation is still favorable 
based on the Investigator’s clinical assessment. 
The use of rescue medication should be specifically avoided during the first 4 months (16 
weeks) of treatment, if possible.  
The following medications are defined as rescue medication in the first 16 weeks of this 
study: 
• Initiation of MTX (if not being used at study entry), or increase of MTX above Baseline. 
• Initiation of oral corticosteroids, or increase of oral corticosteroids above Baseline. 
The following medications are defined as rescue medication  when initiated in the first 56 
weeks of the study: 
• Initiation of MTX (if not being used at study entry), and increase of MTX above 15mg/m2 
per week at any time (based upon study participant’s most recent body surface area 
[BSA] prior to an increase in MTX). 
• Initiation of oral corticosteroids, or increase to >10mg or 0.2mg/kg prednisone (or 
equivalent) per day (whichever is the smaller dose).  A study participant’s most recent 
weight prior to an increase of oral corticosteroids will be used to determine if the dosage 
increase meets the criterion. 
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BSA will be calculated using Mosteller’s formula (Mosteller, 1987):  
3600
(kg)
weight 
 
(cm)
height 
)
(m
BSA 
2

=
    
The following medications are defined as rescue medication when initiated at any time up to 
Week 56 during the study: 
• Injection of intra-articular (ia) corticosteroids into more than 2 joints at a single time 
point. 
• Injection of intra-articular (ia) corticosteroids into the same joint more frequently than 
3 times in a 12-month (365 day) period.  When such cases occur, the fourth injection 
within 12 months will be considered the time point at which rescue medication was 
initiated for the study participant. 
• Intravenous (iv) corticosteroids (any dose), if not used for stress dosing for the purposes 
of surgery. 
• Intramuscular (im) corticosteroids. 
Any joint injected with ia corticosteroids will be excluded from the efficacy analysis for a 
period of 3 months (91 days). 
In all cases, any medications recorded in the database will be classified as rescue medication 
only when pcJIA is listed as the indication for that medication. Rescue medication use and 
date of first usage will be confirmed during the data cleaning meetings prior to the database 
lock. Generally, the +1 day rule was applied to the first usage date when considering its 
impact on efficacy endpoints. Therefore, only efficacy data with dates after the first usage 
date of the rescue medication were impacted (using the non-responder imputation (NRI) 
method). The number and percentage of study participants who used rescue medication up to 
the Week 16 visit and after the Week 16 visit will be summarized separately. 
All summaries of rescue medications will be provided for the SS for the Reduced CZP Dose, 
the Original CZP Dose and the Any CZP Dose. All rescue medication will be listed.  
6.7 
Short-acting medications 
Use of the following medications, which are not rescue medications, only results in efficacy 
data at the next scheduled visit being treated as missing/non-response: 
• Higher than Baseline dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and 
cyclooxygenase-2 (COX-2) inhibitors, including as needed (PRN) use within 72 hours 
prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
• Higher than Baseline dose of analgesics or opioids including PRN use within 48 hours 
prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
• Any increase in dose of oral corticosteroids within 7 days prior to scheduled study visit 
(Note: The increase has to be higher than baseline). 
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All medication data resulting in efficacy data being treated as missing/non-response will be 
flagged in the concomitant medication listing. 
6.8 
Medical procedure history and concomitant medical 
procedures 
All medical procedures, in history or concomitant, will be presented in data listings.  The 
historical procedures with no start date will be assigned to Reduced CZP dose (for those 
study participants who started the study taking Reduced CZP) or Original CZP dose (for 
those study participants who started the study taking Original CZP). 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Compliance with study drug administration will be based upon comparing the actual number 
of injections administered Ninj.actual with the expected number of injected administered 
Ninj.expected. If a study participants is in derived CRM and is not dosed, then no doses are 
expected for the compliance calculation. Since study participants are dosed on a Q2W or 
Q4W schedule, the week number of the visit is used to identify weeks where doses are 
expected starting with Week 0 (Baseline). 
𝐶𝑅=
𝑁 𝑖𝑛𝑗. 𝑎𝑐𝑡𝑢𝑎𝑙
𝑁 𝑖𝑛𝑗. 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 
Descriptive statistics will be presented for the compliance ratio for the SS. Total number of 
CZP administrations expected differs depending on the loading phase or maintenance phase 
as well as depends on the different dosing scheduling of the 3 different weight groups. For 
example, in the Original CZP Dose, a study participant is expected to receive 3 loading CZP 
administrations and then a maintenance dose of CZP Q2W through the Early 
Discontinuation/EOT Visit, with the exception of following implementation of Protocol 
Amendment 4; study participants in the 10 to <20kg weight group change from Q2W to a 
maintenance dose of CZP Q4W.  
In addition, a study participant could change dose (or frequency of dosing if in 10-20kg 
group) if a study participant crossed into a new weight group, which is considered in the 
above expected calculations of number of CZP administration If a study participant crossed 
into the 20 to <40kg weight group, the calculations are updated to reflect the weight change. 
Note that the dose reduction of ongoing study participants following Protocol Amendment 4 
is considered in the calculations. Note also the dose escalation of ongoing study participants 
following Protocol Amendment 9 is considered in the calculations.  
For the Original CZP Dose and Reduced CZP Dose groups, treatment compliance is 
calculated from the first dose of CZP, for the entire time the study participant is taking study 
medication up to the dose change. For the results presented for Any CZP Dose, treatment 
compliance is calculated for the entire time the study participant is taking CZP from first dose 
until the last dose.  
The ratios of compliance will be summarized as a continuous variable and categorically (eg. 
0 - <0.80, 0.8 - 1.0 and >1.0). Treatment compliance will be summarized and listed for the SS 
for the Reduced CZP Dose, Original CZP Dose, and Any CZP Dose for the final analysis; for 
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the Updated week 24 Interim Analysis, treatment compliance was summarized and listed for 
the SS for the Reduced CZP Dose and Original CZP Dose. 
8 
PHARMACOKINETICS AND IMMUNOLOGICAL 
PROCEDURES  
All study participants enrolled following Protocol Amendment 9 will have plasma CZP 
concentrations and anti-CZP antibodies analyzed using the ECLIA methods. In addition, PK 
and ADAb samples (for which sufficient volume is available) collected in this study prior to 
Protocol Amendment 9, will be analyzed with the ECLIA methods. 
Data from the ECLIA methods, that are within the stability coverage of the assay, will 
constitute the study’s main PK and ADAb evaluations; all reported ECLIA assay results will 
be listed.  As such, PK and ADAb data generated with the original ELISA methods will be 
reported only in study participant listings. 
8.1 
CZP plasma concentrations  
Only CZP plasma results analyzed using the ECLIA method will be summarized using the 
participants in the PK-PP set. CZP plasma concentrations are measured at Baseline, Weeks 1, 
4, 12, 16, 17, 24, 32, 40, 48, every 24 weeks thereafter, the Early Discontinuation/EOT Visit, 
and the Final Visit; for study participants enrolled prior to Protocol Amendment 8, samples 
were not collected after implementation of Protocol Amendment 8. CZP plasma 
concentrations will be summarized by CZP dose (Original CZP Dose, Reduced CZP Dose) 
using geometric means, 95% CIs for the geometric mean, geometric CV, and the median, 
minimum and maximum concentrations.  
The geometric CV will be calculated using the following formula: 
, 
where SD=standard deviation from the log-transformed data. 
For the two CZP Dose groups, summaries at all available visits and plots of plasma 
concentration results will be produced separately by Baseline weight group, Baseline age 
group, ADAb participant status classification, ADAb titer classification (see Section 8.2) and, 
concomitant MTX use in combination with Baseline weight group.  
Line-plots will be produced to summarize geometric mean (+/- 95% CI) plasma concentration 
over time.  On each plot there will be separate plot lines for each subgroup category as 
described above.  Plasma concentration will be plotted on both linear and semi-logarithmic 
scales.  
In addition, spaghetti plots of CZP plasma concentrations over time will be produced for 
individual study participants, separately for each CZP dose group. Plots will be provided by 
Baseline age group, Baseline weight group, concomitant MTX use in combination with 
Baseline weight group. In each plot, different symbols/colors will be used to identify 
subgroup categories.    
Concentrations below the limit of quantification of 320.0 ng/mL (0.32μg/mL) (BLQ) will be 
replaced by the LLOQ divided by 2 for the calculation of descriptive statistics. The geometric 
100
*
1
)
exp(
(%)
2 −
=
SD
geoCV
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mean and CV% will be derived when at least two-thirds of the concentrations at a certain 
visit are above the LLOQ and not missing. A minimum of 3 values are required to calculate 
summary statistics. If only 2 values are available then these should be presented as the 
minimum and maximum with other descriptive statistics reported as missing (“-“) When the 
mean value includes one or more replaced BLQ values then a footnote should be included to 
say “contains one or more BLQ value replaced by half the LLOQ value”. If the criteria are 
not met, only the maximum and minimum values will be shown. Similarly, the 95% CI of the 
geometric mean will be calculated if at least 5 samples are available at a time point.  
All summaries will be provided for the PK-PP Set.  All plasma concentration data will be 
listed. Concentrations should be listed to the same number of significant figures supplied by 
the bioanalytical laboratory. For listings concentrations below the limit of quantification 
should be reported as BLQ (below the limit of quantification). 
8.1.1 
ECLIA vs ELISA samples 
In line with 
 response, 
the proportion of study participants and the proportion of PK samples with sufficient volume 
for re-analysis with the ECLIA method out of all PK samples initially analyzed with the 
ELISA method were summarized for the Updated Week 24 Interim analysis only. 
First, the number and percentage of study participants with at least one PK sample re-
analyzed using the ECLIA method (after previous analysis using the ELISA method) were 
presented.  For this percentage, the denominator is the number of study participants with at 
least one non-missing PK result from the ELISA method, and the numerator is the number of 
study participants with at least one non-missing PK result from the ECLIA method that had 
also been analyzed with the ELISA method previously. (Below LLOQ is considered a non-
missing result.) 
Second, the number and percentage of post-baseline PK samples that were re-analyzed using 
the ECLIA method (after previous analysis using the ELISA method) were presented. For 
this percentage, the denominator is the number of post-baseline PK samples with non-missing 
ELISA results. The numerator is the number of post-baseline PK samples with non-missing 
ECLIA results where the same PK sample had previously been analyzed using the ELISA 
method. (Below LLOQ is considered a non-missing result.)  
Additionally, the proportion of study participants and the proportion of PK samples with 
sufficient volume for re-analysis with the ECLIA method out of all PK samples analyzed 
with the ECLIA method (either originally or via re-analysis) were summarized. 
First, the number and percentage of study participants with at least one PK sample re-
analyzed using the ECLIA method (after previous analysis using the ELISA method) were 
presented.  For this percentage, the denominator is the number of study participants with at 
least one non-missing PK sample that was analyzed using the ECLIA method (either 
originally or via re-analysis).  The numerator is the number of study participants with at least 
one non-missing PK result from the ECLIA method for a sample that had also been analyzed 
with the ELISA method previously. Also, the number and percentage of study participants 
that did not have any PK sample re-analyzed with the ECLIA method were presented. The 
denominator is the same, but the numerator is the number of study participants for whom all 
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non-missing PK results obtained using the ECLIA method were on samples that had never 
been analyzed using the ELISA method. (Below LLOQ is considered a non-missing result.)  
Second, the number and percentage of post-baseline PK samples that were re-analyzed using 
the ECLIA method (after previous analysis using the ELISA method) were presented.  For 
this percentage, the denominator is the number of non-missing post-baseline PK results that 
were obtained using the ECLIA method (either originally or via re-analysis). The numerator 
is the number of those non-missing post-baseline PK results that were obtained by re-analysis 
with the ECLIA method, after having also been analyzed by the ELISA method previously. 
Also, the number and percentage of those post-baseline samples that were not re-analyzed 
with the ECLIA method (out of those analyzed with ECLIA method) were presented. The 
denominator is the same, but the numerator is the number of those non-missing post-baseline 
PK results for samples that were only ever analyzed using the ECLIA method. (Below LLOQ 
is considered a non-missing result.) 
All summaries were provided for the Safety Set and presented for Original CZP Dose, 
Reduced CZP Dose, Complete Original CZP Dose and Complete Reduced CZP Dose by 
baseline weight. 
8.2 
Anti-CZP antibodies 
Immunogenicity will be assessed through listing of individual results by study participant and 
summary tables and graphs for data generated with the ECLIA method only for the SS. 
Immunogenicity data will be related to PK (using the PK-PP set), efficacy (using the FAS) 
and safety (using the SS). All data including those results at the Final Visit will be used for 
analyses for the entire study. 
Anti-drug antibodies will be assessed by a three-tiered approach: screening (positive or 
negative screen), confirmatory (positive or negative immuno-depletion) and titer assays, 
using ECLIA methods. Cut points will be determined during assay validation and used by the 
bioanalytical laboratory to determine the status of ADAb in the test samples as described in 
Table 8‒1. 
Table 8‒1: 
ADAb status at sample level 
ADAb positive 
(ADAb+) 
Sample values that are ‘positive screen’ and ‘positive immuno-
depletion.’ 
ADAb negative 
(ADAb-) 
Sample values that are either ‘negative screen’ or ‘positive screen’ and 
‘negative immuno-depletion’ if corresponding drug levels are equal or 
below the validated drug tolerance limit of the assay allowing detection 
of 100 ng/ml ADAb positive control or limit dictated by the ADAb assay 
and project needs (e.g. 250 ng/ml positive control). 
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Table 8‒1: 
ADAb status at sample level 
ADAb 
inconclusive 
Sample values that are either ‘negative screen’ or ‘positive screen’ and 
‘negative immuno-depletion’ but with corresponding drug levels above 
the validated drug tolerance limit of the assay allowing detection of 100 
ng/ml ADAb positive control or limit dictated by the ADAb assay and 
project needs (e.g. 250 ng/ml positive control). 
Missing  
Samples that were not collected per schedule or that could not be tested 
for ADAb status due to inadequate sample volume, mishandling, or 
errors in sample collection, processing, storage, etc. 
Confirmed positive samples will be titrated and the titer will be reported including the 
minimum required dilution (MRD) of the assay.    
• If the titer, for an ADAb level that is 'positive screen' and 'positive immunodepletion' 
status, is missing, then ADAb status will be considered as positive and no imputation 
rules apply for the missing titer. 
• If the ADAb level is 'positive screen' but no confirmatory result could be determined, 
then a conservative approach will be used and ADAb status will be considered as 
positive.  No imputation rules apply for the missing titer. 
 
8.2.1 
Participant ADAb classification 
Study participants from the SS will be classified based on their baseline and treatment-
emergent ADAb status (Table 8‒2). Classification will be done separately for two time 
periods of interest: (1) using the study participants’ data for the entire study treatment period 
and (2) using the study participants’ data up to and including Week 24 (to facilitate 
comparison with adult RA data from study RA0138 in the Updated Week 24 Interim 
Analysis). Baseline ADAb values are defined as the latest (not missing, not inconclusive) 
measurements up to and including the date of administration of first CZP treatment.  
Table 8‒2: 
ADAb status classification at participant level 
1. 
Baseline ADAb negative and 
treatment-emergent ADAb 
negative  
Study participants who were negative at Baseline and 
negative at all sampling points post treatment until the time 
point of interest  
 
Note: study participants with Baseline samples missing and 
negative ADAb status at all sampling points post treatment 
are included in this category because participants who are 
pre ADAb positive are expected to have ADAb positive 
samples post-dosing. 
 
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Table 8‒2: 
ADAb status classification at participant level 
2. 
Baseline ADAb negative and 
treatment-emergent induced 
ADAb positive 
Study participants who were negative at Baseline and 
positive at any sampling point post treatment until the 
timepoint of interest. This group also included study 
participants who had a missing Baseline sample with 1 or 
more positive post treatment samples. 
3. 
Baseline ADAb positive and 
treatment-emergent reduced 
ADAb negative 
Study participants who were positive at Baseline and 
negative at all sampling points post treatment until the 
timepoint of interest. 
4. 
Baseline ADAb positive and 
treatment-emergent unaffected 
ADAb positive 
Study participants who were positive at Baseline and were 
positive at any sampling point post treatment until the 
timepoint of interest with all titer values of the same 
magnitude as Baseline (i.e., less than or equal to a 
predefined fold increase from the Baseline value of 2.10 
which is defined with the validation of the assay). 
5. 
Baseline ADAb positive and 
treatment-emergent boosted 
ADAb positive 
Study participants who were positive at Baseline and were 
positive at any sampling point post treatment until the 
timepoint of interest with any increased titer values 
compared to Baseline (greater than a predefined fold 
increase of 2.10 from Baseline value which is defined 
within the validation of the assay). 
6. 
ADAb inconclusive 
Study participants who were positive at Baseline and some 
post-treatment samples until the timepoint of interest were 
missing or inconclusive, while other post-treatment samples 
until the timepoint of interest were negative.  
Note: study participants who were positive at Baseline and 
all post-treatment samples up to the timepoint of interest 
were missing or inconclusive are also included in this 
category.  
7. 
Treatment emergent ADAb 
positive 
Study participants that were classified as 2 or 5. 
8. 
Baseline treatment ADAb positive  Study participants who are positive ADAb at baseline, so 
those classified as 3, 4, 5 or 6. 
9. 
Missing 
Study participants who were negative at Baseline or 
missing their Baseline assessment, were not positive at any 
post-Baseline visit, and have at least one missing/or 
inconclusive post-treatment scheduled assessment (until the 
timepoint of interest).  
10 
ADAb positive 
Study participants who have a positive ADAb sample status 
at any timepoint (either Baseline or post dose). 
Unscheduled visits including early discontinuation visits (ED) or Final visits with missing 
results are disregarded. Thus, study participants who had missing ADAb measurements at ED 
but were ADAb negative at all other post-treatment visits will be classified in category 1 
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above . Study participants who were negative at Baseline or missing their Baseline 
assessment and whose only post-treatment ADAb assessment was at ED and was missing 
will be classified in category 9 above. Study participants who were positive at Baseline and 
whose only post-treatment assessment was at ED and was missing will be classified in 
category 6 above. Only positive data at unscheduled visits will be used for classification.   
 
Table 8‒3: 
Aid to Programming ADAb participant status category 
ADAb Participant Status Category  
 
Post-Treatment ADAb Sample Statusa 
Baseline ADAb Sample Status 
Any Positive 
All Scheduled 
Negative 
Some/ All Scheduled 
Missingb 
Missing 
2 
1 
9 
Negative 
2 
1 
9 
Positive 
4 or 5c 
3 
6 
a  Unscheduled (including withdrawal visits) with missing data disregarded. Missing data at other (scheduled) 
visits considered. 
b  And no positive ADAb samples post-treatment (including positive in either scheduled or unscheduled). 
c  Highest ADAb titer used to determine category.  
 
Post-treatment ADAb sample status categories are mutually exclusive and applied left to right. Thus 
study participants with both positive and missing post-treatment ADAb samples are considered in the 
“Any Positive” category.  
Time point of interest is the entire treatment period including SFU and the treatment period 
up to Week 24. 
8.2.2 
ADAb Titer Classification 
To further evaluate the impact of ADAb on PK, efficacy and safety, grouped ADAb titer 
categories will be defined based on ADAb quartiles (see Section 4.7) observed in the study.  
Quartiles will be calculated separately for the entire treatment period, and then for the period 
up to and including Week 24, using each study participant’s highest post-treatment ADAb 
titer (ADAb negative participants will be deemed to have zero titer levels for calculation 
purposes). If all post-baseline scheduled visit results are Negative, then the study participant 
will be assigned to the lowest titer classification (lowest quartile); unscheduled visits with 
missing results are disregarded. If a study participant doesn’t have any positive results at 
post-baseline scheduled visits and any of the results at scheduled visits are deemed missing or 
inconclusive, then the study participant will be assigned to “Missing”. 
If interpretation of the grouped titer summaries is inconclusive or results from other studies 
suggest other groupings, additional post-hoc analyses may be conducted to further 
investigate. 
Immunogenicity will be assessed through summary tables and figures and listing of 
individual results by study participant on the SS. Summaries will be by CZP dose (Reduced 
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CZP Dose, Original CZP Dose) and each of Baseline weight group, Baseline age group, and 
concomitant MTX use, unless specified otherwise.  
• All individual study participant-level ADAb results will be listed for all study 
participants. This will include the screening assay, confirmatory assay, and titer (if 
applicable). A separate listing showing CZP plasma concentrations, ADAb sample status 
classification, ADAb participant classification, ADAb titer, and ADAb titer 
classifications will be produced showing concentration and ADAb data in adjacent 
columns.  
• Number and percentage of study participants with positive, negative, inconclusive or 
missing ADAb sample status (Table 8‒1) will be summarized at each visit and overall 
and by dose (Original CZP dose, Reduced CZP Dose).  
• The number and percentage of study participants in each of the ADAb participant status 
categories (overall and up to Week 24 as defined according to Table 8‒2) will be 
summarized. Percentages for the denominator will include all the participants that have 
been classified as per Table 8‒2, so including missing /inconclusive participants.   
Prevalence and incidence: 
• Prevalence of Baseline ADAb positivity: number and percentage of study participants 
that have Baseline positive ADAb sample status, with the denominator for percentages 
defined as all participants having an evaluable (not missing, not inconclusive) Baseline 
ADAb sample.  
• Incidence of treatment-emergent ADAb positivity: number and percentage of study 
participants with either treatment boosted ADAb or treatment induced ADAb, with the 
denominator for percentages all participants except those categorized as inconclusive or 
missing (overall for the entire treatment period and then up to and including Week 24). 
8.2.3 
Time to first occurrence of treatment-emergent ADAb positivity 
Study participants will be considered to have an event at the first ADAb sampling time point 
with ADAb positive status in the entire treatment period if the participant is Baseline ADAb 
negative or first ADAb sampling time point with fold difference increase from Baseline > 2.1 
if participant is Baseline ADAb positive. Study participants who are never treatment-
emergent ADAb positive will be censored at the date of the last evaluable (not missing, not 
inconclusive) ADAb sample or on date of first CZP if no evaluable post-treatment ADAb 
samples. In case of Baseline ADAb positivity present in more than 10% of the study 
participants, the table will be produced separately for ADAb participant category 2 (induced) 
and 5 (boosted).   
• Summary tables based on Kaplan-Meier (KM) estimates will be produced.   
• Kaplan-Meier plots of time to first treatment-emergent ADAb positivity will also be 
produced separately for the CZP doses (Original CZP dose, Reduced CZP dose). All 
available data timepoints will be included. 
 
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8.2.4 
ECLIA vs ELISA samples 
In line with 
 response, 
the proportion of study participants and the proportion of ADAb samples with sufficient 
volume for re-analysis with the ECLIA method out of all ADAb samples initially analyzed 
with the ELISA method were summarized for the Updated Week 24 Interim analysis only.   
First, the number and percentage of study participants with at least one ADAb sample re-
analyzed using the ECLIA method (after previous analysis using the ELISA method) were 
presented.  For this percentage, the denominator is the number of study participants with at 
least one non-missing ADAb result from the ELISA method and the numerator is the number 
of study participants with at least one non-missing ADAb result from the ECLIA method that 
had also been analyzed with the ELISA method previously. (BLQ is considered a non-
missing result.) 
Second, the number and percentage of baseline and post-baseline ADAb samples that were 
re-analyzed using the ECLIA method (after previous analysis using the ELISA method) were 
presented separately. For the percentage of baseline and post-baseline re-analyzed ADAb 
samples, the denominator is the number of baseline or post-baseline ADAb samples with 
non-missing ELISA results, respectively. The numerator is the number of baseline or post-
baseline ADAb samples, respectively, with non-missing ECLIA results previously where the 
same ADAb sample had previously been analyzed with the ELISA method. (Below LLOQ is 
considered a non-missing result.) 
Additionally, the proportion of study participants and the proportion of ADAb samples with 
sufficient volume for re-analysis with the ECLIA method out of all ADAb samples analyzed 
with the ECLIA method (either originally or via re-analysis) were summarized. 
First, the number and percentage of study participants with at least one ADAb sample re-
analyzed using the ECLIA method (after previous analysis using the ELISA method) were 
presented.  For this percentage, the denominator is the number of study participants with at 
least one non-missing ADAb sample that was analyzed using the ECLIA method (either 
originally or via re-analyses). The numerator is the number of study participants with at least 
one non-missing ADAb result from the ECLIA method for a sample that had also been 
analyzed with the ELISA method previously.  Also, the number and percentage of study 
participants that did not have any ADAb sample re-analyzed with the ECLIA method were 
presented.  The denominator is the same, but the numerator is the number of study 
participants for whom all non-missing ADAb results obtained using the ECLIA method were 
on samples that had never been analyzed using the ELISA method. (Below LLOQ is 
considered a non-missing result.) 
Second, the number and percentage of baseline and post-baseline ADAb samples that were 
analyzed using the ECLIA method (after previous analysis using the ELISA method) were 
presented.  For this percentage, the denominator is the number of non-missing baseline or 
post-baseline ADAb results, respectively, that were obtained using the ECLIA method (either 
originally or via re-analysis). The numerator is the number of those non-missing baseline or 
post-baseline ADAb results, respectively, that were obtained by re-analysis with the ECLIA 
method, after having been analyzed by the ELISA method previously. Also, the number and 
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percentage of those baseline or post-baseline samples, respectively, that were not re-analyzed 
with the ECLIA method (out of those analyzed with the ECLIA method) were presented. The 
denominator is the same for each, respectively, but the numerator is the number of those non-
missing baseline or post-baseline ADAb results, respectively, for samples that were only ever 
analyzed using the ECLIA method. (Below LLOQ is considered a non-missing result.) 
All summaries were provided for the Safety Set and presented for Original CZP Dose, 
Reduced CZP Dose, Complete Original CZP Dose and Complete Reduced CZP Dose by 
baseline weight. 
8.3 
CZP plasma concentrations, anti-CZP antibody titers, and 
PedACR response 
The plots described in this section that include an efficacy endpoint will be generated on the 
FAS, otherwise on the PK-PPS. Individual participants plots displaying CZP plasma 
concentrations, ADAb titers, and maximum PedACR response (the highest PedACR response 
at a given visit) will be produced by visit on the same plot. At each time point, the maximum 
PedACR response at that visit will be plotted on a linear scale.  CZP plasma concentration 
will be plotted on a (natural) log scale and ADAb titer will be plotted on a log 2 scale.  CZP 
dosing and ADAb inconclusive values will be flagged in this plot. A vertical line will be 
plotted when dose was changed for the study participant. For each study participant, the 
category of ADAb participant status and demographic information at baseline (body weight 
and age) will be displayed.  
Multi-panel spaghetti plots of individual participant (natural) log CZP plasma concentration 
by visit will be produced separately for each CZP dose (Original CZP dose, Reduced CZP 
dose) and ADAb titer classification and ADAb participant classification for the PK-PPS. 
Concomitant MTX use will be shown in different line colors and CZP concentrations for 
which ADAb positive samples were positive will be plotted with a red dot.  These individual 
plots will be repeated replacing CZP plasma concentration with maximum PedACR response 
(linear scale) on the FAS. 
Scatter plots of the plasma CZP concentration at each visit with different colors/symbols 
depending on ADAb participant classification and ADAb titer classification will be produced 
separately for the doses (Original CZP Dose, Reduced CZP Dose) for the PK-PPS.  
8.4 
PopPK analyses 
Plasma concentrations will be used to build a PopPK model with the nonlinear mixed-effect 
modeling (NONMEM) software. Details of the PopPK modeling procedures will be 
described in a separate data analysis plan. This analysis was generated for the Updated Week 
24 Interim analysis only. 
9 
SAFETY ANALYSES 
All study participants in the SS will be included in the safety analyses. In addition to the 
safety summaries described below, all safety results will be listed by study participant. 
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9.1 
Extent of exposure 
Over the course of the RA0043 study, study participants follow one of 5 dosing scenarios for 
CZP exposure: 
Table 9‒1: 
Dosing periods 
Starting the study 
taking: 
1st dosing period (of 
variable length) 
2nd dosing period (of 
variable length) 
3rd dosing period (of 
variable length) 
Reduced CZP dose 
Reduced CZP (A) 
 
 
 
Reduced CZP (B) -> 
Original CZP (E) 
 
Original CZP dose 
Original CZP (F) 
 
 
 
Original CZP (G) -> 
Reduced CZP (C) 
 
 
Original CZP (H) -> 
Reduced CZP (D) - > 
Original CZP (J) 
 
The extent of exposure to study drug will be evaluated by summarizing the total amount of 
CZP received in mg and the total duration of exposure in days. Total duration of exposure 
will be calculated using this general formula as: the Date of Last Dose of study medication – 
Date of First Dose of study medication + 14 days if administration of CZP is Q2W, +28 days 
if administration of CZP is Q4W. Dosing gaps (which occur between 2 CZP doses) are not 
considered in (does not reduce) the duration of exposure calculation. 
 
Duration of exposure will be calculated as appropriate for each of the following dosing 
periods: 
A: use the general formula; 
B: Date of Escalation – Date of First Dose; 
C: Date of Last Dose – Date of Dose Reduction +14 or 28 days depending on administration 
of CZP; 
D: Date of Escalation – Date of Reduction; 
E: Date of Last Dose – Date of Dose Escalation + 14 or 28 days depending on administration 
of CZP; 
F: use the general formula: see A above 
G: Date of Dose Reduction – Date of First Dose; 
H: Date of Dose Reduction – Date of First Dose; 
J: Date of Last Dose – Date of Dose Escalation + 14 or 28 days depending on administration 
of CZP 
Duration of exposure was calculated as appropriate for each of the following CZP Dose 
groups for the Updated Week 24 Interim Analysis but will only be calculated for Any CZP 
Dose, Reduced CZP Dose and Original CZP Doze for the final analysis: 
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• Any CZP Dose: includes the exposure to all CZP doses for all treated study participants; 
the exposure period is calculated using the general formula. 
• Reduced CZP Dose: includes period of exposure to the Reduced CZP Dose for all study 
participants enrolled on the Reduced CZP dose; use the following formulas:  
− Period A - for study participants without dose escalation; and 
− Period B - for study participants with dose escalation.  
• Original CZP Dose: includes period of exposure to the Original CZP Dose for all study 
participants enrolled on the Original CZP Dose; use the following formulas:  
− Period F - for study participants without dose reduction;  
− Period G - for study participants with dose reduction and without dose escalation; and 
− Period H - for study participants with dose reduction and dose escalation. 
• Complete Reduced CZP Dose: includes all periods of exposure to Reduced CZP Dose for 
all study participants (periods A, B, C and D); use the following formulas:  
− Period A - for study participants enrolled on Reduced CZP Dose without dose 
escalation;  
− Period B - for study participants enrolled on Reduced CZP Dose with dose escalation; 
− Period C - for study participants enrolled on Original CZP Dose with dose reduction 
and without dose escalation; and 
− Period D - for study participants enrolled on Original CZP Dose with dose reduction 
and dose escalation. 
• Complete Original CZP Dose: includes all periods of exposure to Original CZP dose for 
all study participants (periods E, F, G H and J); use the following formulas:  
− Period E - for study participants enrolled on Reduced CZP Dose with dose escalation; 
− Period F - for study participants enrolled on Original CZP Dose without dose 
reduction;  
− Period G - for study participants enrolled on Original CZP Dose with dose reduction 
and without dose escalation; and 
− Period H+J - for study participants enrolled on Original CZP Dose with dose 
reduction and dose escalation.   
9.1.1 
Subject time at risk 
Subject time at risk will also be calculated. Subject time at risk represents the time a study 
participant is at risk for having an AE while taking CZP. Subject time (in days) at risk will 
generally be calculated using this general formula: (date of the last dose of study medication 
– date of the first dose of study medication + 70 days) (70 days = 5 CZP half-lives).  
However, the calculation of subject time at risk will be modified for study participants who 
change from Original CZP Dose to Reduced CZP Dose, or who dose escalate from Reduced 
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CZP Dose to the Original CZP Dose; the subject time at risk will further be modified for 
study participants who have dosing gaps > 70 days during the study – eg. meaning if a study 
participant has 100 consecutive day dosing gap, only the first 70 days will be included in the 
subject time at risk. For the period of exposure prior to a dose change, subject time at risk 
ends on the date of dose change (ie, do not add 70 days).  For the period of exposure on the 
final CZP dose for a study participant, time at risk should include the additional 70 days.  
Subject years at risk will be calculated as subject time at risk (in days) divided by 365.25. 
Subject time at risk will be calculated as appropriate for each of the following CZP dosing 
periods: 
A: use the general formula; 
B: Date of Escalation – Date of First Dose; 
C: Date of Last Dose – Date of Dose Reduction +70 days; 
D: Date of Escalation – Date of Reduction; 
E: Date of Last Dose – Date of Dose Escalation + 70 days; 
F: use the general formula; 
G: Date of Dose Reduction – Date of First Dose; 
H: Date of Dose Reduction – Date of First Dose; 
J: Date of Last Dose – Date of Dose Escalation + 70 days; 
Subject time at risk was calculated as appropriate for each of the following CZP Dose groups 
for the Updated Week 24 Interim Analysis but will only be calculated for Any CZP Dose, 
Reduced CZP Dose and Original CZP Doze for the final analysis: 
• Any CZP Dose: includes the time at risk to all CZP doses for all treated study 
participants; the time at risk is calculated using the general formula. 
• Reduced CZP Dose: includes time at risk during the exposure to the Reduced CZP Dose 
for all study participants enrolled on the Reduced CZP dose up to the first dose change; 
use the following formulas:  
− Period A - for study participants without dose escalation; and 
− Period B - for study participants with dose escalation.  
• Original CZP Dose: includes time at risk during the exposure to the Original CZP Dose 
for all study participants enrolled on the Original CZP Dose up to the first dose change; 
use the following formulas:  
− Period F - for study participants without dose reduction;  
− Period G - for study participants with dose reduction and without dose escalation; and 
− Period H - for study participants with dose reduction and dose escalation. 
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• Complete Reduced CZP Dose: includes time at risk during all periods of exposure to 
Reduced CZP Dose for all study participants (periods A, B, C and D); use the following 
formulas:  
− Period A - for study participants enrolled on Reduced CZP Dose without dose 
escalation;  
− Period B - for study participants enrolled on Reduced CZP Dose with dose escalation; 
− Period C - for study participants enrolled on Original CZP Dose with dose reduction 
and without dose escalation; and 
− Period D - for study participants enrolled on Original CZP Dose with dose reduction 
and dose escalation. 
• Complete Original CZP Dose: includes all time at risk during all periods of exposure to 
Original CZP dose for all study participants (periods E, F, G H and J); use the following 
formulas:  
− Period E - for study participants enrolled on Reduced CZP Dose with dose escalation; 
− Period F - for study participants enrolled on Original CZP Dose without dose 
reduction;  
− Period G - for study participants enrolled on Original CZP Dose with dose reduction 
and without dose escalation; and 
− Period H+J - for study participants enrolled on Original CZP Dose with dose 
reduction and dose escalation.   
 
The extent of study drug exposure will be summarized for the Reduced CZP Dose, Original 
CZP Dose, and Any CZP Dose groups. Exposure over time will be presented as follows: >0 
months, ≥6 months, ≥12 months, ≥24 months, ≥36 months, ≥48 months, ≥60 months, 
≥72months, ≥84 months, and ≥96 months.  In line with 
 
 response, the extent of study drug exposure as well as 
exposure over time were presented by Complete Original CZP Dose and Complete Reduced 
CZP Dose.  
Study medication administration will be listed. 
9.1.2 
Updated Week 24 Interim Analysis and other interim analyses 
For interim analyses such as for the SSD, DSMB and the Updated Week 24, the following 
modifications were made to more accurately calculate exposure and time at risk. 
For an interim analysis with a database cutoff date,  
• if the study participant is ongoing, the exposure calculation was database cutoff date – 
date of first dose of study medication + 1 day.  No data was presented in the analyses 
that was dated after the database cutoff date 
• if the study participant was ongoing, the time at risk calculation was database cutoff 
date – date of first dose of study medication + 1 day.    
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• if the study participant had discontinued from the study >28 days before the database 
cutoff date and had Q4W dosing at the time of study discontinuation, then the 
exposure was date of last dose of study medication – date of first dose of study 
medication + 28 days 
• if the study participant had discontinued from the study ≤28 days before the database 
cutoff date and had Q4W dosing at the time of study discontinuation, then the 
exposure was database cutoff date – date of first dose of study medication + 1 day 
• if the study participant had discontinued from the study >14 days before the database 
cutoff date and had Q2W dosing at the time of study discontinuation, then the 
exposure was date of last dose of study medication – date of first dose of study 
medication + 14 days 
• if the study participant had discontinued from the study ≤14 days before the database 
cutoff date and had Q2W dosing at the time of study discontinuation, then the 
exposure was database cutoff date – date of first dose of study medication + 1 day 
• if the study participant had discontinued from the study >70 days before the database 
cutoff date, then the time at risk was date of last dose of study medication – date of 
first dose of study medication + 70 days 
• if the study participant had discontinued from the study ≤70 days before the database 
cutoff date, then the time at risk was the database cutoff date – date of first dose of 
study medication + 1 day. 
9.2 
Adverse events 
Only treatment emergent adverse events (TEAE) will be included in the summary tables. 
Treatment emergent AEs are defined as AEs starting on or after the first administration of 
CZP and up to 70 days after the last (most recent) dose of study medication; then only the 
adverse events occurring up to 70 days after the last (most recent) dose of study medication 
will be counted as treatment emergent; all other adverse events occurring after first dose will 
not be flagged as treatment emergent. AEs that are pre-treatment or that start more than 70 
days after the last (most recent) dose of study medication will be in the listing but excluded 
from summaries. 
A glossary for the TEAE listing will detail the verbatim terms that are coded to each SOC, 
HLT, and PT. 
Treatment-related TEAEs are those with relationship to study medication of “Related” or 
“Possibly related” or those with a missing relationship.  Severe TEAEs are those with an 
intensity of “Severe” or those with a missing intensity. 
All TEAE summaries will be provided for the Reduced CZP Dose, Original CZP Dose, and 
Any CZP Dose groups. TEAEs occurring on the day of dose reduction or dose escalation, 
respectively, will be summarized in the dose groups that it appears. 
The overview of the incidence of TEAEs, overall and by Baseline weight group (10 to <20kg, 
20 to <40kg, and ≥40kg), will include the number of events and number of study participants 
and percentage of study participants with: 
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• Any TEAE 
• Any serious TEAE 
• Any treatment-related TEAE 
• Any severe TEAE 
• Any TEAE leading to permanent withdrawal of IMP 
• Any TEAE leading to discontinuation 
• All deaths 
• Any TEAE leading to death 
The overview of the incidence of TEAEs will also be presented by the following subgroups: 
• Baseline age group (2 to 5 years, 6 to 11 years, and 12 to 17 years),  
• concomitant MTX use,  
• gender, 
• race,   
• ADAb participant status classification, and 
• ADAb titer classification pooling across all Baseline weight groups.  
The incidence and event rate (per 100 subject-years) of TEAEs will be presented as follows:   
• All TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight group 
• All TEAEs by primary SOC, HLT, and PT by Baseline age group 
• All TEAEs by primary SOC, HLT, and PT by concomitant MTX use 
• All TEAEs by primary SOC, HLT, and PT by ADAb titer classification 
• All TEAEs by primary SOC, HLT, and PT by ADAb participant status classification 
• All serious TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight group 
• All TEAEs leading to study drug discontinuation by primary SOC, HLT, and PT, overall 
and by Baseline weight group 
• All TEAEs leading to death by primary SOC, HLT, and PT, overall and by Baseline 
weight group 
• Injection reaction TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight 
group, further subdivided into injection site reactions and systemic reactions, with 
systemic reactions further subdivided into acute vs. delayed systemic reactions 
The incidence of TEAEs will be presented as follows: 
• Injection reaction TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight 
group, further subdivided into injection site reactions and systemic reactions, with 
systemic reactions further subdivided into acute vs. delayed systemic reactions 
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• All TEAEs by primary SOC, PT, and intensity, overall and by Baseline weight group 
• All TEAEs by primary SOC, PT, and relationship, overall and by Baseline weight group 
• All serious TEAEs by primary SOC, PT, and relationship, overall and by Baseline weight 
group 
• All non-serious TEAEs by primary SOC, PT, and relationship, overall and by Baseline 
weight group 
• All fatal TEAEs by primary SOC, PT, and relationship, overall and by Baseline weight 
group  
• TEAEs occurring in at least 5% of study participants by primary SOC, HLT, and PT, 
overall and by Baseline weight group 
• Non-serious TEAEs occurring in more than 5% of study participants by primary SOC and 
PT, overall and by Baseline weight group 
Incidence tables summarizing TEAEs will include the number of TEAEs, number of study 
participants experiencing the TEAEs and percentage of study participants with the TEAE (all 
occurrences of the same event will be counted under the number of TEAEs but the study 
participant will only be counted once).  
For disclosure on public registries (eg, ClinicalTrials.gov), information from the incidence 
tables of TEAEs and treatment-emergent SAEs will be published. 
 
For the Updated Week 24 Interim Analysis only, in line with 
 
response, incidence tables of TEAEs were presented by 
primary SOC, HLT, and PT, overall and Baseline weight group by Original CZP, Reduced 
CZP, Any CZP, Complete Original CZP and Complete Reduced CZP doses. Also, incidence 
and event rate tables of TEAEs up to Week 24 were presented by primary SOC, HLT, and 
PT, overall and by Baseline weight group for Reduced CZP and Original CZP dose groups.  
For the final analysis, incidence tables of TEAEs will be presented by primary SOC, HLT, 
and PT, overall and by Baseline weight group by Original CZP, Reduced CZP and Any CZP 
doses. The incidence and event rate tables of TEAEs up to Week 24 will not be presented for 
the final analysis. 
Incidence and event rate tables will include the descriptive statistics on the incidence table 
but also include the exposure-adjusted incidence rate (EAIR) with associated 95% confidence 
interval, and the exposure-adjusted event rate (EAER).  
For EAIR, the numerator will be the total number of study participants experiencing a 
particular TEAE. The denominator will be 100 subject-years, ie, the total summation of 
individual subject-years at risk up to the first occurrence of the given TEAE for study 
participants with that TEAE, plus the total subject-years at risk for those study participants 
not experiencing that TEAE, divided by 100.  Details regarding calculation of subject-years 
at risk are described in Section 9.1.  EAIR will be presented with exact 95% confidence 
intervals based on the link between the chi-square distribution and the Poisson distribution 
(Ulm, 1990). 
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For EAER, the numerator will be the number of TEAEs including repeat occurrences in 
individual study participants. The denominator will be in 100 subject-years (total summation 
of individual subject-years at risk divided by 100). No confidence interval will be computed. 
Listings: 
• Individual study participant numbers experiencing a given adverse event, grouped by 
SOC, PT, intensity, and relation to study drug 
• Individual study participant numbers experiencing a serious treatment emergent adverse 
event, grouped by SOC, PT, intensity, and relation to study drug 
• Individual study participant numbers experiencing a TEAE leading to study drug 
discontinuation, grouped by SOC, PT, intensity and relation to study drug 
• Individual study participant numbers experiencing an AE leading to death, grouped by 
SOC, PT, intensity and relation to study drug 
9.2.1 
TEAEs of interest 
The following are TEAEs of interest for this study and will be summarized in incidence and 
event rate tables (ie will include the number of events, the number and percentage of study 
participants with an event, the EAIR with associated 95% CIs and the EAER) as described 
below: 
1) Serious infections, including opportunistic infections.   Serious infections will be 
summarized using the previously described All SAEs table.  No separate table is planned.  In 
addition, opportunistic infections (including tuberculosis) will be presented in a table using 
UCB-defined search criteria.     
2) Malignancies, including lymphoma. These will be presented in 2 tables using the criteria 
SMQ = “Malignant or unspecified tumours” and its subset, SMQ=”Malignant tumours”, 
respectively. 
3) Congestive heart failure.  These will be manually identified by the study physician from 
the previously described All TEAEs table.  In addition, major adverse cardiac events 
(MACE) will be presented in a table. using UCB-defined search criteria and will include fatal 
and serious non-fatal myocardial infarction, cerebrovascular events and congestive heart 
failure.     
4) Demyelinating-like disorders.   These will be presented in a table based on the 
SMQ=”Demyelination” in the TEAEs.   
5) Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leucopenia.   These 
will be presented in a table using the criteria SMQ = “Haematopoietic cytopenias” in the 
subset of SAEs. 
6) Serious bleeding events.  These will be presented in a table using the criteria SMQ = 
“Haemorrhage terms (excl laboratory terms)” in the subset of SAEs. 
7) Lupus and lupus-like illness.  These will be manually identified by the study physician 
from the previously described All TEAEs table and not tabulated separately.   
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8) Serious skin reactions (eg, Stevens-Johnson Syndrome, toxic epidermal necrosis, 
anderythema multiforme).   These will be manually identified by the study physician from the 
previously described All SAEs table and not tabulated separately.   
9) Hepatic events. These will be summarized in a table that includes all TEAEs in the 
following SMQs: Cholestasis and jaundice of hepatic origin; hepatic failure, fibrosis and 
cirrhosis and other liver damage-related conditions; hepatitis, noninfectious; liver-related 
investigations, signs and symptoms; liver-related coagulation and bleeding disturbances. 
10)Hypersensitivity reactions. These will be determined from all TEAEs that either emerged 
on the same day as or next day after the administration of study medication injection and 
summarized in a table.  The PTs are: administration site hypersensitivity, documented 
hypersensitivity to administered product, drug hypersensitivity, hypersensitivity, 
hypersensitivity vasculitis, infusion site hypersensitivity, injection site hypersensitivity, 
medical device site hypersensitivity, type II hypersensitivity, type IV hypersensitivity 
reaction. 
11) Anaphylactic reactions. These will be determined from all TEAEs that either emerged on 
the same day as or next day after the administration of study medication injection. 
Anaphylactic reactions will be summarized in a table using UCB-defined search criteria. 
Further information regarding search criteria and algorithms is provided in the guidance 
document “AEs of Interest – Cimzia Program”. 
9.2.2 
AE of special interest 
Potential Hy’s Law is an AE of special interest for this study; the definition is below.  The 
occurrence of this AE of special interest is dependent upon laboratory parameters, given that, 
the associated analysis of these AEs will be described in the Clinical laboratory evaluations 
section, PDILI paragraph in Section 9.3: 
Potential Hy’s Law, defined as ≥3xULN alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the absence of ≥2xULN 
alkaline phosphatase (ALP), with no alternative explanation for the biochemical abnormality 
(ie, without waiting for any additional etiologic investigations to have been concluded). 
Follow-up information should be reported if an alternative etiology is identified during 
investigation and monitoring of the participant. 
 
9.2.3 
Covid vaccine sensitivity analysis 
A summary of the incidence and event rate (per 100 subject-years) of TEAEs by primary 
SOC, HLT, and PT, overall and by Baseline weight group will be presented which will 
exclude TEAEs occurring up to and including 7 days from the date of covid vaccination.  The 
list of the PTs of these TEAEs to be excluded if reported with Mild or Moderate intensity are: 
Table 9‒2: 
Covid vaccination related adverse events for sensitivity analysis 
ARTHRALGIA 
INJECTION SITE INDURATION 
AXILLARY SWELLING 
INJECTION SITE PAIN 
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AXILLARY TENDERNESS 
INJECTION SITE WARMTH 
BACKACHE 
MYALGIA 
BODY TEMPERATURE INCREASED 
NAUSEA 
CHILLS 
PRURITUS 
DIARRHOEA 
RASH 
FEVER 
TENDERNESS 
HEAD DISCOMFORT 
URTICARIA 
HEADACHE 
VOMITING 
INJECTION SITE ERYTHEMA 
 
 
9.3 
Clinical laboratory evaluations 
All laboratory summaries described in this section will be provided for Reduced CZP Dose, 
Original CZP Dose, and Any CZP Dose and by Baseline weight group. All laboratory data 
will be listed. 
Descriptive statistics for observed values and change from Baseline will be presented for 
each visit for the following hematology and biochemistry parameters: 
• Hematology: RBC, hemoglobin, hematocrit, platelets, WBC, neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils. 
• Biochemistry: sodium, potassium, chloride, bicarbonate, total calcium, inorganic 
phosphorus, creatinine kinase, glucose, creatinine, uric acid, urea, total protein, albumin, 
ALP, gamma glutamyl transferase (GGT), AST, ALT, lactate dehydrogenase, bilirubin, 
and total cholesterol. 
The following urinalysis parameters will be tested locally only: pH, protein, glucose, and 
blood. If abnormalities are found from the dipstick test, microscopic analysis (WBC, RBC, 
casts, crystals, and bacteria) will be performed, and these results will be listed. A summary of 
the shift from Baseline to end of treatment will also be provided for hematology and 
biochemistry parameters. Results will be classified as low, normal, or high based on the 
normal ranges provided by the central laboratory. 
A summary of the incidence of markedly abnormal laboratory results by visit will be 
presented for hematology and biochemistry parameters.  Details of markedly abnormal values 
will be listed by study participant and parameter for hematology and biochemistry variables 
for which there is at least 1 markedly abnormal result recorded. Definitions of markedly 
abnormal values are adopted from the UCB Therapeutic Area: Central Nervous System : 
Clinical and Laboratory Markedly Abnormal (MA) Values and are given below Table 9‒3 for 
markedly abnormal hematology values and Table 9‒4 for markedly abnormal biochemistry 
values).  
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Table 9‒3: 
Definitions of Markedly Abnormal Hematology Values 
Parameter (Unit) 
Age Range 
Abnormal Definition 
Low 
High 
Hematocrit (%) 
<2y 
≤27 
>45 
2y-<18y 
≤29 
>47 
≥18y 
≤85% of LLN 
≥115% of ULN 
Hemoglobin (g/L) 
<2y 
≤90 
>150 
2y-<18y 
≤95 
>160 
≥18y 
≤85% of LLN 
≥115% of ULN 
WBC/Leukocytes 
(G/L) 
<12y 
<3.5 
>15.0 
≥12y 
<3.0 
>12.0 
Neutrophils Absolute 
(G/L) 
>1m 
<1.5 
NA 
Lymphocytes (%) 
<6m 
≤30.0 
NA 
6m-<6y 
≤22.0 
NA 
6y-<18y 
≤12.0 
≥80.0 
≥18y 
≤10.0 
≥80.0 
Basophils (%) 
>1m 
NA 
≥3.0 
Eosinophils (%) 
>1m 
NA 
≥10.0 
Monocytes (%) 
>1m 
NA 
≥20.0 
Platelets (G/L) 
>1m 
≤100 
>600 
RBC/Erythrocytes 
(T/L) 
<2y 
<3.0 
NA 
≥2y 
<3.5 
NA 
y=year; m=month; LLN=lower limit of normal; ULN=upper limit of normal. 
 
 
Table 9‒4: 
Definitions of Markedly Abnormal Biochemistry Values 
Parameter (Unit) 
Age Range 
Abnormal Definition 
Low 
High 
AST(SGOT) (U/L) 
<14y 
NA 
>180 
≥14y 
NA 
>144 
ALT(SGPT) (U/L) 
1y-<18y 
NA 
>90 
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Table 9‒4: 
Definitions of Markedly Abnormal Biochemistry Values 
Parameter (Unit) 
Age Range 
Abnormal Definition 
Low 
High 
≥18y 
NA 
>123 
Alkaline Phosphatase 
(U/L) 
<4y 
NA 
>690 
4y-<10y 
NA 
>834 
10y-<17y 
NA 
>1174 
≥18y 
NA 
>432 (F) 
>933 (M) 
GGT (U/L) 
<6m 
NA 
>522 
6m-<1y 
NA 
>279 
1y-<13y 
NA 
>66 
13y-<18y 
NA 
>126 
≥18y 
NA 
>255 
Total Bilirubin 
(umol/L) 
>1m 
NA 
≥25.656 
Total Protein (g/L) 
2m-<1y 
<30 
>100 
≥1y 
<43 
>100 
Albumin (g/L) 
<1y 
<16 
>60 
≥1y 
<24 
>70 
Urea (mmol/L) 
<1y 
NA 
>7.014 
≥1y 
NA 
>10.02 
Creatinine (umol/L) 
1y-<10y 
NA 
>79.56 
10y-<16y 
NA 
>123.76 
≥16y 
NA 
>141.44 
Calcium (mmol/L) 
<1y 
<1.725 
>3.05 
1y-<18y 
<1.85 
>2.925 
≥18y 
≤1.975 
≥2.775 
Lactate dehydrogenase 
(LDH) (IU/L) 
2-17y 
 
>1300 
Phosphorus (mmol/L) 
<1y 
<0.5814 
>2.6486 
≥1y 
<0.5814 
>2.3902 
Potassium (mmol/L) 
<1y 
<3.0 
>6.5 
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Table 9‒4: 
Definitions of Markedly Abnormal Biochemistry Values 
Parameter (Unit) 
Age Range 
Abnormal Definition 
Low 
High 
≥1y 
<3.0 
>5.8 
Sodium (mmol/L) 
>1m 
≤130 
≥150 
Glucose (mmol/L) 
>1m 
<2.775 
>9.99 
Total Cholesterol 
(mmol/L) 
1y-<18y 
NA 
>6.475 
≥18y 
NA 
>7.77 
Uric Acid (umol/L) 
<1y 
NA 
>457.996 
1y-<13y 
NA 
>386.62 
13y-<18y 
NA 
>511.528 
≥18y 
NA 
>404.464 (F) 
>571.008 (M) 
Creatine Kinase (CPK) 
(IU/L) 
2-17y 
 
>600  
y=year; m=month; F=female; M=male. 
Reference: Based on CTCAE version 5.0  
PDILI IMP discontinuation criteria as outlined in the Appendix of Protocol Amendment 9 
will be evaluated at all laboratory assessments, for all study participants. The number and 
percentage of study participants meeting PDILI criteria will be presented.  The following 
criteria will be presented: 
• AST or ALT ≥ 3xULN and Total Bilirubin < 2xULN 
• AST or ALT ≥ 3xULN and Total Bilirubin ≥ 2xULN 
• AST or ALT ≥ 3xULN and Total Bilirubin ≥ 2xULN and Alkaline Phosphatase < 2xULN 
(Hy’s Law if all criteria met at the same visit) 
• AST or ALT ≥ 5xULN 
Any data that meets the PDILI criteria or is captured regarding PDILI will be listed. Any data 
that is captured as being a suspected hepatic event will be listed. 
A listing of when blood and urine samples were taken as well as serum pregnancy tests were 
performed will also be produced. 
9.4 
Vital signs, physical findings, and other observations related 
to safety 
9.4.1 
Vital Signs 
Vital signs will be measured within approximately 15 minutes prior to dosing, and in addition 
(following implementation of Protocol Amendment 3), pulse and blood pressure only will be 
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measured approximately 30 minutes after dosing with study medication. Study participants 
should be sitting for at least 5 minutes prior to and during the collection of blood pressure and 
pulse rate measurements. Vital signs to be collected are pulse, systolic/diastolic blood 
pressure measurement, and temperature. 
For pre-dose measurements, if more than one results appears for a specific visit, then the pre-
dose results are averaged.  The same will occur for post dose measurements.  All data will be 
listed, including the averages. If measurements are labeled as pre-dose in the CRF, but when 
compared to dosing, it is actually post-dose, the analysis label will reflect a post dose 
measurement. The same will occur for post-dose measurements.  
Descriptive statistics for observed values and change from pre-dose to post-dose pulse and 
blood pressure when available, will be presented for each visit for each vital sign parameter. 
Vital signs summaries will be provided for the Reduced CZP Dose, Original CZP Dose, and 
Any CZP Dose) and by Baseline weight group. 
A summary of the incidence of markedly abnormal vital signs results by post-baseline 
scheduled visit will be presented for temperature, blood pressure, and pulse rate parameters.  
Details of markedly abnormal values will be listed by study participant and parameter for 
which there is at least 1 markedly abnormal result recorded. Definitions of markedly 
abnormal values are given below in Table 9‒5. 
Markedly abnormal high temperature is >40.0 degrees Celsius (>104.0 degrees Fahrenheit) 
while a markedly abnormal low temperature is 32 – 35 degrees Celsius (89.6 – 95 degrees 
Fahrenheit). Vital signs data will be listed, including the flagging of markedly abnormal 
values. 
Table 9‒5: 
Definitions of Markedly Abnormal Vital Signs Values 
Parameter 
Age 
Range 
Abnormality 
Criteria 
Pulse Rate 
(beats/minute) 
  
  
3y - 
<12y 
<60 
>130 
12y - 
<17y 
<50 
>120 
≥17y 
<60 
 >100  
Systolic Blood 
Pressure 
(mmHg) 
3y - 
<12y 
<80 
>140 
12y - 
<17y 
<90 
>160 
≥17y 
<90 
>140 
>160 
3y - 
<12y 
<50 
>80 
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Parameter 
Age 
Range 
Abnormality 
Criteria 
Diastolic Blood 
Pressure 
(mmHg) 
12y - 
<17y 
<50 
>105 
≥17y 
<50 
>90 
>100 
 
9.4.2 
Other safety variables 
9.4.2.1 
Height and weight 
Descriptive statistics for Baseline and post-Baseline values at selected time points of interest, 
and change from Baseline for selected time points for percentile height-for-age and percentile 
weight –for-age (based on growth curves and percentile calculation methods published by 
CDC for children age 2-20  that was available on 27April 2016 at 
http://www.cdc.gov/growthcharts/clinical_charts.htm  ) will be summarized by Baseline age 
group and gender for the Reduced CZP Dose, Original CZP Dose, and Any CZP Dose. All 
weights and heights will also be listed. 
9.4.2.2 
Tanner stages 
Assessments of study participants’ developmental stages on external genitalia and pubic hair 
(boys) and on breast and pubic hair (girls) will be performed to determine Tanner stages, for 
those who have not reached Tanner stage V. A summary of shift table of Tanner stages from 
baseline to relevant post-treatment visit(s) (48 week, 96 week, etc) by age and gender will be 
provided for the Reduced CZP Dose, Original CZP Dose, and Any CZP Dose. Overall 
Tanner stage at each visit is derived as the minimum stage of the 2 components. If one 
component is missing at a visit, then the overall stage will be set to missing for that visit. 
No imputation of missing data will be implemented. Tanner stages will be listed by visit for 
each study participant. 
9.4.2.3 
Physical examination 
Physical examination findings will be recorded in the CRF only at Screening. Details of 
subsequent physical examinations should be recorded in the source documentation. Clinically 
relevant changes in subsequent physical examinations will be recorded as AEs.   
Physical examination findings at Screening will be listed.   
9.4.2.4 
Reproductive potential and birth control 
The reproductive potential of all study participants will be assessed by clinical questioning at 
Screening, Baseline, and every visit thereafter except at Visits 3 and 4 and at Unscheduled 
Visits. If the study participant is not of reproductive potential, the reason will be recorded. If 
the study participant is of reproductive potential and is sexually active, the method of birth 
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control used will be recorded. Reproductive potential and birth control information will be 
listed by visit for each study participant. 
9.4.2.5 
Autoantibodies 
Autoantibodies (ANA and anti-dsDNA) will be assessed at Baseline, Weeks 16 and 48, and 
Early Discontinuation/EOT. For ANA antibodies, normal corresponds to dilutions of <1:160 
and antibodies present corresponds to dilutions of 1:160 or higher. A summary of the 
maximum shift from the Baseline to anytime while on CZP treatment will be summarized for 
both the ANA and anti-dsDNA antibodies.   
All autoantibodies summaries will be provided for the Reduced CZP Dose, Original CZP 
Dose, and Any CZP Dose) and by Baseline weight group. All autoantibody assay data will be 
listed. 
9.4.2.6 
Tuberculosis assessments 
A tuberculin purified protein derivative (PPD) skin test, which is not mandatory for all study 
participants, will be done ≤3months before Screening, at Week 48, and then yearly thereafter. 
PPD tests should be read by a trained health care worker between 48 and 72 hours after 
injection. QuantiFERON TB GOLD testing at Screening is required to be performed by the 
central lab if the study participant has a documented history of severe positive PPD reaction 
or a documented history of BCG vaccination. 
Following implementation of Protocol Amendment 3, a chest radiograph (anterior-posterior 
view at minimum, but preferably anterior-posterior and lateral) must be taken for study 
participants with a positive or repeatedly indeterminate IGRA or PPD testing or TB 
questionnaire indicating an increased study participant’s risk of exposure or infection with 
TB (study participants 2 to 4 years of age with a written documentation of BCG vaccination) 
at Screening. If a study participant has had a recent radiograph of the chest within 
approximately 3 months prior to Screening, it may be used in lieu of the protocol required 
radiograph. All chest imaging must be read by a qualified radiologist/pulmonary physician 
who is specifically required to look for evidence of active TB or inactive TB. 
The TB questionnaire will be completed twice at each visit, once by the study participant and 
once by the caregiver. 
Tuberculosis testing, chest radiograph results and questionnaire results will be listed for each 
study participant. 
10 
EFFICACY ANALYSES 
Efficacy will be analyzed using the FAS.  All efficacy results will be summarized overall and 
by Baseline weight group and will be provided for the Original CZP Dose, Reduced CZP 
Dose, and the Any CZP Dose. For subgroup efficacy analyses, summaries by Baseline age 
group, concomitant MTX use, and ADAb titer classification will be presented pooling across 
all weight groups unless otherwise specified. In addition, selected summaries will also be 
presented by gender and race. 
In addition to the efficacy summaries described below, all efficacy results will be listed by 
study participant data listings.  
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In Section 10, the analyses described for all efficacy variables below will be generated for the 
final analysis.  For the Updated Week 24 Interim analysis, only efficacy data up to and 
including Week 24 was presented in the analyses described in Section 10 for the following 
variables:  
• PedACR30/50/70/90 
• Number of joints with active arthritis 
• Number of joints with limitation of range of motion 
• Physician’s Global Assessment of Disease Activity 
• Childhood Health Assessment Questionnaire 
• Parent’s Global Assessment of Overall Well-Being 
• C-Reactive protein 
• Juvenile Arthritis Disease Activity Score 71-joint 
For the Updated Week 24 Interim analysis, all reported data for other efficacy variables were 
listed only; any calculations described for the final analysis were not performed. These 
included the following variables: 
• Clinically Inactive Disease 
• CRM 
• Duration of Morning Stiffness 
• Parent’s Assessment of Arthritis Pain 
• Faces Pain Scale Revised 
• JIA Pain 
• Fatigue Assessment Scale, and 
• Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey. 
10.1 
Statistical analysis of the primary efficacy variable 
The primary objective of this study is to evaluate PK and safety; therefore there is no primary 
efficacy variable. 
10.2 
Statistical analysis of the secondary efficacy variables 
The PedACR30, PedACR50, PedACR70, and PedACR90 clinical response rates are based on 
a 30%, 50%, 70%, and 90% or greater improvement from Baseline in at least 3 of the 6 core 
set measures with no more than 1 of the remaining worsened by >30%. PedACR30, 
PedACR50, PedACR70, and PedACR90 clinical response will be calculated by statistical 
programming based upon the core set measures.  The 6 core set measures are: 
• Number of joints with active arthritis (see Section 10.3.2.1 for definition) 
• Number of joints with limitation of range of motion (see Section 10.3.2.2  for definition) 
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• Physician’s Global Assessment of Disease Activity VAS 
• CHAQ completed by parent or caregiver  
• Parent’s Global Assessment of Overall Well-Being VAS 
• Acute phase reactant CRP 
If 2 or more core set measures are missing, the corresponding PedACR30, PedACR50, 
PedACR70 and PedACR90 responses will also be treated as missing.  For core set measures 
with values of 0 at Baseline, the percentage change from Baseline cannot be calculated for 
improvement, however, for worsening, the following rules will be applied:  
• If Baseline number of joints for active arthritis or with LoM was 0, an increase to at 
least 2 joints is required; 
• If Baseline Global Assessment scores are 0, worsen to a score at least 20 is required to 
be considered as a worsening of at least 30%;   
• If Baseline CHAQ score is 0, worsen to a score of at least 0.125 is required to be 
considered as a worsening of at least 30%;  
In addition, CRP is used in the determination of worsening or improvement only when either 
the Baseline value and/or the visit values are higher than the upper limit of the normal 
reference range (ie, >8mg/L). 
The frequency and percentage of study participants achieving a PedACR30, PedACR50, 
PedACR70, and PedACR90 response and associated 95% exact binomial CIs will be 
summarized for Week 16 (as well as for the other visits). Results will be presented overall 
and by Baseline weight group (10 to <20kg, 20 to <40kg, and ≥40kg), as well as by Baseline 
age group (2 to 5 years, 6 to 11 years, and 12 to 17 years), concomitant MTX use, ADAb titer 
classification, gender and race pooling across all Baseline weight groups.   
 
Plots will be produced to show the percentage of PedACR30/50/70/90 responders by visit 
and ADAb titer classification. 
10.3 
Analysis of other efficacy variables 
Continuous endpoints will be summarized using observed case, as for the Physician’s Global 
Assessment of Disease Activity.  
10.3.1 
PedACR30, PedACR50, PedACR70, and PedACR90 
The PedACR30, PedACR50, PedACR70, and PedACR90 response rates as compared to 
Baseline at every visit (including Week 16) except the Final Visit will be summarized. Plots 
of PedACR30, PedACR50, PedACR70 and PedACR90 response rates (combined on the 
same plot) by visit will be provided by the same CZP dose groups as in the summary tables 
above, overall and by Baseline weight group. 
PedACR30, PedACR50, PedACR70, and PedACR90 response rates will also be summarized 
by Baseline age group, concomitant MTX use, ADAb titer classification, gender and race 
pooling across all Baseline weight groups.  
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Plots will be produced to show the percentage of PedACR30/50/70/90 responders by visit 
and ADAb titer classification. 
10.3.2 
PRINTO/PRCSG standard joint examination 
The following 75 joints are to be examined for swelling, pain on motion (POM), tenderness, 
and limitation of motion (LOM) by the Investigator, another delegated physician, or an 
appropriately qualified medical professional who has had documented training on how to 
perform these assessments correctly. Preferably the same assessor should evaluate the study 
participant at each arthritis assessment, as per PRINTO/PRCSG guidelines. The individual 
with this delegated duty must be listed on Form 1572. 
• Upper body (6) - bilateral temporomandibular, sternoclavicular, and acromioclavicular 
joints 
• Upper extremity (34) - bilateral shoulders, elbows, wrists, metacarpals (MCP I, II, III, IV, 
and V), proximal interphalangeals (PIP I, II, III, IV, and V) and distal interphalangeals 
(DIP II, III, IV, and V) 
• Lower extremity (30) - bilateral hips, knees, ankles, subtalar, tarsi, metatarsophalangeals 
(MTP I, II, III, IV, and V), and proximal interphalangeals (PIP I, II, III, IV, and V) 
• Spinal (5) – cervical spine, thoracic spine, and lumbar spine, and bilateral sacroiliac joints 
Joint assessment will be based on a 2-point scale as unaffected (Grade 0) and affected (Grade 
1). If a joint is not evaluable at Baseline, then that joint is set to missing throughout the study. 
10.3.2.1 
Joints with active arthritis 
The number of joints with active arthritis is the number of joints with: 
• Grade 1 for swelling, or  
• Grade 1 for LOM with POM, or  
• Grade 1 for LOM with tenderness.  
The count of joints with active arthritis is based on 71 of 75 joints from the PRINTO/PRCSG 
standard joint examination.  Although 75 joints are included in the PRINTO/PRCSG standard 
joint examination, bilateral sacroiliac joints are not assessed for swelling or LOM and as a 
result are not included in the active arthritis count.  Additionally, cervical, thoracic and 
lumbar joints are treated as a single composite joint in the computation of the number of 
joints with active arthritis.  If 1 or more of these 3 spinal joints satisfy the criteria for joints 
with active arthritis, then the composite joint will be counted as a joint with active arthritis. 
The assessment for swelling is made on 66 joints from the above list. The hip, subtalar, 
cervical spine, thoracic spine, lumbar spine, and sacroiliac joints are excluded. Artificial and 
ankylosed joints are excluded from both tenderness and swelling assessments. Joints treated 
with an intra-articular corticosteroid are also not assessed. 
Eleven joints are not assessed for both LOM and swelling, and consequently active arthritis 
status will be based on the available partial assessments performed for those joints. Bilateral 
sternoclavicular and acromioclavicular joints are not assessed for LOM and as a result the 
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joints with active arthritis status will be based only on swelling.  Conversely, bilateral hip and 
subtalar joints are not assessed for swelling and as a result active arthritis status will be based 
only on LOM. Cervical, thoracic and lumbar spine joints are also not assessed for swelling 
and as a result active arthritis status will be based only on LOM. 
In addition, joints with completely missing assessments that are otherwise expected to be 
evaluated will be treated as missing with respect to joints with active arthritis status.  For 
example, MCP joints should be assessed for swelling, POM, tenderness and LOM at all 
visits.  If all assessments for a given MCP joint are missing at a given visit, the joint will be 
treated as missing and will not be included as an assessed joint in the calculation of the active 
arthritis count. However, if partial data are available for a given joint, and the available data 
are sufficient to indicate that a given joint has active arthritis (eg, joint is assessed as swollen, 
but LOM and/or POM assessment is missing), the joint will be classified as a joint with 
active arthritis.  However, if only partial data are available, and the partial data indicate that 
the joint is unaffected, the joint will also be treated as missing for the determination of the 
number of joints with active arthritis at that time point. 
  The active arthritis count will be weighted by the number of joints assessed:    
𝐴𝐴𝐶= 71 ∗∑
𝐽𝐴𝐴
𝑛
𝑖=1
∑
𝐽𝐴
𝑛
𝑖=1
 
where AAC=active arthritis count, JAA=number of joints with active arthritis, and 
JA=number of joints assessed. If more than 50% of the joints are not assessed, then the count 
of joints with active arthritis will be set to missing. 
The number of joints with active arthritis and change from Baseline in number of joints with 
active arthritis will be summarized (observed case) for every visit except the Final Visit.  
10.3.2.2 
Joints with limitation of range of motion 
The assessment for LOM is made on 67 joints from the PRINTO/PRCSG standard joint 
examination. The sternoclavicular, acromioclavicular, and sacroiliac joints are excluded. 
Cervical, thoracic and lumbar joints are treated as a single composite joint; LOM in 1 or more 
of these 3 joints is counted as LOM for the composite joint. The number of joints with 
limitation of range of motion is the number of joints with Grade 1 for LOM and is weighted 
by the number of joints assessed: 
𝐿𝑀𝐶= 67 ∗∑
𝐽𝐿𝑀
𝑛
𝑖=1
∑
𝐽𝐴
𝑛
𝑖=1
 
where LMC=limitation of motion count, JLM=number of joints with limitation of range of 
motion, and JA=number of joints assessed. If more than 50% of the joints are not assessed for 
LOM, then the limitation of motion count will be set to missing. 
The number of joints with limitation of range of motion and change from Baseline in number 
of joints with limitation of range of motion will be summarized (observed case) for every 
visit except the Final Visit.   
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10.3.3 
Physician’s Global Assessment of Disease Activity VAS 
The Investigator will assess the overall status of the study participant with respect to their 
pcJIA signs and symptoms and functional capacity using a 0 to 100mm VAS where 0 is “very 
good, asymptomatic and no limitation of normal activities” and 100 is “very poor, very 
severe symptoms which are intolerable and inability to carry out all normal activities.” 
The Physician’s Global Assessment of Disease Activity (VAS) will be completed at 
Screening, Baseline, and every visit through the Early Discontinuation/EOT Visit. 
Descriptive statistics of the observed values and change from Baseline will be presented by 
visit. 
10.3.4 
Childhood Health Assessment Questionnaire 
The CHAQ is an adaptation of the Health Assessment Questionnaire-Disability Index which 
is a questionnaire developed to assess physical function in adults (Singh et al, 1994). The 
CHAQ was developed specifically as a measure of function for children with juvenile RA 
and the population evaluated for the development of this questionnaire comprised study 
participants between ages 1 to 19 years old with JIA. The CHAQ is a parent/caregiver-
reported questionnaire and the recall period is “the past week.”  CHAQ data will be included 
regardless of the actual age of the study participant at the time the CHAQ was completed (eg. 
for ages > 19 years old). 
The disability section of the CHAQ uses 30 questions (5-point Likert scale) to assess 8 
domains of daily living, namely dressing and grooming, arising, eating, walking, hygiene, 
reach, grip, and activities. The scoring system used is: 0 = “without any difficulty”, 1 = “with 
some difficulty”, 2 = “with much difficulty”, and 3 = “unable to do.” In addition to the 
questions on activities of daily living, the CHAQ asks if any aids or devices or help from 
another person is needed to complete the specified activities. The question with the highest 
score determines the score for that domain. If aids or devices are used or help is needed to 
complete tasks in a certain area, a minimum score of 2 is recorded for the corresponding 
domain. Table 10‒1  indicates which aids/devices correspond to each domain; any aids or 
devices other than those indicated below will not be considered in the calculation of domain 
scores. The scores for each of the 8 domains are averaged to calculate the Disability Index 
which yields a score from 0 representing “no disability” to 3 representing “very severe 
disability.” A study participant must have scores for at least 6 of the 8 domains to calculate 
the Disability Index.  If there is not a score for at least 6 of the 8 domains (ie 3 or more 
domains scores are missing), the Disability Index is considered missing. 
Table 10‒1: CHAQ Aids and Devices 
CHAQ Domain 
Aids/Devices  
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Table 10‒1: CHAQ Aids and Devices 
CHAQ Domain 
Aids/Devices  
The CHAQ will be completed by the parents/caregivers at Screening, Baseline, and every 
visit through the Early Discontinuation/EOT Visit. The same parent/caregiver should 
complete the questionnaire for each visit. The questionnaire should be checked by site 
personnel for completeness. The recall period is the past week. To eliminate discrepancies 
introduced by growth and development, parents/caregivers are asked to note only those 
difficulties that are caused by arthritis.   
Descriptive statistics of the observed scores and change from Baseline will be presented by 
visit. 
No additional analyses are planned to handle instances where the questionnaire is not 
completed by the same parent/caregiver at each visit.  The person completing the CHAQ at 
each visit will be identified on the listing. 
10.3.5 
Parent’s Assessment of Arthritis Pain VAS 
10.3.5.1 
Updated Week 24 Interim Analysis 
This data was only listed. 
10.3.5.2 
Final Analysis 
The parent/caregiver is asked the following question “How much pain do you think your 
child has had because of his or her illness in the past week?” and then rates the severity on a 
100mm VAS where 0 = “no pain” and 100 = “very severe pain.” 
The Parent’s Assessment of Arthritis Pain VAS will be completed at Screening, Baseline, and 
every visit through the Early Discontinuation/EOT Visit.   
Descriptive statistics of the observed values and change from Baseline will be presented by 
visit. 
No additional analyses are planned to handle instances where the Parent’s Assessment of 
Arthritis Pain VAS is not completed by the same parent/caregiver at each visit.  The person 
completing the Parent’s Assessment of Arthritis Pain VAS at each visit will be identified on 
the listing. 
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10.3.6 
Parent’s Global Assessment of Overall Well-Being VAS 
For the Parent’s Global Assessment of Overall Well-Being, the parent/caregiver is asked the 
following question “Considering all the ways that arthritis affects your child, rate how your 
child is doing on the following scale by placing a mark on the line.” The parent/caregiver 
rates their response on a 100mm VAS where 0 = “very well” and 100 = “very poor.” 
The Parent’s Global Assessment of Overall Well-Being VAS will be completed at Screening, 
Baseline, and every visit through the Early Discontinuation/EOT Visit.   
Descriptive statistics of the observed values and change from Baseline will be presented by 
visit. 
No additional analyses are planned to handle instances where the Parent’s Global Assessment 
of Overall Well-Being VAS is not completed by the same parent/caregiver at each visit.  The 
person completing the Parent’s Global Assessment of Overall Well-Being VAS at each visit 
will be identified on the listing. 
10.3.7 
C-reactive protein 
The acute phase reactant CRP will be analyzed by 3 central laboratories.  
Given the precision with which CRP values are reported, the following specific algorithms 
will be followed for each of the central laboratories: 
• Cirion laboratory (lab=’C_RA0043_1’):  the minimum threshold of detection is 
0.05mg/L; any CRP value reported as ‘0mg/L’ will be set to 0.05mg/L for the 
summaries described in this section. 
• LFK laboratory (lab=’C_RA0043_2’): the minimum threshold of detection is 
0.2mg/L.  Due to LFK reporting conventions, CRP imputations will be as follows: 
o when reported value is <0.000g/L, impute as 0.2mg/L 
o when reported value is 0g/L, impute as 0.5mg/L  
• LBM laboratory (lab=’C_RA0043_3’): the threshold of detection is 0.5mg/L; any 
CRP value reported as ‘0mg/L’ will be set to 0.5mg/L for the summaries described in 
this section. 
CRP will be analyzed at Screening, Baseline, and every visit through the Early 
Discontinuation/End of Treatment Visit. The observed values and the percent change from 
Baseline of CRP will be summarized for each post-Baseline visit.   
As the normality assumptions are not expected to be met for CRP, the geometric mean and 
the corresponding CV of the geometric mean will be summarized by visit for CRP and the 
percent change from Baseline of CRP values.  The n, median, first quartile, third quartile, 
minimum, and maximum will also be presented.  
10.3.8 
Juvenile Arthritis Disease Activity Score 71-joint 
The JADAS-71 is a composite disease activity score based on a 71-joint count and includes 
the measures: 
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• Physician’s Global Assessment of Disease Activity VAS normalized to a 0 to 10 scale by 
dividing the score by 10 
• The Parent’s Global Assessment of Overall Well-Being VAS normalized to a 0 to 10 
scale by dividing the score by 10 
• The number of joints with active arthritis (0 to 71, weighted by the number of joints 
assessed) 
• CRP normalized to a 0 to10 scale as follows: if CRP is expressed in mg/dl, any values 
above 10 are converted to 10. If expressed in mg/L, the value will be first divided by 10 
and then any values above 10 will be converted to 10. Values below the minimum 
threshold for the method used for CRP determination are converted to 0 (see Section 
10.3.7 for minimum CRP thresholds). 
The JADAS-71 is calculated as the linear sum of scores of the 4 components with a total 
score range of 0 to 101.  If any component of the JADAS-71 is missing, the JADAS-71 will 
be set to missing for the corresponding visit. 
Descriptive statistics of the observed composite scores and change from Baseline will be 
presented by visit (except at Final Visit).  
10.3.9 
Clinically Inactive Disease 
10.3.9.1 
Updated Week 24 Interim Analysis 
This data was only listed. 
10.3.9.2 
Final Analysis 
A study participant will be considered to be in CID at a given point in time if they meet all of 
the following criteria: 
• No joints with active arthritis:  based upon both (1) a “No” response to the question “Has 
the subject experienced any of the following since the last visit - Joint(s) with active 
arthritis?”, and 0 joints with active arthritis at the current visit 
• No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to 
JIA:  based upon a “No” response to the question “Has the subject experienced any of the 
following since the last visit - Fever, rash, serositis, splenomegaly, or generalized 
lymphadenopathy attributable to JIA?” 
• No active uveitis as defined by the Standardization of Uveitis Nomenclature Working 
Group:  based upon a “No” response to the question “Has the subject experienced any of 
the following since the last visit - Active uveitis as defined by the Standardization of 
Uveitis Nomenclature Working Group?” 
• CRP within normal limits in the laboratory where tested or, if elevated, not attributable to 
JIA:  based upon a “No” response to the question “Has the subject experienced any of the 
following since the last visit - Elevated CRP levels attributable to JIA?” 
• Physician’s Global Assessment of Disease Activity score of best possible on the scale 
used (ie, 0mm on the 100mm VAS):  based upon VAS score at current visit 
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• Duration of morning stiffness of ≤15 minutes:  based upon duration of morning stiffness 
at current visit 
The 6 criteria above will be used to derive CID. If any of the 6 criteria cannot be assessed due 
to missing data, the study participant will be assumed not to have achieved derived CID at the 
corresponding visit.   
Derived CID will be assessed at every post-Baseline visit except the Final Visit. 
The n and percentage of study participants with derived CID will be summarized for each 
post-Baseline visit. The exact 95% CI for the percentage will also be presented.  
Time to initial derived CID in days will be calculated as date of first visit where derived CID 
is achieved – date of first dose of study medication + 1 day. Time to initial derived CID in 
days will be presented using Kaplan-Meier product limit estimation.  Study participants that 
discontinue without achieving derived CID will be censored at the time of discontinuation; 
ongoing study participants that have not achieved derived CID at the time of interim analyses 
(Week 24 and other interim analyses) and the final analysis will be censored at the time of the 
last available assessment. The median and 95% CI for the time to initial derived CID will be 
presented. The 95% CI for the median will be based on the method of Brookmeyer and 
Crowley. Kaplan-Meier product limit survival estimates of the cumulative proportion of 
study participants with derived CID (1 minus the product limit estimate of the proportion of 
study participants without derived CID) will also be presented.  Kaplan-Meier plots of time to 
CID will be presented overall and by Baseline weight group. 
Both summaries of derived CID and time to derived CID will be provided as well as listed. 
10.3.10 
Clinical Remission  
10.3.10.1 
Updated Week 24 Interim Analysis 
This data was only listed. 
10.3.10.2 
Final Analysis 
CRM as indicated by the PI in the eCRF will only be listed. 
Derived CRM is defined as achieving the criteria for derived CID for at least 6 continuous 
months; study participants who reach derived CRM can either stay on CZP or stop taking 
CZP; so being in derived CRM is not an indicator of whether the study participant is taking 
CZP while in derived CRM.  Derived CRM will be considered achieved at a given visit if the 
study participant has derived CID at the visit and if the time from the first visit where derived 
CID is achieved to the given visit is ≥ 6 months (182 days) and the study participant had 
derived CID at all attended visits in between; if missed visits occur between visits where 
derived CID is achieved, then derived CID will be assumed for the missed visits. Derived 
CRM is defined as criteria for derived CID achieved for at least 6 continuous months. 
Derived CRM will be assessed at every post-Baseline visit from Week 24 onwards, except 
the Final Visit. 
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The n and percentage of study participants with derived CRM will be summarized for each 
post-Baseline visit starting at Week 24. The exact 95% CI for the percentage will also be 
presented.  
Time to initial derived CRM in days will be calculated as date of first visit where derived 
CRM is achieved – date of first dose of study medication + 1 day. Time to derived CRM in 
days will be presented using Kaplan-Meier product limit estimation.  Study participants that 
discontinue without achieving derived CRM will be censored at the time of discontinuation; 
ongoing study participants that have not achieved derived CRM at the time of interim 
analyses (Week 24 and other interim analyses) and the final analysis will be censored at the 
time of the last available assessment. The median and 95% CI for the time to initial derived 
CRM in days calculated using Kaplan-Meier product limit estimators will be presented. The 
95% CI for the median will be based on the method of Brookmeyer and Crowley. Kaplan-
Meier product limit survival estimates of the cumulative proportion of study participants in 
derived CRM (1 minus the product limit estimate of the proportion of study participants 
without derived CRM) from 6 months onwards will also be presented.  Kaplan-Meier plots of 
time to derived CRM will be presented overall and by Baseline weight group. 
Both summaries of derived CRM and time to derived CRM will be provided as well as 
listings.  
10.3.11 
Duration of morning stiffness  
10.3.11.1 
Updated Week 24 Interim Analysis 
This data was only listed. 
10.3.11.2 
Final Analysis 
Duration of morning stiffness is defined as the time elapsed between the time of usual 
awakening (even if not in the morning) and the time the study participant is as limber as 
he/she will be during a day involving typical activities. The study participant/caregiver will 
be asked the following question (Kirwan, JR and Reeback TS, 1986):  
“How long does it take, from the time you (your child) wake up, for you (your child) to 
become as limber as you (your child) will be?”  
For those experiencing relief, the actual hours elapsed should be recorded no matter how 
long. The duration in hours and minutes will be recorded. For those study participants with 
unrelenting stiffness, 24 hours should be recorded. 
Descriptive statistics of the observed duration and change from Baseline in duration of 
morning stiffness in hours will be summarized by visit. 
10.3.12 
Faces Pain Scale-Revised 
10.3.12.1 
Updated Week 24 Interim Analysis 
This data was only listed. 
10.3.12.2 
Final Analysis 
The Faces Pain Scale-Revised (FPS-R) is a self-reported measure used to assess the intensity 
of children’s pain (Hicks et al, 2001). The original version of the scale consists of 7 faces 
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increasing in pain intensity and approximating equal intervals as assessed by children (Bieri 
et al, 1990). Children have to select a level on the scale that matches their own pain. A 
numerical value is associated with the different levels on the scale. The FPS-R was adapted 
from the FPS in order to make scoring possible on the widely accepted 0 to 10 metric. It 
includes 6 faces (instead of 7). This tool has been validated for children aged 5 to 12 years 
and will be assessed in children ages 5 to 11 years at Baseline.  
The 6 faces have scores of 0, 2, 4, 6, 8, and 10 where 0 = “no pain” and 10 = “very much 
pain.” 
Descriptive statistics of the observed values and change from Baseline will be presented for 
each of the specified visits. 
Study participants who age out of the 5 to 11 years age group while still on study will 
continue to be administered the FPS-R for consistency.  No combined analyses of the FPS-R 
and JIA Pain VAS will be done for these study participants. Study participants who are less 
than 5 years old when they enter the study but then reach 5 years of age while on study will 
not be administered any pain scale questionnaire.   
10.3.13 
Patient’s Assessment of Arthritis Pain 
10.3.13.1 
Updated Week 24 Interim Analysis 
This data was only listed. 
10.3.13.2 
Final Analysis 
In the JIA Pain VAS, study participants 12 to 17 years old at Baseline are asked the following 
question, “How much pain have you had because of your illness today (acute version)/in the 
past week (standard version)?” (as applicable). The study participant should then place a 
mark on a 100mm VAS to indicate the severity of the pain, where 0 = “no pain” and 100 = 
“very severe pain”.  
Descriptive statistics of the observed values and change from Baseline will be presented 
separately for the acute and standard versions (See Protocol Amendment 9, Section 11.13) for 
each of the specified visits. 
Study participants who are past 17 years old while still on the study will continue to be 
administered the JIA Pain VAS. 
10.3.14 
FASCA – Fatigue Assessment Scale 
10.3.14.1 
Updated Week 24 Interim Analysis 
This data was only listed. 
10.3.14.2 
Final Analysis 
The study participant’s level of tiredness (fatigue) will be assessed by the FASCA numeric 
rating scale where the parent/caregiver is asked the question "Please rate your child's fatigue 
(weariness, tiredness) during the past week on a scale of 0 to 10," where 0 is "no fatigue" and 
10 is "fatigue as bad as you can imagine."  
The recall period for this instrument is the past week. 
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Descriptive statistics of the observed values and change from Baseline will be presented by 
visit. 
No additional analyses are planned to handle instances where the FASCA is not completed by 
the same parent/caregiver at each visit.  The person completing the FASCA at each visit will 
be identified on the listing. 
10.3.15 
Juvenile Arthritis School Attendance and Caregiver Work 
Productivity Survey 
10.3.15.1 
Updated Week 24 Interim Analysis 
This data was only listed. 
10.3.15.2 
Final Analysis 
The Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey is a 
parent/caregiver-reported self-administered questionnaire which captures information related 
to the impact of the disease on the child’s ability to participate in school and social/after-
school activities and evaluates the impact of disease on the parent or caregiver’s productivity 
at their paid work and in the household. The same parent/caregiver should complete the 
questionnaire at each visit. The recall period for the questions relating to the child’s school 
attendance and parent/caregiver’s work productivity is the past 4 weeks. This survey collects 
information related to the child’s attendance to school, number of school days missed due to 
the disease, number of school days impacted due to the disease, level of difficulty in 
performing school activities, the parent or caregiver’s employment status, number of days 
missed from work due to the child’s disease, number of days with work productivity reduced 
by half or more due to child’s disease, days with no household work due to child’s disease, 
and days with productivity within household reduced by half or more due to child’s disease. 
Questions 1 – 5 address how many and what types of caregivers provide care and support to 
the child with arthritis. Questions 6 – 12 address how arthritis affects the child’s attendance 
and performance at school. Questions 13 – 20 address how the child’s arthritis impacts the 
caregivers’ work productivity. 
The Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey will be 
completed at Baseline, Week 4, and every visit through the Early Discontinuation/EOT Visit. 
The following analysis will be presented for the Any CZP dose only. The n and percentages 
for each of the question responses will be summarized for the following categorical 
questions: 6, 10-12. Descriptive statistics for the responses to the quantitative questions (8-9, 
14-20) will be summarized. 
Observed case will be used for all analyses in Juvenile Arthritis School Attendance and 
Caregiver Work Productivity Survey data. 
No additional analyses are planned to handle instances where the Juvenile Arthritis School 
Attendance and Caregiver Work Productivity Survey is not completed by the same 
parent/caregiver at each visit.  The person completing the Juvenile Arthritis School 
Attendance and Caregiver Work Productivity Survey at each visit will be identified on the 
listing. 
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11 
REFERENCES 
Bieri D, Reeve RA, Champion GD, Addicoat L, Ziegler JB. The Faces Pain Scale for the 
self-assessment of the severity of pain experienced children: development, initial validation, 
and preliminary investigation for ratio scale properties. Pain. 1990;41:139-50 
Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain 
Scale-Revised: toward a common metric in pediatric pain measurement. Pain. 2001; 
93(2):173-83. 
Kirwan JR, Reeback TS. Stanford Health Assessment modified to assess disability in British 
patients with rheumatoid arthritis. Br J Rheumatol. 1986;25:206-9. 
Mosteller RD. Simplified calculation of body surface area. N Engl J Med 1987 Oct22; 
317(17):1098 (letter). 
Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in children with 
juvenile rheumatoid arthritis. Arthritis Rheum. 1994;37:1761-9. 
Ulm K. A simple method to calculate the confidence interval of a standardized mortality 
ratio. American Journal of Epidemiology 1990;131(2):373-375. 
 
12 
APPENDIX 
12.1 
Comparisons with RA0138 data 
The following analysis was only completed for the Updated Week 24 Interim Analysis; it will 
not be regenerated for the final analysis.   
Comparisons between RA0043 and RA0138 data focused on common timepoints (Weeks 12 
and 24).  The dose groups that were compared are the Original CZP Dose and the Reduced 
CZP Dose from RA0043 (Section 3.1) and the 200 mg Q2W maintenance dose from 
RA0138. 
Separate boxplots were generated for Week 12 and Week 24 showing plasma CZP 
concentrations for the two CZP dose groups (Original CZP Dose or Reduced CZP Dose) for 
RA0043 and the single CZP dose group for RA0138 in the same plot. Box plots of the PK 
concentrations at Weeks 12 and 24 were presented by CZP dose group for Baseline weight 
group, Baseline age group, ADAb participant status classification, ADAb titer classification, 
and concomitant MTX use in combination with Baseline weight group. In the box plots the 
5th and 95th percentiles of the concentrations distribution were shown. 
Separate plots of individual participant (natural) log CZP plasma concentration versus log2 
ADAb titer were produced for Week 12 and Week 24 data for both studies. In these plots, 
participants study (RA0043 or RA0138) and CZP dose group (Original or Reduced) were 
shown as a different symbol/color to aid comparison. In addition, for RA0138 only, plots of 
individual participant area under the plasma concentration curve over the 2-week dosing 
interval (AUC0-tau) versus log2 ADAb titer at Week 12 were produced. 
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If there were signs that higher titer levels were associated with lower plasma concentrations, 
further investigations were performed to attempt to determine at which titer levels differences 
are observed and to assess the impact on efficacy and safety. 
Further analyses were defined in the integrated summary of immunogenicity including 
comparisons of ADAb titer levels between studies (no pooling of studies across indications 
are planned) allowing us to put the pcJIA/RA data in context of the AS and PSO indications. 
 
13 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
(SAP) 
13.1 
AMENDMENT 1 
Rationale for the amendment 
The primary reason for this SAP amendment was to implement feedback received from FDA 
on analyses to be done for the different CZP dose regimens and for additional subgroups 
(gender and race). 
 
Modifications and changes 
Global changes 
The terms “Baseline concomitant MTX use” have been changed globally to “concomitant 
MTX use” in SAP amendment1 except for section 6.1 Demographics. In section 6.1 
Demographics, “Baseline concomitant MTX” should still be used.  
Specific changes 
Change #1 
 SAP Amendment 1      23 Sept 2015  
has been added to cover page. 
Change #2 
Section 2 Protocol Summary 
The following protocol amendments 
Amendment 5.2 (Russia): 23 Feb 2014 
Amendment 6: 17 Sep 2015 
Amendment 6.1 (Russia): 17 Sep 2015 
has been added. 
Change #3 
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Section 2.3 Study design and conduct 
A minimum of 10 study participants will be enrolled on the reduced CZP dose regimen 
(Protocol Amendment 5) in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 
to <88lb), and ≥40kg (≥88lb). A minimum of 10 study participants will be enrolled in each 
age category of 2 to 5 years, 6 to 11 years, and 12 to 17 years, irrespective of the dose 
regimen. A minimum of 25 study participants will be enrolled who receive CZP as 
monotherapy (ie, study participants with established intolerability or inadequate response to 
methotrexate), irrespective of the dose regimen. A minimum of 10 study participants with 
ERA will be enrolled, irrespective of the dose regimen. Each of these categories is assessed 
independently. 
Has been changed to: 
A minimum of 10 study participants will be enrolled on the reduced CZP dose regimen 
(Protocol Amendment 5) in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 
to <88lb), and ≥40kg (≥88lb). A minimum of 10 study participants will be enrolled in each 
age category of 2 to 5 years, 6 to 11 years, and 12 to 17 years, irrespective of the dose 
regimen. A minimum of 25 study participants will be enrolled who receive CZP as 
monotherapy irrespective of the dose regimen. A minimum of 10 study participants with 
ERA will be enrolled, irrespective of the dose regimen. Each of these categories is assessed 
independently. 
Change #4 
Section 2.4 Determination of sample size 
Data from all 156 study participants will be included in the final PopPK analysis, and 
therefore should allow CL/F and V/F to be determined with sufficient precision. 
Has been changed to: 
Available data from all study participants will be included in the final PopPK analysis, and 
therefore should allow CL/F and V/F to be determined with sufficient precision. 
Change #5 
Section 4.7 Examination of subgroup 
• Baseline age group:  
o 2-5 years 
o 6-11 years 
o 12-17 years 
Has been changed to: 
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• Baseline age group:  
o 2-<6 years 
o 6-<12 years 
o 12-17 years 
Change #6 
Section 4.7 Examination of subgroup 
For subgroup analyses of incidence of anti-CZP antibody formation and CZP plasma 
concentrations, results will be presented by Baseline age group, overall anti-CZP antibody 
status, ERA status, and Baseline concomitant MTX use group in combination with Baseline 
weight group.  
As specified in Section 3.3, Baseline for all subgroup analyses will always be the original 
Baseline (ie, prior to the 1st CZP Dose in this study). 
In addition, selected outputs will only be summarized for the Any CZP Dose Regimen as 
specified in each relevant section. 
Has been changed to: 
For subgroup analyses of incidence of anti-CZP antibody formation and CZP plasma 
concentrations, results will also be presented by Baseline age group. In addition, summaries 
will be provided by overall anti-CZP antibody status, ERA status, and Concomitant MTX use 
group in combination with Baseline weight group. As specified in Section 3.3, Baseline for 
all subgroup analyses will always be the original Baseline (ie, prior to the 1st CZP Dose in 
this study). 
For efficacy endpoints PedACR30, PedACR50, PedACR70, and PedACR90, results will also 
be presented by gender and race. 
In addition, selected outputs will only be summarized for the Any CZP Dose Regimen as 
specified in each relevant section. 
Change #7 
Section 6.4 Prior and concomitant medications 
All prior medications will be summarized by anatomical therapeutic chemical (ATC) 
classification level 3 (Pharmacological Subgroup) and WHO-DD generic name. In addition, 
past DMARDs will be summarized separately by ATC level 3 and WHO-DD generic name.  
These summaries will be provided for the SS for the Any CZP Dose Regimen only. 
Has been changed to: 
All prior medications will be summarized by anatomical therapeutic chemical (ATC) 
classification level 3 (Pharmacological Subgroup) and WHO-DD generic name. In addition, 
past DMARDs will be summarized separately by ATC level 3 and WHO-DD generic name.  
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These summaries will be provided for the SS for the Reduced CZP Dose Regimen, the 
Original CZP Dose Regimen Overall and the Any CZP Dose Regimen. 
Change #8 
Section 6.5 Prohibited medications 
All summaries of prohibited medications will be provided for the FAS for the Any CZP Dose 
Regimen only.  
Has been changed to: 
All summaries of prohibited medications will be provided for the SS for the Reduced CZP 
Dose Regimen, the Original CZP Dose Regimen Overall and the Any CZP Dose Regimen.  
Change #9 
Section 6.6 Rescue medications  
All summaries of rescue medications will be provided for the FAS for the Any CZP Dose 
Regimen only. All rescue medication will be listed. 
Has been changed to: 
All summaries of rescue medications will be provided for the SS for the Reduced CZP Dose 
Regimen, the Original CZP Dose Regimen Overall and the Any CZP Dose Regimen. All 
rescue medication will be listed. 
Change #10 
Section 8.1 CZP plasma concentrations 
Summaries of concentration results will be provided by Baseline weight group, as well as 
Baseline age group, overall anti-CZP antibody status, and concomitant MTX use in 
combination with Baseline weight group.  
Has been changed to: 
Summaries of concentration results will be provided by Baseline weight group, as well as 
Baseline age group. In addition, summaries will be provided by overall anti-CZP antibody 
status and concomitant MTX use in combination with Baseline weight group.  
Change #11 
Section 8.2 Anti-CZP antibodies 
Summaries of overall anti-CZP antibody status will be provided by Baseline weight 
group, as well as Baseline age group, and concomitant MTX use in combination with 
Baseline weight group. Each subgroup summary will be provided for the Reduced, 
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Original (overall, and prior to and following dose reduction), and Any CZP Dose 
Regimen groups. 
These summaries will be provided for the PK-PP Set. All anti-CZP antibody data will be 
listed. 
Has been changed to: 
Summaries of overall anti-CZP antibody status will be provided by Baseline weight 
group, as well as Baseline age group. In addition, summaries will be provided by 
concomitant MTX use in combination with Baseline weight group. Each subgroup 
summary will be provided for the Reduced, Original (overall, and prior to and following 
dose reduction), and Any CZP Dose Regimen groups. 
 
These summaries will be provided for the PK-PP Set. All anti-CZP antibody data will be 
listed. 
Change #12 
Section 8.4 PopPK and PK-PD analyses 
Plasma concentrations will be used to build a PopPK model using either a Bayesian approach 
with the Winbugs software or meta-analysis with the nonlinear mixed-effect modeling 
(NONMEM) software. Details of the PopPK and PK-PD modeling procedures will be 
described in a separate data analysis plan. 
Has been changed to: 
Plasma concentrations will be used to build a PopPK model using either a Bayesian approach 
with the Winbugs software or meta-analysis with the nonlinear mixed-effect modeling 
(NONMEM) software. A graphical analysis of the relationship between PK and the clinical 
effect will be performed, and if data merits, a more formal modeling exercise will be 
performed. Details of the PopPK and PK-PD modeling procedures will be described in a 
separate data analysis plan. 
Change #13 
Section 9.2 Adverse events 
The tables for 1, 2, 3, 5, and 6 above will be summarized by SOC, HLT, and PT and will 
include the number of events, the number and percentage of study participants with an event, 
the EAIR with associated 95% CIs and the EAER.  AEs of interest tables will be provided for 
the Any CZP Dose Regimen only. 
Has been changed to: 
The tables for 1, 2, 3, 5, and 6 above will be summarized by SOC, HLT, and PT and will 
include the number of events, the number and percentage of study participants with an event, 
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the EAIR with associated 95% CIs and the EAER.  AEs of interest tables will be provided for 
the Reduced CZP Dose Regimen, the Original CZP Dose Regimen Overall, the Original CZP 
Dose Regimen Prior to Dose Reduction, the Original CZP Dose Regimen Following Dose 
Reduction, and the Any CZP Dose Regimen. 
Change #14 
Section 9.3 Clinical laboratory evaluations  
Table 9-2 Definitions of markedly Abnormal Biochemistry Values 
Parameter (Unit) 
Age Range 
Abnormal Definition 
Low 
High 
Lactate dehydrogenase 
(U/L) 
2-17y 
>170 
 
Has been changed to: 
Parameter (Unit) 
Age Range 
Abnormal Definition 
Low 
High 
Lactate dehydrogenase 
(U/L) 
2-17y 
 
>170 
Change #15 
Section 9.4.2.5 Autoantidobies 
Autoantibodies (ANA and anti-dsDNA) will be assessed at Baseline, Weeks 16 and 48, and 
Early Discontinuation/EOT. For ANA antibodies, normal corresponds to dilutions of <1:160 
and antibodies present corresponds to dilutions of 1:160 or higher. For anti-dsDNA 
antibodies, negative corresponds to dilutions of <1:10 and positive corresponds to dilutions of 
1:10 or higher. A summary of the cumulative shift from the Baseline through the Early 
Discontinuation/EOT Visit will be summarized for both the ANA and anti-dsDNA 
antibodies.   
Has been changed to: 
Autoantibodies (ANA and anti-dsDNA) will be assessed at Baseline, Weeks 16 and 48, and 
Early Discontinuation/EOT. For ANA antibodies, normal corresponds to dilutions of <1:160 
and antibodies present corresponds to dilutions of 1:160 or higher. A summary of the 
cumulative shift from the Baseline through the Early Discontinuation/EOT Visit will be 
summarized for both the ANA and anti-dsDNA antibodies.   
Change #16 
Section 10 EFFICACY ANALYSES 
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Efficacy will be analyzed using the FAS.  All efficacy results will be provided for the 
Reduced CZP Dose Regimen, the Original CZP Dose Regimen Prior to Dose Reduction, and 
the Any CZP Dose Regimen.   Efficacy data collected on the day of dose reduction will be 
grouped with all other data classified as occurring prior to dose reduction; any efficacy 
assessments collected after dose reduction will be classified as occurring following dose 
reduction. For subgroup efficacy analyses, summaries by Baseline age group, Baseline 
concomitant MTX use, and anti-CZP antibody status will be presented pooling across all 
weight groups.  
Has been changed to: 
Efficacy will be analyzed using the FAS.  All efficacy results will be provided for the 
Reduced CZP Dose Regimen, the Original CZP Dose Regimen Prior to Dose Reduction, and 
the Any CZP Dose Regimen unless otherwise specified.  Efficacy data collected on the day of 
dose reduction will be grouped with all other data classified as occurring prior to dose 
reduction; any efficacy assessments collected after dose reduction will be classified as 
occurring following dose reduction. For subgroup efficacy analyses, summaries by Baseline 
age group, concomitant MTX use, and anti-CZP antibody status will be presented pooling 
across all weight groups unless otherwise specified. 
Change #17 
Section 10.2 Statistical analysis of the secondary efficacy variables 
The frequency and percentage of study participants achieving a PedACR30, PedACR50, 
PedACR70, and PedACR90 response and associated 95% exact binomial CIs will be 
summarized for Week 16 as compared to Baseline. Results will be presented overall and by 
Baseline weight group, as well as by Baseline age group, Baseline concomitant MTX use, 
and overall anti-CZP antibody status.   
Has been changed to: 
The frequency and percentage of study participants achieving a PedACR30, PedACR50, 
PedACR70, and PedACR90 response and associated 95% exact binomial CIs will be 
summarized for Week 16 as compared to Baseline. Results will be presented overall and by 
Baseline weight group, as well as by Baseline age group, concomitant MTX use, overall anti-
CZP antibody status, gender and race.   
Change #18 
Section 10.3 Analysis of other efficacy variables 
All efficacy variables described in this section will be summarized overall and by Baseline 
weight group, and will be provided for the Reduced CZP Dose Regimen, the Original CZP 
Dose Regimen Prior to Dose Reduction, and the Any CZP Dose Regimen.   
Has been changed to: 
All efficacy variables described in this section will be summarized overall and by Baseline 
weight group, and will be provided for the Reduced CZP Dose Regimen, the Original CZP 
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Dose Regimen Prior to Dose Reduction, and the Any CZP Dose Regimen unless specified 
otherwise.  
Change #19 
Section 10.3.1 PedACR30, PedACR50, PedACR70, and PedACR90 
PedACR30, PedACR50, PedACR70, and PedACR90 response rates will also be summarized 
by Baseline age group, Baseline concomitant MTX use, and overall anti-CZP antibody status 
pooling across all weight groups.  
Has been changed to: 
PedACR30, PedACR50, PedACR70, and PedACR90 response rates will also be summarized 
by Baseline age group, concomitant MTX use, overall anti-CZP antibody status, gender and 
race pooling across all weight groups.  
Change #20 
Section 10.3.10 Clinical Remission on Medication 
Both summaries of CRM and time to CRM will be provided.  
Has been changed to: 
Both summaries of CRM and time to CRM will be provided by the Reduced CZP Dose 
Regimen, the Original CZP Dose Regimen Overall, and the Any CZP Dose Regimen. 
13.2 
AMENDMENT 2 
Rationale for the amendment 
The primary reason for this SAP amendment was to add growth analyses and also change 
efficacy analysis to present Original CZP Dose Regimen Overall which is more appropriate 
for long term data post week 24. 
Modifications and changes 
Global changes 
All efficacy and health outcome summaries were changed from presented by “Original CZP 
Dose Regimen prior to dose reduction” to “Original CZP Dose Regimen” regardless of dose 
reduction. 
Specific changes 
Change #1 
 SAP Amendment 2      24 June 2016  
has been added to cover page. 
Change #2 
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NRI 
Nonresponder Imputation 
has been added to List of Abbreviations. 
Change #3 
Section 1 Introduction 
This document describes the planned analyses and summary tables, figures, and listings to be 
included in the interim and final clinical study reports (CSR) for RA0043. 
Has been changed to: 
This document describes the planned analyses and summary tables, figures, and listings to be 
included in the Week 56 interim and final clinical study reports (CSR) for RA0043. Note that 
Week 16 and Week 24 interim analyses were completed as specified in SAP Amendment 1 
and text about these analyses will be kept as is. 
Change #4 
Section 2.3 Study design and conduct (last two paragraphs) 
An interim analysis of the PedACR30 Week 16 response rate will be performed after all 
active study participants have completed the Week 16 (Visit 8) assessments. If less than 50% 
of the study population enrolled on the reduced CZP dose regimen (Protocol Amendment 5) 
achieves a PedACR30 response at Week 16, the study will be discontinued.  Statistical output 
for this Week 16 interim analysis will be restricted to a limited subset of the tables and 
listings described in the current SAP (see Section 3.1). 
For purposes of regulatory submissions, full interim analyses will be performed after all 
active study participants have completed the Week 24 (Visit 10) assessments and after all 
active study participants have completed the Week 56 (Visit 14) assessments.  All statistical 
tables, figures and listings comprising the current SAP will be produced for both Week 24 
and Week 56 full interim analyses, as well as the final analysis of the study. 
Has been changed to: 
An interim analysis of the PedACR30 Week 16 response rate will be performed after all 
active study participants have completed the Week 16 (Visit 8) assessments. If less than 50% 
of the study population enrolled on the reduced CZP dose regimen (Protocol Amendment 5) 
achieves a PedACR30 response at Week 16, the study will be discontinued.  Statistical output 
for this Week 16 interim analysis were completed and were restricted to a limited subset of 
the tables and listings as described in SAP Amendment 1 
Full interim analyses will be performed after all active study participants have completed the 
Week 24 (Visit 10) assessments and after all active study participants have completed the 
Week 56 (Visit 14) assessments.  Week 24 full interim analyses were completed as described 
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in SAP Amendment 1. All statistical tables, figures and listings comprising this SAP will be 
produced for Week 56 full interim analyses, as well as the final analysis of the study. 
Change #5 
Section 3.1 General presentation of summaries and analyses 
However, for efficacy data, summaries will generally be presented by the Reduced CZP Dose 
Regimen, the Original CZP Dose Regimen Prior to Dose Reduction, and the Any CZP Dose 
Regimen. 
Has been changed to: 
Note that for efficacy data, summaries will be presented by the Reduced CZP Dose Regimen, 
the Original CZP Dose Regimen (regardless of dose reduction), and the Any CZP Dose 
Regimen. 
Change #6 
Section 3.2 General study level definitions 
The analysis time points of interest are Screening, Baseline, Week 1, Week 2, Week 4, Week 
8, Week 12, Week 16, Week 17, Week 20, Week 24, Week 32, every 8 weeks after Week 32, 
and the Early Discontinuation/End of Treatment (EOT) Visit. Safety assessments will also be 
done at the Final Visit 12 weeks after the final dose of CZP. 
For study participants who withdraw prior to the last time point for the particular analysis 
being conducted (ie, Week 16, Week 24, Week 56, Final), data recorded at the Early 
Discontinuation/EOT Visit will be assigned to what would have been the next scheduled visit 
for the particular assessment that is being summarized, unless unavailable or otherwise 
specified. These data will be included in the summaries of the assigned visit and the “Early 
Discontinuation/EOT” Visit if applicable. 
Has been changed to: 
The analysis time points of interest are Screening, Baseline, Week 1, Week 2, Week 4, Week 
8, Week 12, Week 16, Week 17, Week 20, Week 24, Week 32, every 8 weeks after Week 32, 
and the Early Discontinuation /End of Treatment (EOT) Visit. Safety assessments will also be 
done at the Final Visit 12 weeks after the final dose of CZP. 
For study participants who withdraw prior to the last time point for the particular analysis 
being conducted (ie, Week 16, Week 24, Week 56, Final), data recorded at the Early 
Discontinuation/EOT Visit will be assigned to what would have been the next scheduled visit  
, unless unavailable or otherwise specified. These data will be included in the summaries of 
the assigned visit and the “Early Discontinuation/EOT” Visit if applicable. For efficacy data, 
the Early Discontinuation/EOT Visit will not be summarized and only the re-assigned visit 
will be included in the summary tables. Note that data from the Early Discontinuation Visit or 
EOT will be listed as “Visit X (Week Y)/ED” or “Visit X (Week Y)/EOT” where the X was 
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the re-assigned visit number and Y was the re-assigned week number in all safety and 
efficacy data listings as applicable. 
Change #7 
Section 3.6 Treatment assignment and treatment groups 
For PK, safety and efficacy analyses, study participants will be grouped by their Baseline 
weight group. Selected analyses will also group study participants by their Baseline age 
group, concomitant MTX use, and overall anti-CZP antibody status (as defined in Section 
8.2).  Additionally, PK and selected safety data will be presented by CZP dose regimen 
(Reduced vs. Original CZP Dose Regimen).  For study participants enrolled on the original 
CZP dose regimen, data will be tabulated overall, and selected data will be further subdivided 
into events and assessments occurring prior to and following dose reduction. Efficacy 
summaries will generally be presented by the Reduced CZP Dose Regimen, the Original CZP 
Dose Regimen Prior to Dose Reduction, and the Any CZP Dose Regimen. 
Has been changed to: 
For PK, safety and efficacy analyses, study participants will be grouped by their Baseline 
weight group. Selected analyses will also group study participants by their Baseline age 
group, concomitant MTX use, and overall anti-CZP antibody status (as defined in Section 
8.2).  Additionally, PK and selected safety data will be presented by CZP dose regimen 
(Reduced vs. Original CZP Dose Regimen).  For study participants enrolled on the original 
CZP dose regimen, data will be tabulated overall, and selected data will be further subdivided 
into events and assessments occurring prior to and following dose reduction. Efficacy 
summaries will be presented by the Reduced CZP Dose Regimen, the Original CZP Dose 
Regimen, and the Any CZP Dose Regimen. 
Change #8 
Section 3.9 Changes to protocol-defined analyses 
For all efficacy analyses, the protocol stated that results would be presented by the Reduced, 
Original, and Any CZP Dose Regimen groups. However, for more relevant comparisons of 
interest, summaries of all efficacy endpoints are generally presented by the Reduced CZP 
Dose Regimen, the Original CZP Dose Regimen Prior to Dose Reduction, and the Any CZP 
Dose Regimen. 
has been deleted. 
Change #9 
Section 3.9 Changes to protocol-defined analyses 
For joints with limitation of motion (LOM), it was stated in the protocol that the assessment 
of LOM would be made using 69 of the 75 joints from the standard PRINTO/PRCSG 
standard joint examination; however, the assessment described in the SAP that utilized 
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67 joints was conducted. This was according to an updated definition of LOM in the 
PRINTO/PRCSG assessment at the time of finalization of the original SAP. 
has been added. 
Change #10 
Section 4.2 Handling of dropouts or missing data 
For continuous efficacy endpoints, missing assessments will be imputed using an LOCF 
approach.  
Has been changed to: 
For continuous efficacy endpoints, missing assessments will be imputed using an LOCF 
approach. For Week 56 and final analyses, LOCF will only be applied to study participants 
who have discontinued early prior to reaching the Week 56 visit and data will be carried 
forward up to the Week 56 visit as appropriate. Data beyond Week 56 will be analyzed as 
observed cases without any imputation. The same rule will also be applied in nonresponder 
imputation (NRI) calculations for binary efficacy outcomes. 
Change #11 
Section 4.2.1 Handling of questionnaire data 
The following rules will apply for analysis of (1) out of range and (2) ambiguous answers 
(i.e. invalid or unable to interpret answers) to questionnaires completed by study participants 
or parents/caregivers: 
Has been changed to: 
When relevant, the following rules will apply for analysis of (1) out of range and (2) 
ambiguous answers (i.e. invalid or unable to interpret answers) to questionnaires completed 
by study participants or parents/caregivers: 
Change #12 
Section 4.3 Interim analysis and data monitoring 
Comparisons will be made between the geometric mean and median values for the pediatric 
and adult study participants, as well as between the individual pediatric data and the adult 5th 
and 95th percentile and minimum and maximum observed values. 
If the pediatric plasma concentrations demonstrate that the geometric mean and median 
concentrations are below the adult 5th percentile or above the 95th percentile, the PK data will 
be used to re-evaluate the weight-based dose adjustment algorithm for pediatric study 
participants. If necessary, a revised pediatric dosing algorithm will be derived. Any change in 
dose regimen will require a protocol amendment prior to implementation. 
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Has been changed to: 
Comparisons will be made between the geometric mean for the pediatric and adult study 
participants, as well as between the individual pediatric data and the adult 5th and 95th 
percentile and minimum and maximum observed values. 
If the pediatric plasma concentrations demonstrate that the geometric mean and pediatric data 
are below the adult 5th percentile or above the 95th percentile, the PK data will be used to re-
evaluate the weight-based dose adjustment algorithm for pediatric study participants. If 
necessary, a revised pediatric dosing algorithm will be derived. Any change in dose regimen 
will require a protocol amendment prior to implementation. 
Change #13 
Section 4.7 Examination of subgroups 
• Concomitant MTX use:  
o with 
o without 
Has been changed to: 
• Concomitant MTX use (distinct from Baseline MTX use presented in Section 6.1 and 
defined as any concomitant MTX use during the Treatment Period)::  
o With concomitant MTX use 
o Without concomitant MTX use 
Change #14 
Section 5.1 Subject disposition 
The number and percentage of study participants who were treated, who completed the study, 
and who discontinued from the study, along with the discontinuation reasons, will be 
summarized for the Enrolled Set.  For the Week 16, Week 24 and Week 56 interim analyses, 
number of study participants completing Week 16, Week 24 and Week 56 (respectively) will 
replace number completing the study. The number of study participants in each analysis set 
will be presented for the Enrolled Set. Both summaries will be provided for the Reduced, 
Original, and Any CZP Dose Regimen groups. 
Has been changed to: 
The number and percentage of study participants who were treated, who completed the study, 
and who discontinued from the study, along with the discontinuation reasons, will be 
summarized for the Safety Set.  For the Week 16, Week 24 and Week 56 interim analyses, 
number of study participants completing Week 16, Week 24 and Week 56 (respectively) will 
be added in addition to the number completing the study as appropriate. The number of study 
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participants in each analysis set will be presented. Summaries will be provided for the 
Reduced, Original, and Any CZP Dose Regimen groups. 
Change #15 
Section 5.2 Protocol deviations 
The number and percentage of study participants with important protocol deviations will be 
summarized by type for the ES for the Any CZP Dose Regimen. All important protocol 
deviations will also be listed. 
Has been changed to: 
The number and percentage of study participants with important protocol deviations will be 
summarized by type for the SS for the Any CZP Dose Regimen. All important protocol 
deviations will also be listed. 
Note that partial PK data exclusion is implemented due to certain protocol deviations (eg, 
incorrect treatment or dose, procedural noncompliance related to PK sampling), minor 
deviations from the planned treatment schedule (eg, delays or missing doses not considered 
as important protocol deviations), CZP interruption or CZP discontinuation due to AEs, 
TB prophylactic treatment, or clinical remission. These exclusions will be reviewed and 
identified at data cleaning meetings and are only applicable for group PK summary tables and 
graphs where the geometric mean for plasma concentration are calculated and displayed. 
However, all PK data will be included in listings, individual graphs, and PopPK analysis. 
Study participants with at least one PK data exclusion are summarized and listed. 
When applicable, exclusion from analysis set will also be summarized and listed. 
Change #16 
Section 6.1 Demographics 
Demographics will be summarized for the SS and the PK-PP Set for the Reduced, Original, 
and Any CZP Dose Regimen groups. The following continuous variables will be summarized 
by Baseline weight group: age (years), weight (kg), height (cm), and body mass index (BMI) 
(kg/m2) at Baseline. 
The following categorical variables will be summarized by Baseline weight group: gender 
(male, female), racial group (American Indian/Alaskan Native, Asian, Black, Native 
Hawaiian or Other Pacific Islander, White, Other/Mixed), ethnicity (Hispanic or Latino, Not 
Hispanic or Latino), Baseline age group (2 to 5 years, 6 to 11 years, and 12 to 17 years), and 
Baseline concomitant MTX use group (with, without). 
Has been changed to: 
Demographics will be summarized for the SS and the PK-PP Set for the Reduced, Original, 
and Any CZP Dose Regimen groups. The following continuous variables will be summarized 
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by Baseline weight group: age (years), weight (kg), height (cm), body surface area (BSA) and 
body mass index (BMI) (kg/m2) at Baseline. 
The following categorical variables will be summarized by Baseline weight group: gender 
(male, female), racial group (American Indian/Alaskan Native, Asian, Black, Native 
Hawaiian or Other Pacific Islander, White, Other/Mixed), ethnicity (Hispanic or Latino, Not 
Hispanic or Latino), Baseline age group (2 to 5 years, 6 to 11 years, and 12 to 17 years), and 
Baseline MTX use group (with, without). 
Change #17 
Section 6.2 Other baseline characteristics 
Baseline characteristics described in this section will be summarized for the SS and the PK-
PP Set for the Reduced, Original, and Any CZP Dose Regimen groups. Time since first 
diagnosis of JIA (or onset of signs and symptoms consistent with a diagnosis of JIA for those 
enrolled after Protocol Amendment 3) will be summarized in years. The time will be 
calculated as the duration from the date of first diagnosis of JIA to the date of informed 
consent; time since diagnosis will not be calculated when date of diagnosis is missing. The 
number and percentage of study participants with a history of each of the following JIA 
categories will also be summarized: 
Has been changed to: 
Baseline characteristics described in this section will be summarized for the SS and the PK-
PP Set for the Reduced, Original, and Any CZP Dose Regimen groups. Time since first 
diagnosis of JIA (or onset of signs and symptoms consistent with a diagnosis of JIA for those 
enrolled after Protocol Amendment 3) will be summarized in years. The time will be 
calculated as the duration from the date of first diagnosis of JIA to Baseline (Week 0 
[Visit2]); time since diagnosis will not be calculated when date of diagnosis is missing. The 
number and percentage of study participants with a history of each of the following JIA 
categories will also be summarized: 
Change #18 
Section 6.4 Prior and concomitant medications 
Prior medications include any medications that started prior to the start date of study 
medication, and also include any medications that continue post-Baseline. Past medications 
are a subset of prior medications, and include prior medications with a stop date before the 
date of first study medication administration. Concomitant medications are medications taken 
at least one day in common with the study medication dosing period. For Cimzia, the dosing 
period is from the date of first dose up to (but not including) 14 days post last dose.  Thus a 
concomitant medication is any medication whose start date is prior to the date of last study 
medication administration + 14 days, and whose stop date is either missing, or on or after the 
date of first study medication administration . 
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Has been changed to: 
Prior medications include any medications that started prior to the start date of study 
medication, and also include any medications that continue post-Baseline. Past medications 
are a subset of prior medications, and include prior medications with a stop date before the 
date of first study medication administration. Concomitant medications are medications taken 
at least one day in common with the study medication dosing period. For Cimzia, the dosing 
period is from the date of first dose up to (but not including) 14 days Q2W (or 28 days if 
Q4W) post last dose if a subject discontinued early or at end of treatment per protocol. For 
ongoing study participants, the dosing period is from the date of first dose up to the data 
cutoff date in interim analyses.  Thus a concomitant medication is any medication whose start 
date is prior to the date of last study medication administration + 14 days Q2W (or +28 days 
if Q4W) or data cutoff date, and whose stop date is either missing, or on or after the date of 
first study medication administration. 
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Change #19 
Section 6.5 Prohibited medications 
The +1 day rule was applied to the first usage date when considering its impact on efficacy 
endpoints. Therefore, only efficacy data with dates after the first usage date of the prohibited 
medication were impacted (using the nonresponder imputation (NRI) or LOCF imputation 
method). 
has been added. 
Change #20 
Section 6.6 Rescue medications 
• Higher than Baseline dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and 
cyclooxygenase-2 (COX-2) inhibitors, including as needed (PRN) use within 72 hours 
prior to scheduled study visit. 
• Higher than Baseline dose of analgesics or opioids including PRN use within 48 hours 
prior to scheduled study visit. 
• Any increase in dose of oral corticosteroids within 7 days prior to scheduled study visit. 
Has been changed to: 
• Higher than Baseline dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and 
cyclooxygenase-2 (COX-2) inhibitors, including as needed (PRN) use within 72 hours 
prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
• Higher than Baseline dose of analgesics or opioids including PRN use within 48 hours 
prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
• Any increase in dose of oral corticosteroids within 7 days prior to scheduled study visit 
(Note: The increase has to be higher than baseline). 
Change #21 
  Section 6.6 Rescue medications 
Generally, the +1 day rule was applied to the first usage date when considering its impact on 
efficacy endpoints. Therefore, only efficacy data with dates after the first usage date of the 
rescue medication were impacted (using the nonresponder imputation (NRI) or LOCF 
imputation methods). Exceptions are nonsteroidal anti-inflammatory drugs (NSAIDs), 
cyclooxygenase-2 (COX-2) inhibitors, analgesics or opioids, or oral corticosteroids as 
specified above. 
has been added. 
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Change #22 
Section 7 Measurements of treatment compliance 
Descriptive statistics will be presented for the total dose received/total dose expected for the 
SS. Total dose received is the sum of the dose level for each recorded study medication 
administration. Total dose expected is based on the loading and maintenance doses for the 3 
different Baseline weight groups.  A subject is expected to receive 3 loading doses and then a 
maintenance dose Q2W through the Early Discontinuation/EOT Visit, with the exception of 
study participants enrolled after the implementation of Protocol Amendment 4; study 
participants in the 10 - <20kg weight group receive a maintenance dose Q4W. In addition, a 
subject’s expected dose could change if a subject crosses into a new weight group which will 
be considered in the above calculations. 
Treatment compliance will be provided for the SS for the Any CZP Dose Regimen only. 
Has been changed to: 
Descriptive statistics will be presented for the compliance ratio defined as total number of 
CZP administrations received/total number of CZP administrations expected for the SS. Total 
number of CZP administrations expected differs depending on the loading phase or 
maintenance phase as well as depends on the different dosing scheduling of the 3 different 
weight groups. For example, in the Original CZP Dose Regimen, a subject is expected to 
receive 3 loading CZP administrations and then a maintenance dose of CZP Q2W through the 
Early Discontinuation/EOT Visit, with the exception of following implementation of Protocol 
Amendment 4; study participants in the 10 to <20kg weight group change from Q2W to a 
maintenance dose of CZP Q4W. In addition, a subject could change dose (or frequency of 
dosing if in 10-20kg group) if a subject crossed into a new weight group, which is not 
considered in the above expected calculations of number of CZP administration since all 
expectations are based on baseline weight group dosing regimen regardless of weight change. 
This specifically applies to the change of dose frequency from Q4W to Q2W if a subject 
crossed into the 20 to <40kg weight group, which is not considered in the expected 
calculations. Note that the dose reduction of ongoing study participants following Protocol 
Amendment 4 is considered in the calculations. 
Treatment compliance is provided for the SS for the Reduced CZP Dose Regimen, Original 
CZP Dose Regimen Prior to Dose Reduction, Original CZP Dose Regimen Following Dose 
Reduction and Original CZP Dose Regimen Overall. 
Change #23 
Section 8.1 CZP plasma concentrations 
The geometric mean and CV% was derived when at least two-thirds of the concentrations at a 
certain visit were above the limit of quantification (LoQ).If that criteria was not met, only the 
maximum and minimum values were shown. Similarly, the 95% CI of the geometric mean 
was only calculated if at least 5 samples were available at that time point. Note that a separate 
partial PK exclusion regarding concentration calculation is detailed in section 5.2. 
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has been added. 
Change #24 
Section 8.2 Anti-CZP antibodies 
In addition, overall antibody status will be summarized: 
 
• Overall AB+ is defined as having a value > 2.4units/mL at any time in the 
treatment period (not including the safety follow-up period) 
 
• Overall AB- is defined as having no values > 2.4units/mL during the treatment period. 
Has been changed to: 
In addition, overall antibody status will be summarized: 
• Overall AB+ is defined as having a value > 2.4units/mL at any time in the 
treatment period (Note: All post-baseline data will be included except for the safety 
follow-up visit). 
 
• Overall AB- is defined as having no values > 2.4units/mL during the treatment period. 
Change #25 
Section 8.2 Anti-CZP antibodies 
In addition, graphical presentation of cumulative percentage of positive Anti-CZP antibody 
status will be presented by Reduced CZP Dose Regimen, Original CZP Dose Regimen Prior 
to Dose Reduction, and Original CZP Dose Regimen Following Dose Reduction respectively. 
has been added. 
Change #26 
Section 9.2 Adverse events 
Treatment emergent AEs (TEAEs) are defined as AEs starting on or after the first 
administration of CZP and up to 70 days after the last dose of study medication. AEs that 
start more than 70 days after the last dose of study medication will be flagged in the listing 
but excluded from summaries. 
Has been changed to: 
Only treatment emergent adverse events (TEAE) will be included in the summary tables. 
Treatment emergent AEs are defined as AEs starting on or after the first administration of 
CZP and up to 70 days after the last dose of study medication. AEs that are pre-treatment or 
that start more than 70 days after the last dose of study medication will be flagged in the 
listing but excluded from summaries. 
Change #27 
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Section 9.3 Clinical laboratory evaluations 
The following urinalysis parameters will be listed: pH, protein, glucose, and blood. If 
abnormalities are found from the dipstick test, microscopy (WBC, RBC, casts, crystals, and 
bacteria) will be performed. These results will also be listed. 
Has been changed to: 
The following urinalysis parameters will be tested locally only: pH, protein, glucose, and 
blood. If abnormalities are found from the dipstick test, microscopy (WBC, RBC, casts, 
crystals, and bacteria) will be performed, and these results will be listed. XXXX 
Change #28 
Section 9.3 Clinical laboratory evaluations (Table 9-2) 
Parameter (Unit) 
Age Range 
Abnormal Definition 
Low 
High 
Lactate 
dehydrogenase 
(LDH) (IU/L) 
2-17y 
 
>1300 
Creatine Kinase (CPK) 
(IU/L) 
2-17y 
 
>600 
Reference: Based on Rheumatology CTC (Standardizing Assessment and Reporting of Adverse Effects 
in Rheumatology Clinical Trials II: the Rheumatology Common Toxicity Criteria v.2.0) 
THASIAWOODWORTH, DANIEL E. FURST, RIEKE ALTEN, CLIFTON BINGHAM, DAVID YOCUM, VICTOR 
SLOAN, WAYNE TSUJI, RANDALL STEVENS, JAMES FRIES, JAMES WITTER, KENT JOHNSON, MARISSA 
LASSERE, and PETER BROOKS  
has been added and updated. 
Change #29 
Section 9.4.2.1 Height and Weight 
Descriptive statistics for observed Baseline and post-Baseline values, and change from 
Baseline for post-Baseline measurements, will be presented separately for height (in cm) and 
weight (in kg). Pre-study values of height and weight will only be included in the listings. 
Summaries of Baseline and post-Baseline height and weight will be provided for the Any 
CZP Dose Regimen only. 
Has been changed to: 
Descriptive statistics for Baseline and post-Baseline values at selected time points of interest, 
and change from Baseline for selected time points for percentile height-for-age and percentile 
weight –for-age (based on growth curves and percentile calculation methods published by 
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CDC for children age 2-20  that was available on 27April 2016 at 
http://www.cdc.gov/growthcharts/clinical_charts.htm  ) will be summarized by age group and 
gender for the Any CZP Dose Regimen. All weight and height will also be listed. 
Change #30 
Section 9.4.2.2 Tanner stages 
Assessments of study participants’ developmental stages on external genitalia and pubic hair 
(boys) and on breast and pubic hair (girls) will be performed to determine Tanner stages. 
Tanner stages will be assessed at Baseline, Weeks 24 and 48, every 24 weeks thereafter, and 
the Early Discontinuation/EOT Visit. Tanner stages will be listed by visit for each subject. 
Has been changed to: 
Assessments of study participants’ developmental stages on external genitalia and pubic hair 
(boys) and on breast and pubic hair (girls) will be performed to determine Tanner stages. 
Tanner stages will be assessed at Baseline, Weeks 24 and 48, every 24 weeks thereafter, and 
the Early Discontinuation/EOT Visit. A summary of shift table of Tanner stages from 
baseline to relevant post-treatment visit(s) (eg., 48 week) by age and gender will be provided 
for the Any CZP Dose Regimen. Overall Tanner stage at each visit is derived as the 
minimum stage of the 2 components. If one component is missing at a visit, then the overall 
stage will be set to missing for that visit. 
No imputation of missing data will be implemented. Tanner stages will be listed by visit for 
each subject. 
Change #31 
Section 10 Efficacy Analysis 
Efficacy will be analyzed using the FAS.  All efficacy results will be provided for the 
Reduced CZP Dose Regimen, the Original CZP Dose Regimen Prior to Dose Reduction, and 
the Any CZP Dose Regimen unless otherwise specified. Efficacy data collected on the day of 
dose reduction will be grouped with all other data classified as occurring prior to dose 
reduction; any efficacy assessments collected after dose reduction will be classified as 
occurring following dose reduction. For subgroup efficacy analyses, summaries by Baseline 
age group, concomitant MTX use, and anti-CZP antibody status will be presented pooling 
across all weight groups unless otherwise specified. 
In addition to the efficacy summaries described below, all efficacy results will be listed by 
subject. 
Has been changed to: 
Efficacy will be analyzed using the FAS.  All efficacy results will be provided for the 
Reduced CZP Dose Regimen, the Original CZP Dose Regimen, and the Any CZP Dose 
Regimen. For subgroup efficacy analyses, summaries by Baseline age group, concomitant 
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MTX use, and anti-CZP antibody status will be presented pooling across all weight groups 
unless otherwise specified. In addition, selected summaries will also be presented by gender 
and race. 
In addition to the efficacy summaries described below, all efficacy results will be listed by 
subject. However, some listings for study participants in Original CZP Dose Regimen may be 
grouped by study participants with dose reduction and study participants without dose 
reduction within each weight group. 
Change #32 
Section 10.2 Statistical analysis of the secondary efficacy variables 
If 2 or more core set measures are missing, the corresponding PedACR30, PedACR50, 
PedACR70 and PedACR90 responses will also be treated as missing.  For core set measures 
with values of 0 at Baseline, the percentage change from Baseline cannot be calculated and is 
treated as missing. 
Has been changed to: 
If 2 or more core set measures are missing, the corresponding PedACR30, PedACR50, 
PedACR70 and PedACR90 responses will also be treated as missing.  For core set measures 
with values of 0 at Baseline, the percentage change from Baseline cannot be calculated for 
improvement, however, for worsening, the following rules will be applied:  
• If Baseline number of joints for active arthritis or with LoM was 0, an increase to at 
least 2 joints is required; 
• If Baseline Global Assessment scores is 0, worsen to a score at least 20 is required to 
be considered as a worsening of at least 30%;   
• If Baseline CHAQ scores is 0, worsen to a score of at least 0.125 is required to be 
considered as a worsening of at least 30%;  
Change #33 
Section 10.3 Analysis of other efficacy variables 
All efficacy variables described in this section will be summarized overall and by Baseline 
weight group, and will be provided for the Reduced CZP Dose Regimen, the Original CZP 
Dose Regimen Prior to Dose Reduction, and the Any CZP Dose Regimen unless specified 
otherwise. 
Continuous endpoints will be summarized using LOCF for missing values. 
Has been changed to: 
All efficacy variables described in this section will be summarized overall and by Baseline 
weight group, and will be provided for the Reduced CZP Dose Regimen, the Original CZP 
Dose Regimen, and the Any CZP Dose Regimen unless specified otherwise. 
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Continuous endpoints will be summarized using LOCF for missing values, unless otherwise 
specified, as for the Juvenile Arthritis School Attendance and Caregiver Work Productivity 
Survey.  
Change #34 
Section 10.3.10 Clinical Remission on Medication 
Both summaries of CRM and time to CRM will be provided by the Reduced CZP Dose 
Regimen, the Original CZP Dose Regimen Overall, and the Any CZP Dose Regimen. 
Has been changed to: 
Both summaries of CRM and time to CRM will be provided.  
Change #35 
Section 10.3.15 Juvenile Arthritis School Attendance and Caregiver Work Productivity 
Survey 
No LOCF imputation will be implemented and observed case will be used for all analyses in 
Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey data. 
has been added. 
13.3 
AMENDMENT 3 
Rationale for the amendment 
The primary reason for this SAP amendment was to update the text based on Protocol 
Amendment #9. 
Modifications and changes 
Global changes 
The use of “subjects” has been changed to “study participants” throughout the document to 
match Protocol Amendment #9. 
The use of “AE” has been changed to “TEAE” when used in reference to summary analyses 
and listings. 
When referring to summarizing the data for the entire Reduced CZP Dose Regimen, Original 
CZP Dose Regimen or Any CZP Dose Regimen, the use of “overall” has been added for 
consistency to “Reduced CZP Dose Regimen Overall” (or “Reduced Overall”) and “Original 
CZP Dose Regimen Overall” (or Original Overall)” throughout sections 6, 7, 8, 9 and 10. 
Specific changes 
Change #1 
SAP/Amendment  
Date 
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Final SAP 
23 Jun 2015 
SAP Amendment 1 
29 Sep 2015 
SAP Amendment 2 
24 Jun 2016 
 
Has changed to: 
SAP/Amendment  
Date 
Final SAP 
23 Jun 2015 
SAP Amendment 1 
29 Sep 2015 
SAP Amendment 2 
24 Jun 2016 
SAP Amendment 3 
30 Jun 2021 
 
Change #2 
The list of tables was added. 
Change #3 
The list of abbreviations has been updated to include the following abbreviations: 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
AST 
alanine aminotransferase 
aspartate aminotransferase 
COVID-19 
Coronavirus disease 2019 
ECG 
electrocardiogram 
ECLIA 
electrochemiluminescence immunoassay 
IMP 
investigational medicinal product 
IXRS 
interactive voice/web response system 
MAR 
missing at random 
NRS 
numeric rating scale 
PD 
Pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
TE 
Treatment-emergent 
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Change #4 
Section 1 Introduction 
This document describes the planned analyses and summary tables, figures, and listings to be 
included in the Week 56 interim and final clinical study reports (CSR) for RA0043. Note that 
Week 16 and Week 24 interim analyses were completed as specified in SAP Amendment 1 
and text about these analyses will be kept as is. 
Has been changed to: 
This document describes the planned analyses and summary tables, figures, and listings to be 
included in the final clinical study report (CSR) for RA0043 as well as for the Updated Week 
24 and Week 56 interim analyses. Note that Week 16 and the 2016 Week 24 interim analyses 
were completed as specified in SAP Amendment 1 and text about these analyses will be kept 
as is. 
Change #5 
Section 2 Protocol Summary 
The primary objectives of the study are to evaluate the PK and safety including the 
immunogenicity of CZP administered subcutaneously (sc) in children and adolescents with 
moderate to severe polyarticular-course JIA. The secondary objective of the study is to assess 
the effectiveness of CZP on the clinical response in children and adolescents with moderate 
to severe polyarticular-course JIA. 
Has been changed to: 
The primary objectives of the study are to evaluate the PK and safety including the 
immunogenicity of CZP administered subcutaneously (sc) in children and adolescents with 
moderate to severe polyarticular-course JIA.  The primary PK and immunological variables 
are CZP plasma concentration and anti-CZP antibody levels at Week 16 and Week 48. 
Change #6 
The primary objectives of the study are to evaluate the PK and safety including the 
immunogenicity of CZP administered subcutaneously (sc) in children and adolescents with 
moderate to severe polyarticular-course JIA. The secondary objective of the study is to assess 
the effectiveness of CZP on the clinical response in children and adolescents with moderate 
to severe polyarticular-course JIA. 
An interim analysis of the American College of Rheumatology Pediatric 30% (PedACR30) 
response rate will be performed after all active subjects have completed the Week 16 (Visit 8) 
assessments. The study will be discontinued if less than 50% of the study population enrolled 
on the reduced CZP dose regimen (Protocol Amendment 5) achieves a PedACR30 response 
at Week 16. 
Full interim analyses will be performed after all active subjects have completed the Week 24 
(Visit 10) assessments and after all active subjects have completed the Week 56 (Visit 14) 
assessments. 
Has been changed to: 
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The primary objectives of the study are to evaluate the PK and safety including the 
immunogenicity of CZP administered subcutaneously (sc) in children and adolescents with 
moderate to severe polyarticular-course JIA.  The primary PK and immunological variables 
are CZP plasma concentration and anti-CZP antibody levels at Week 16 and Week 48. 
An interim analysis of the American College of Rheumatology Pediatric 30% (PedACR30) 
response rate was performed after all active study participants completed the Week 16 
(Visit 8) assessments. The study will be discontinued if less than 50% of the study population 
enrolled on the reduced CZP dose regimen (Protocol Amendment 5) achieves a PedACR30 
response at Week 16. A further futility analysis will not be performed using the additional 
study participants that will be enrolled after Protocol Amendment 9.  
A full interim analysis was performed in 2016 for all active study participants that had 
completed the Week 24 (Visit 10) assessments. After Protocol Amendment 9, full interim 
analyses will be performed after all active study participants have completed the Week 24 
(Visit 10) assessments and after all active study participants have completed the Week 56 
(Visit 14) assessments. 
Change #7 
The following updates have been added to the end of the Section 2 Protocol Summary 
section: 
Amendment 7: 22 Sep 2016 
Amendment 7.1 (Russia): 22 Sep 2016 
Amendment 8: 24 Jun 2019 
Amendment 8.1 (Russia): 18 Jul 2019 
Amendment 9: 27 Apr 2020 
Amendment 9.1 (Russia): 28 Jul 2020 
In order to adequately assess the exposure levels and clinical experience of CZP in JIA at 
both the reduced and original CZP dose regimen and also to adequately support the safety 
assessment of the original CZP dosing regimen, as more of the safety data collected in the 
study to date has been on the reduced dose, 30 additional study participants will be enrolled 
on the original CZP dose regimen following Protocol Amendment 9. 
All study participants enrolled under Protocol Amendment 9 or later will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using and 
electrochemiluminescence immunoassay (ECLIA) method that meets current regulatory 
standards. In addition, PK and ADA samples (for which sufficient volume is available) 
collected in this study prior to Protocol Amendment 9 will be analyzed with the ECLIA 
method. The collective ECLIA-based PK data for this study will form the basis of any future 
CZP modeling and simulation work. 
Change #8 
Section 2.2.1.1 Primary pharmacokinetic and immunological variables 
• CZP plasma concentrations 
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• Anti-CZP antibody concentrations 
has been changed to: 
• CZP plasma concentrations at Weeks 16 and 48 
• Anti-CZP antibody levels at Weeks 16 and 48 
Change #9 
Section 2.2.2.1 Primary safety variables 
The primary safety variable is the incidence of adverse events (AEs). 
Has been changed to: 
Section 2.2.1.2 
The primary safety variables are the incidence of serious treatment-emergent adverse events 
(TEAEs) and TEAEs leading to permanent withdrawal of investigational medicinal product 
(IMP). 
Adverse events will be solicited at every visit, recorded and coded according to Medical 
Dictionary for Regulatory Activities (MedDRA®) criteria. 
Change #10 
Section 2.2.2.1 Other safety variables 
• Clinical laboratory values (hematology, biochemistry, urinalysis) at every visit except 
Visits 3 and 4 (Week 1 and Week 2) and Unscheduled Visits 
• Vital signs at every visit 
• Developmental stages and growth (Tanner stages, height, weight) at Baseline, every 
24 weeks thereafter, and the Early Discontinuation/End of Treatment Visit (weight at 
every visit through Final Visit) 
• Autoantibody concentrations (antinuclear antibodies (ANA) and anti-double-stranded 
desoxyribonucleic acid (anti-dsDNA) antibodies) at Baseline (testing for anti-dsDNA 
antibodies only if ANA is positive), Weeks 16 and 48, and at the Early 
Discontinuation/End of Treatment Visit 
Has been changed to: 
Section 2.2.3.1 
Other PK and immunological variables 
• CZP plasma concentrations and anti-CZP antibody levels at other study timepoints 
Other safety variables are: 
• Incidence of TEAEs, TEAEs of interest, TEAEs by relatedness, TEAEs by severity, and 
TEAEs by duration of exposure 
• Clinical laboratory values (hematology, biochemistry, urinalysis) at every visit except 
Visits 3 and 4 (Week 1 and Week 2) and Unscheduled Visits 
• Vital sign abnormalities at every visit 
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• Developmental stages and growth (Tanner stages, height, weight) at Baseline, every 
24 weeks thereafter, and the Early Discontinuation/End of Treatment Visit (weight at 
every visit through Final Visit). For study participants enrolled prior to Protocol 
Amendment 9, Tanner stages assessment will be performed every 48 weeks following 
Protocol Amendment 8, and only for those study participants who have not reached 
Tanner stage V. 
• Autoantibody concentrations (antinuclear antibodies (ANA) and anti-double-stranded 
desoxyribonucleic acid (anti-dsDNA) antibodies) at Baseline (testing for anti-dsDNA 
antibodies only if ANA is positive), Weeks 16 and 48, and at the Early 
Discontinuation/End of Treatment Visit 
 Change #11 
Section 2.2.3.3 Other efficacy and health outcomes variables 
• Change from Baseline in Faces Pain Scale-Revised (FPS-R), daily during the first week 
of treatment; Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter through the 
Early Discontinuation/End of Treatment Visit. 
• Change from Baseline in JIA Pain VAS, daily during the first 7 days of the study (acute 
and standard versions); and at Weeks 4, 12, 16, and 24; and then every 8 weeks thereafter 
through the Early Discontinuation/End of Treatment Visit (standard version). 
Has been changed to: 
• Change from Baseline in Faces Pain Scale-Revised (FPS-R) (child-reported, ages 5 to 11 
years), at every post-Baseline visit except Final Visit 
• Change from Baseline in JIA Pain VAS, (acute and standard versions); at every post-
Baseline visit except Final Visit. 
Change #12 
Section 2.3 Study design and conduct 
Approximately 195 subjects will be screened to enroll 156 subjects in this study. The study 
consists of a Screening Period of up to 4 weeks; eligible subjects will then enter an open-label 
Treatment Period which will continue until the approval of the marketing application for the 
indication of polyarticular-course JIA in the subject’s country or region or until further notice 
from UCB. A Final Visit will be conducted 12 weeks after last dose of study medication. 
A minimum of 10 subjects will be enrolled on the reduced CZP dose regimen (Protocol 
Amendment 5) in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), 
and ≥40kg (≥88lb). A minimum of 10 subjects will be enrolled in each age category of 2 to 5 
years, 6 to 11 years, and 12 to 17 years, irrespective of the dose regimen. A minimum of 25 
subjects will be enrolled who receive CZP as monotherapy irrespective of the dose regimen. 
A minimum of 10 subjects with ERA will be enrolled, irrespective of the dose regimen. Each 
of these categories is assessed independently. 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 (minimum=50mg every 2 weeks 
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[Q2W], maximum=200mg Q2W) followed by a maintenance dose (minimum=50mg every 4 
weeks [Q4W], maximum=100mg Q2W). Prior to implementation of Protocol Amendments 4 
and 5, the minimum and maximum loading doses in the study were CZP 100mg Q2W and 
CZP 400mg Q2W, respectively, and the minimum and maximum maintenance doses were 
CZP 50mg Q2W and CZP 200mg Q2W, respectively.  
Interim analysis of PK data will compare plasma concentration data from this study with CZP 
plasma concentrations observed previously in adult subjects with rheumatoid arthritis (RA) 
(study C87050). This CZP plasma concentration analysis will be done on an ongoing basis 
throughout the study, starting when 6 subjects in 1 of the age groups have completed Week 
12 (Visit 7). Interim CZP plasma concentration data available at the time of Protocol 
Amendment 3 indicated that no change to the dosing algorithm was required. The protocol 
stated that if future analyses indicate that plasma concentrations of JIA subjects are outside of 
the exposure range observed in previous adult RA studies, the dosing algorithm may be 
changed via a protocol amendment. 
Results of an interim population PK (PopPK) analysis suggest that while observed CZP 
plasma concentrations have remained in the adult range, they have been at the upper end of 
the distribution. Simulations predict that for some subjects in RA0043 receiving the 
originally determined loading doses up to Week 4 (Visit 5), plasma concentrations are likely 
to exceed the range previously seen in adult subjects receiving CZP 400mg Q2W. 
Furthermore, plasma concentrations of subjects receiving the originally determined 
maintenance dose after Week 4 (Visit 5) are predicted to exceed the concentration range 
observed in adults receiving CZP 200mg Q2W. Based on these findings, the dosing regimen 
will be changed with Protocol Amendments 4 and 5, and the doses to be administered will be 
reduced by 50% for all weight groups. This dose change is intended to achieve plasma 
concentrations that are similar to the effective concentrations observed in previous studies in 
adult subjects with RA. Continued analysis of CZP plasma concentrations (including 
additional assessments for subjects undergoing a dose reduction with Protocol Amendments 4 
and 5) will be performed to confirm that the 50% dose reduction will result in plasma 
concentrations within the target range of those observed in adults. 
An interim analysis of the PedACR30 Week 16 response rate will be performed after all 
active subjects have completed the Week 16 (Visit 8) assessments. If less than 50% of the 
study population enrolled on the reduced CZP dose regimen (Protocol Amendment 5) 
achieves a PedACR30 response at Week 16, the study will be discontinued.  Statistical output 
for this Week 16 interim analysis were completed and were restricted to a limited subset of 
the tables and listings as described in SAP Amendment 1 
Full interim analyses will be performed after all active subjects have completed the Week 24 
(Visit 10) assessments and after all active subjects have completed the Week 56 (Visit 14) 
assessments.  Week 24 full interim analyses were completed as described in SAP 
Amendment 1. All statistical tables, figures and listings comprising this SAP will be 
produced for Week 56 full interim analyses, as well as the final analysis of the study. 
Has been changed to: 
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The study consists of a Screening Period of up to 4 weeks; eligible study participants will 
then enter an open-label Treatment Period which will continue until the approval of the 
marketing application for the indication of polyarticular-course JIA in the study participant’s 
country or region or until further notice from UCB.  A Final Visit will be conducted 12 weeks 
after last dose of study medication. 
The table below shows the data collection schedule prior to Protocol Amendment 8 and after 
implementing Protocol Amendment 8. For the study participants who switch to the 16 week 
schedule, the date of the first visit of this schedule will be captured on the “Study 
Participation” CRF module. 
Table 2-2 Visit Schedule  
Collected/ Assessed/ 
Administered at 
Prior to Protocol Amendment 8 
Following Protocol Amendment 8 
Most parameters  
Screening, Baseline, Weeks 4, 8, 12, 16, 
20, 24, 32 and every 8 weeks thereafter, 
the Early Discontinuation/End of 
Treatment Visit, and the Final Visit 
Screening, Baseline, Weeks 4, 8, 12, 16, 
20, 24, 32 and every 16 weeks thereafter, 
the Early Discontinuation/End of 
Treatment Visit, and the Final Visit 
Height 
Screening, Baseline, every 24 weeks 
thereafter and Early 
Discontinuation/End of Treatment Visit 
Screening, Baseline, every 48 weeks 
thereafter and Early Discontinuation/End 
of Treatment Visit; assessed study 
participants who have not reached Tanner 
stage V 
Tanner 
Screening, Baseline, every 24 weeks 
thereafter and Early 
Discontinuation/End of Treatment Visit 
Screening, Baseline, every 48 weeks 
thereafter and Early Discontinuation/End 
of Treatment Visit; assessed study 
participants who have not reached Tanner 
stage V 
FPS-R and JIA Pain 
VAS 
Baseline and then daily during the first 
week of the study; at Weeks 4, 12, 16, 
24 and 32; and then every 8 weeks 
thereafter through the Early 
Discontinuation/End of Treatment 
Baseline and then daily during the first 
week of the study; at Weeks 4, 12, 16, 24 
and 32; and then every 16 weeks 
thereafter through the Early 
Discontinuation/End of Treatment 
NRS 
Baseline, Weeks 1, 2, 4, 8, and then 
every 8 weeks thereafter through the 
Early Discontinuation/End of Treatment 
Baseline, Weeks 1, 2, 4, 8, 16, 24, 32 and 
then every 16 weeks thereafter through 
the Early Discontinuation/End of 
Treatment 
 
Prior to Protocol Amendment 9, approximately 195 study participants are planned to be 
screened to enroll 156 study participants in this study, as follows: 
• A minimum of 10 study participants will be enrolled on the reduced CZP dose regimen 
(Protocol Amendment 5) in each weight range of 10 < 20kg (22 to <44lb), 20 to <40kg 
(44 to <88lb), and >40kg (>88lb). 
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• A minimum of 10 study participants will be enrolled in each age category of 2 to 5 years, 
6 to 11 years, and 12 to 17 years, irrespective of the dose regimen. 
• A minimum of 25 study participants will be enrolled who receive CZP as monotherapy 
(ie, study participants with established intolerability or inadequate response to MTX), 
irrespective of the dose regimen. 
• A minimum of 10 study participants with ERA will be enrolled, irrespective of the dose 
regimen. 
Each of these categories is assessed independently. In order to further support the safety 
assessment of the original CZP dose, as more of the safety data collected in the study to date 
has been on the reduced dose, an additional 30 study participants will be enrolled on the 
original dose regimen with the aim to enroll at least 5 study participants in each weight range 
of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and >40kg (>88lb) following 
Protocol Amendment 9. 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 followed by maintenance doses 
Q2W. The original minimum and maximum loading doses in the study were CZP 100mg 
Q2W and CZP 400mg Q2W, respectively, and the original minimum and maximum 
maintenance doses were CZP 50mg Q2W and CZP 200mg Q2W, respectively.  
Based on interim PopPK analysis of RA0043 data, the minimum and maximum loading doses 
in the study were adjusted to CZP 50mg Q2W and CZP 200mg Q2W, respectively, and the 
minimum and maximum maintenance doses were adjusted to GZP 50mg Q4W and CZP 
100mg Q2W, respectively, following implementation of Protocol Amendments 4 and 5. 
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPk analysis and 
simulations that informed the dose reduction in Protocol Amendments 4 and 5 unusable from 
a regulatory standpoint. Accordingly, PK samples were no longer collected for study 
participants on the reduced CZP dose regimen following implementation of Protocol 
Amendment 8. 
An ECLIA method, for which selectivity had previously been assessed in the RA matrix, has 
now been validated to meet the standards set in the regulatory guidance for analytical 
procedures and methods validations for drugs and biologics. 
Based on 24-week interim results from the first 163 study participants enrolled in RA0043, 
both the original and reduced dose regimens showed safety profiles similar to the approved 
CZP dose regimen in the adult RA population.  The overall clinical response in this analysis 
(taking both dose regimens into account) was PedACR30 and PedACR50 responses of 77.3% 
and 67.5%, respectively at Week 12. The response from the original dose regimen was 75.6% 
for PedACR30 and 64.1% for PedACR50.  PedACR50 response demonstrates a highly 
clinically relevant decrease in disease activity. 
Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
JIA at both the reduced and original CZP dose regimens and also to adequately support the 
safety assessment of the original CZP dose regimen, as more of the safety data collected in 
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the study to date has been on the reduced dose, 30 additional study participants will be 
enrolled on the original CZP dose regimen following Protocol Amendment 9. All study 
participants enrolled following Protocol Amendment 9 will have plasma concentrations of 
CZP and anti-CZP antibodies analyzed using the ECLIA method. In addition, PK and ADA 
samples (for which sufficient volume is available) collected in this study prior to Protocol 
Amendment 9 will be analyzed with the ECLIA method. The collective ECLIA-based PK 
data for this study will form the basis of any future CZP modeling and simulation work. 
Full interim analyses were performed in 2016 after all active study participants completed the 
Week 24 (Visit 10) assessments.  Week 24 full interim analyses were completed as described 
in SAP Amendment 1. SAP Amendment 3 comprises the analyses to be completed for an 
Updated Week 24 (Visit 10) interim, Week 56 (Visit 14) interim and the final analysis of the 
study. 
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Change #13 
Section 2.4 Determination of sample size 
Based upon the ICH guideline for the assessment of safety, it is planned to enroll a sufficient 
number of subjects to this study to have a minimum of 100 with at least 12 months 
continuous exposure to CZP. Assuming a dropout rate of approximately 20%, it was 
originally determined that 125 subjects would need to be enrolled. At the time of Protocol 
Amendment 5, 78 subjects had been enrolled according to the original CZP dose regimen, 
and it is planned to enroll a further 78 subjects on the reduced CZP dose regimen, so that a 
comparable number of subjects on the reduced CZP dose regimen can be analyzed. Thus, the 
total number of subjects planned to be enrolled will be increased to 156 subjects. Assuming a 
Screening failure rate of 25%, it is planned to screen 195 subjects in total. 
Prior to the start of study conduct, simulations using the adult population PK model in 
pediatric subjects with JIA suggested that the planned sample size of 125 subjects was 
adequate for PK assessment purposes. Individual apparent clearance (CL/F) and volume of 
distribution (V/F) were simulated for a total of 125 subjects (using the same approach 
presented in C87079 report addendum 08 Oct 2008 performed for 190 subjects). In all age 
groups, the standard errors of both PK parameters, CL/F and V/F, relative to their mean were 
substantially <20%, with values ranging from 5.5 to 7.0% for CL/F and from 4.6 to 7.5% for 
V/F. 
Available data from all subjects will be included in the final PopPK analysis, and therefore 
should allow CL/F and V/F to be determined with sufficient precision. 
Has been changed to: 
Based upon the ICH guideline for the assessment of safety, it is planned to enroll a sufficient 
number of study participants to this study to have a minimum of 100 with at least 12 months 
continuous exposure to CZP. Assuming a dropout rate of approximately 20%, it was 
originally determined that 125 study participants would need to be enrolled. At the time of 
Protocol Amendment 5, 78 study participants had been enrolled according to the original 
CZP dose regimen, and it was planned to enroll a further 78 study participants on the reduced 
CZP dose regimen, so that a comparable number of study participants on the reduced CZP 
dose regimen could be analyzed. Thus, the total number of study participants planned to be 
enrolled was increased to 156 study participants. Assuming a Screening failure rate of 25%, it 
was planned to screen 195 study participants in total. 
With Protocol Amendment 9, an additional 30 study participants will be enrolled on the 
original dose regimen with the aim to enroll at least 5 study participants in each weight range 
of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and >40kg (>88lb). 
Prior to the start of study conduct, simulations using the adult population PK model in 
pediatric study participants with JIA suggested that the planned sample size of 125 study 
participants was adequate for PK assessment purposes. Individual apparent clearance (CL/F) 
and volume of distribution (V/F) were simulated for a total of 125 study participants (using 
the same approach presented in C87079 report addendum 08 Oct 2008 performed for 190 
study participants). In all age groups, the standard errors of both PK parameters, CL/F and 
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V/F, relative to their mean were substantially <20%, with values ranging from 5.5 to 7.0% for 
CL/F and from 4.6 to 7.5% for V/F. 
Available ECLIA-based data from all study participants will be included in the final PopPK 
analysis, and therefore should allow CL/F and V/F to be determined with sufficient precision.  
Change #14 
Section 3.1 General presentation of summaries and analyses 
• Reduced CZP Dose Regimen: includes all subjects who began treatment in accordance 
with the reduced CZP dosing regimen defined for the study (3 loading doses of CZP at 
Weeks 0, 2, and 4 [minimum=50mg Q2W, maximum=200mg Q2W] followed by a 
maintenance dose for the duration of the study [minimum=50mg Q4W, 
maximum=100mg Q2W]).  
• Original CZP Dose Regimen: includes all subjects who began treatment in accordance 
with the original CZP dosing regimen defined for the study (3 loading doses of CZP at 
Weeks 0, 2, and 4 [minimum=100mg Q2W, maximum=400mg Q2W] followed by a 
maintenance dose for the duration of the study [minimum=50mg Q2W, 
maximum=200mg Q2W]). This subgroup includes all subjects who began the study with 
this CZP dose regimen and received 1 or more doses of this regimen, regardless of any 
subsequent switch to the reduced CZP dose regimen. 
• Any CZP Dose Regimen: includes all subjects in the reduced and original CZP dosing 
regimens. 
For the Original CZP Dose Regimen group, selected data will be further subdivided into 
events and assessments occurring prior to and following dose reduction - namely Original 
CZP Dose Regimen Prior to Dose Reduction vs. Original CZP Dose Regimen Following 
Dose Reduction. Summaries of data following dose reduction for subjects who began 
treatment on the original CZP dose regimen will be restricted to subjects whose CZP dose 
was actually reduced.  Original CZP Dose Regimen subjects whose CZP dose was not 
reduced prior to study discontinuation will be excluded from summaries of data following 
CZP dose reduction. 
Summaries of data that have been subdivided as prior to vs. following dose reduction will 
generally assign data associated with the dose reduction visit to the “prior to dose reduction” 
category.  The only exception to this rule will be for AEs occurring on the same date as the 
dose reduction; classification of AEs occurring on the date of dose reduction will be based 
upon review and classification by the study physician.  
Generally, data will be summarized by the Reduced, Original, and Any CZP Dose Regimen 
groups with selected outputs further summarized by the Original CZP Dose Regimen Prior to 
Dose Reduction vs. the Original CZP Dose Regimen Following Dose Reduction.  
Note that for efficacy data, summaries will be presented by the Reduced CZP Dose Regimen, 
the Original CZP Dose Regimen (regardless of dose reduction), and the Any CZP Dose 
Regimen. 
Has been changed to: 
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• Reduced CZP Dose Regimen Overall: includes all study participants who began treatment 
in accordance with the reduced CZP dosing regimen defined for the study (3 loading 
doses of CZP at Weeks 0, 2, and 4 [minimum=50mg Q2W, maximum=200mg Q2W] 
followed by a maintenance dose for the duration of the study [minimum=50mg Q4W, 
maximum=100mg Q2W]). This subgroup includes all study participants who began the 
study with this CZP dose regimen and received 1 or more doses of this regimen, 
regardless of any subsequent switch to the original CZP dose regimen. 
o Under Protocol Amendment 9, study participants are allowed to escalate to the 
Original CZP Dose  
• Original CZP Dose Regimen Overall: includes all study participants who began treatment 
in accordance with the original CZP dosing regimen defined for the study (3 loading 
doses of CZP at Weeks 0, 2, and 4 [minimum=100mg Q2W, maximum=400mg Q2W] 
followed by a maintenance dose for the duration of the study [minimum=50mg Q2W, 
maximum=200mg Q2W]). This subgroup includes all study participants who began the 
study with this CZP dose regimen and received 1 or more doses of this regimen, 
regardless of any subsequent switch to the reduced CZP dose regimen. 
• Any CZP Dose Regimen: includes all study participants in the reduced and original CZP 
dosing regimens. 
For the Original CZP Dose Regimen Overall group, selected data will be further subdivided 
into events and assessments occurring prior to or without and following dose reduction - 
namely Original CZP Dose Regimen Prior to or Without Dose Reduction vs. Original CZP 
Dose Regimen Following Dose Reduction. Original CZP Dose Regimen study participants 
whose CZP dose was not reduced prior to study discontinuation will be excluded from 
summaries of data following CZP dose reduction; this will include the 30 study participants 
enrolled under Protocol Amendment 9 who do not dose reduce. Summaries of data following 
dose reduction for study participants who began treatment on the original CZP dose regimen 
will be restricted to study participants whose CZP dose was actually reduced and for the time 
that the dose was reduced.  If study participants escalate their dose after reduction (allowed 
after Protocol Amendment 9), that data may be summarized or listed separately.   
Summaries of data that have been subdivided as prior to or without dose reduction vs. 
following dose reduction vs following dose escalation will generally assign data associated 
with the dose reduction visit to the “prior to or without dose reduction” category and data 
associated with the dose escalation visit to the “dose reduction” category.  The only 
exceptions to this rule will be for AEs occurring on the same date as the dose reduction 
whereby the classification of AEs occurring on the date of dose reduction will be based upon 
review and classification by the study physician and for AEs on the same date as the dose 
escalation, whereby the classification of the AEs occurring on the date of dose escalation will 
also be based upon review and classification by study physician.  
Generally, data will be summarized by the Reduced Overall, Original Overall, and Any CZP 
Dose Regimen groups with selected outputs further summarized by the Original CZP Dose 
Regimen Prior to or Without Dose Reduction vs. the Original CZP Dose Regimen Following 
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Dose Reduction. Selected outputs will further summarize the data occurring during the 
Escalation CZP Dose Regimen. 
Note that for efficacy data, summaries will be presented by the Reduced CZP Dose Regimen 
Overall (regardless of dose escalation), the Original CZP Dose Regimen Overall (regardless 
of dose reduction or dose escalation), and the Any CZP Dose Regimen (regardless of dose 
reduction or dose escalation). 
Change #15 
Section 3.2.1 Analysis time points 
The analysis time points of interest are Screening, Baseline, Week 1, Week 2, Week 4, Week 
8, Week 12, Week 16, Week 17, Week 20, Week 24, Week 32, every 8 weeks after Week 32, 
and the Early Discontinuation /End of Treatment (EOT) Visit. Safety assessments will also be 
done at the Final Visit 12 weeks after the final dose of CZP. 
For subjects who withdraw prior to the last time point for the particular analysis being 
conducted (ie, Week 16, Week 24, Week 56, Final), data recorded at the Early 
Discontinuation/EOT Visit will be assigned to what would have been the next scheduled visit  
, unless unavailable or otherwise specified. These data will be included in the summaries of 
the assigned visit and the “Early Discontinuation/EOT” Visit if applicable. For efficacy data, 
the Early Discontinuation/EOT Visit will not be summarized and only the re-assigned visit 
will be included in the summary tables. Note that data from the Early Discontinuation Visit or 
EOT will be listed as “Visit X (Week Y)/ED” or “Visit X (Week Y)/EOT” where the X was 
the re-assigned visit number and Y was the re-assigned week number in all safety and 
efficacy data listings as applicable. 
Was revised to: 
The analysis time points of interest are detailed in Table 2‒2: Visit Schedule  . Safety 
assessments will also be done at the Final Visit 12 weeks after the final dose of CZP. 
For study participants who withdraw prior to the last time point for the particular analysis 
being conducted (ie, Week 16, Week 24, Week 56, Final), data recorded at the Early 
Discontinuation/EOT Visit will be assigned to what would have been the next scheduled 
visit, unless unavailable or otherwise specified, dependent on which visit schedule the study 
participant is following. These data will be included in the summaries of the assigned visit 
and the “Early Discontinuation/EOT” Visit if applicable. For efficacy data, the Early 
Discontinuation/EOT Visit will not be summarized and only the re-assigned visit will be 
included in the summary tables. Note that data from the Early Discontinuation Visit or EOT 
will be listed as “Visit X (Week Y)/ED” or “Visit X (Week Y)/EOT” where the X was the 
re-assigned visit number and Y was the re-assigned week number in all safety and efficacy 
data listings as applicable. 
Change #16The following section 3.2.3 was added describing Medications: 
The UCB study physician will review a listing of all medications and flag those which are 
steroids, DMARDs, anti-TNFs, NSAIDs, Cox 2 inhibitors, analgesics, opioids, experimental 
medications, vaccines, etc. This flagging is then used to generate various medication tables. 
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Change #17 
The following section 3.2.4 was added describing the Final Visit definition: 
Final visit is defined as the visit conducted 12 weeks after the last dose of study medication. 
Most efficacy variables state that the Final Visit data will not be included in table summaries; 
the data will be included in study participant data listings. 
Change #18 
Section 3.4 Protocol Deviations was updated with the following sentence: 
In addition, protocol deviations related to the impact of the global pandemic of coronavirus 
disease 2019 (covid-19) will be documented. 
Change #19 
Section 3.6 Treatment assignment and treatment groups 
All subjects received CZP as a fixed dose based on weight. Prior to implementation of 
Protocol Amendments 4 and 5, the original CZP dose regimen was followed; subjects in the 
10 to <20kg weight group received a CZP loading dose of 100mg and a maintenance dose of 
50mg, subjects in the 20 to <40kg weight group received a CZP loading dose of 200mg and a 
maintenance dose of 100mg, and subjects in the >40kg weight group received a loading dose 
of 400mg and a maintenance dose of 200mg, all Q2W. 
Has been changed to: 
All study participants received CZP as a fixed dose based on weight. Prior to implementation 
of Protocol Amendments 4 and 5, and after Protocol Amendment 9, the original CZP dose 
regimen was followed; study participants in the 10 to <20kg weight group received a CZP 
loading dose of 100mg and a maintenance dose of 50mg, study participants in the 20 to 
<40kg weight group received a CZP loading dose of 200mg and a maintenance dose of 
100mg, and study participants in the >40kg weight group received a loading dose of 400mg 
and a maintenance dose of 200mg, all Q2W. 
Change #20: 
Section 3.6 Treatment assignment and treatment groups, 4th paragraph: 
For PK, safety and efficacy analyses, subjects will be grouped by their Baseline weight 
group. Selected analyses will also group subjects by their Baseline age group, concomitant 
MTX use, and overall anti-CZP antibody status (as defined in Section 8.2).  Additionally, PK 
and selected safety data will be presented by CZP dose regimen (Reduced vs. Original CZP 
Dose Regimen).  For subjects enrolled on the original CZP dose regimen, data will be 
tabulated overall, and selected data will be further subdivided into events and assessments 
occurring prior to and following dose reduction. Efficacy summaries will be presented by the 
Reduced CZP Dose Regimen, the Original CZP Dose Regimen, and the Any CZP Dose 
Regimen. 
Has been changed to: 
For PK, safety and efficacy analyses, study participants will be grouped by their Baseline 
weight group. Selected analyses will also group study participants by their Baseline age 
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group, concomitant MTX use, and overall anti-CZP antibody status (as defined in Section 
8.2).  Additionally, PK and selected safety data will be presented by CZP dose regimen 
(Reduced Overall vs. Original CZP Dose Regimen Overall).  For study participants enrolled 
on the original CZP dose regimen, data will be tabulated overall, and selected data will be 
further subdivided into events and assessments occurring prior to or without and following 
dose reduction. Efficacy summaries will be presented by the Reduced CZP Dose Regimen 
Overall, the Original CZP Dose Regimen Overall, and the Any CZP Dose Regimen. 
Change #21 
Section 3.9 Changes to protocol-defined analyses 
This analysis plan includes plots of CZP plasma concentrations, anti-CZP antibody 
concentrations, JADAS-71 and maximum PedACR response for individual subjects by visit; 
these plots were not pre-specified in the study protocol. In order to simplify the plots of CZP 
plasma concentrations, only reference lines from adult study C87050 will be included in the 
plots.  The reference lines from adult study C87027, specified in the protocol as an additional 
adult study for comparison, will not be included. 
Has been changed to: 
This analysis plan includes plots of CZP plasma concentrations, anti-CZP antibody 
concentrations, JADAS-71 and maximum PedACR response for individual study participants 
by visit; these plots were not pre-specified in the study protocol.  
Change #22 
Section 4.3 Interim analyses and data monitoring 
Interim analysis of PK data will compare CZP plasma concentration data from this study with 
CZP plasma concentrations observed previously in adult subjects with RA (adult study 
C87050). This plasma concentration analysis will be done on an ongoing basis throughout the 
study, starting when 6 subjects in 1 of the age groups have completed Week 12 (Visit 7). 
Comparisons will be made between the geometric mean for the pediatric and adult subjects, 
as well as between the individual pediatric data and the adult 5th and 95th percentile and 
minimum and maximum observed values. 
If the pediatric plasma concentrations demonstrate that the geometric mean and pediatric data 
are below the adult 5th percentile or above the 95th percentile, the PK data will be used to re-
evaluate the weight-based dose adjustment algorithm for pediatric subjects. If necessary, a 
revised pediatric dosing algorithm will be derived. Any change in dose regimen will require a 
protocol amendment prior to implementation. 
An interim analysis of the PedACR30 Week 16 response rate will be performed after all 
active subjects have completed the Week 16 (Visit 8) assessments. The study will be 
discontinued if less than 50% of the study population enrolled on the reduced CZP dose 
regimen achieves a PedACR30 response at Week 16.  Statistical output for this Week 16 
interim analysis will be restricted to a limited subset of the tables and listings described in the 
current SAP, specifically tables and listings related to the following: 
• PedACR30 response at Week 16 
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• Demographic and Baseline characteristics 
• Disposition and discontinuation status 
• Rescue and prohibited medication use 
For purposes of regulatory submissions, full interim analyses will be performed after all 
active subjects have completed the Week 24 (Visit 10) assessments and after all active 
subjects have completed the Week 56 (Visit 14) assessments.   
The study will continue until the approval of the marketing application for the polyarticular-
course JIA indication in the subject’s country or region, or until discontinuation of the study 
based on the Week 16 analysis of response, or until further notice from UCB.  At the 
completion of the treatment period and follow-up period of all subjects at the end of the 
study, a final complete analysis of the study data will be performed. 
All statistical tables, listings and figures comprising the current SAP (including the Week 16 
interim analysis) will be produced for the Week 24 and Week 56 full interim analyses, as 
well as for the final analysis at the end of the study.  
Given the descriptive nature of the data presentations in all data presentations, there are no 
statistical implications of these interim analyses. 
Has been changed to: 
A futility analysis of the PedACR30 response rate was performed after all active study 
participants enrolled on the reduced CZP dose had completed the Week 16 (Visit 8) 
assessments. If less than 50% of the study population enrolled on the reduced CZP dose 
regimen (Protocol Amendment 5) achieved a PedACR30 response at Week 16, the study was 
to be discontinued. The futility analysis confirmed that ≥50% of the study population enrolled 
on the reduced CZP dose regimen achieved a PedACR30 response at Week 16. Given the 
descriptive nature of the data presentations, there were no statistical implications of this 
interim analysis. A further futility analysis will not be performed using the additional study 
participants that will be enrolled on the original CZP dose regimen following the 
implementation of Protocol Amendment 9.  
In addition to the futility analysis, several interim analyses were planned, including interim 
analyses of PK data, and full interim analyses of PK, immunogenicity, safety, and efficacy 
endpoints, as described below. 
Interim analyses of PK data 
Per original protocol, if the pediatric plasma concentrations demonstrate that the geometric 
mean and median concentrations are below the adult 5th percentile or above the 95th 
percentile, the PK data will be used to re-evaluate the weight-based dose adjustment 
algorithm for pediatric study participants. Interim CZP plasma concentration data available at 
the time of Protocol Amendment 3 indicated that no change to the dosing algorithm was 
required. The protocol stated that if future interim analyses, which may include PopPK, 
indicate that plasma concentrations of JIA study participants are outside of the exposure 
range observed in previous adult RA studies, a revised pediatric dose algorithm will be 
derived. Any change in dose regimen will require a protocol amendment prior to 
implementation. 
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An interim analysis of PK data conducted following Protocol Amendment 3 compared CZP 
plasma concentration data from this study with CZP plasma concentrations observed 
previously in adult study participants with RA. Interim analysis of CZP plasma 
concentrations was started when 6 study participants in 1 of the age groups completed 
Week 12 (Visit 7). Comparisons were made between the Week 12 geometric mean and 
median values for the pediatric and adult study participants, as well as between the individual 
pediatric data and the adult 5th and 95th percentile and minimum and maximum observed 
values. 
Based on results of this interim PopPK analysis, the dosing regimen was changed with 
Protocol Amendments 4 and 5, and the doses to be administered were reduced by 50% for all 
weight groups. This change was intended to achieve plasma concentrations similar to the 
effective concentrations observed in previous studies in adult study participants with RA. 
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPK analysis and 
simulations that informed the dose reduction in Protocol Amendments 4 and 5 unusable from 
a regulatory standpoint.  
Interim analyses of PK, immunogenicity, safety, and efficacy endpoints 
An interim analysis of PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants that were enrolled and treated prior to implementation of 
Protocol Amendment 9 had completed the Week 24 (Visit 10) assessments, and the results 
were reported separately; this is referred to as the 2016 Week 24 interim analysis. An interim 
analysis, including all enrolled participants, for all PK, immunogenicity, safety, and efficacy 
endpoints will be performed after all active study participants, including those enrolled 
following the implementation of Protocol Amendment 9, have completed the Week 24 (Visit 
10) assessments; this will be referred to as the Updated Week 24 Interim analysis.  A Week 
56 (Visit 14) interim analysis will also be performed after all those enrolled, following the 
implementation of Protocol Amendment 9, have completed the Week 56 (Visit 14) 
assessments. 
All statistical tables, listings and figures comprising this SAP will be produced for all future 
interim and final analyses. 
Change #23: 
Section 4.7 Examination of subgroups 
• Overall anti-CZP antibody status:  
o AB+ 
o AB- 
Has been changed to: 
• TE Anti-CZP antibody status and titer classification:  
o TE ADAb status negative 
o TE ADAb status positive <=32 
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o TE ADAb status positive >32 to <=128 
o TE ADAb status positive >128 to <=512 
 
o TE ADAb status positive >512 to <=1024 
 
o TE ADAb status positive >1024 to <=4096 
 
TE ADAb status positive >4096 
Change #24 
Section 5.1 Subject disposition – the following analysis was updated or added: 
The number and percentage of study participants who were treated, who completed the study, 
and who discontinued from the study, along with the discontinuation reasons, will be 
summarized for the Safety Set.  For the Week 16, Week 24 and Week 56 interim analyses, 
number of study participants completing Week 16, Week 24 and Week 56 (respectively) will 
be added in addition to the number completing the study as appropriate. The number of study 
participants in each analysis set will be presented. Summaries will be provided for the 
Reduced Overall, Original Overall, and Any CZP Dose Regimen groups. 
Discontinuations due to AEs will be summarized separately for the SS, and will be provided 
for the Reduced Overall, Original Overall, and Any CZP Dose Regimen groups. 
The number and percentages of subjects impacted by COVID-19 will be presented for each 
visit, overall and by impact category, for each relationship to COVID-19 as well as any 
relationship, overall and by country, for all subjects in the SS.  This data will be presented in 
subject data listings. 
Change #25 
Section 5.2 Protocol deviations 
However, all PK data will be included in listings, individual graphs, and PopPK analysis. 
Has been changed to: 
However, all PK data will be included in listings and individual graphs. 
Change #26 
Section 7 Measurements of Treatment Compliance – the following text was added: 
Note also the dose escalation of ongoing study participants following Protocol Amendment 9 
is considered in the calculations. 
Change #27 
Section 8 Pharmacokinetics and immunological procedures – the following text was added: 
All study participants enrolled following Protocol Amendment 9 will have plasma CZP 
concentrations and anti-CZP antibodies analyzed using the ECLIA method. In addition, PK 
and ADA samples (for which sufficient volume is available) collected in this study prior to 
Protocol Amendment 9, will be analyzed with the ECLIA method. 
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Data from the ECLIA method will constitute the study’s main PK and anti-CZP antibody 
evaluations.  As such, PK and anti-CZP antibody data generated with the original ELISA 
method will be reported only in study participant listings. 
Change #28: 
Section 8.1 CZP Plasma concentrations 
CZP plasma concentrations are measured at Baseline, Weeks 1, 4, 12, 16, 17, 24, 32, 40, 48, 
every 24 weeks thereafter, the Early Discontinuation/EOT Visit, and the Final Visit. 
Has been changed to: 
CZP plasma concentrations are measured at Baseline, Weeks 1, 4, 12, 16, 17, 24, 32, 40, 48, 
every 24 weeks thereafter, the Early Discontinuation/EOT Visit, and the Final Visit; for study 
participants enrolled prior to Protocol Amendment 8, samples were not collected after 
implementation of Protocol Amendment 8. 
Change #29 
Section 8.1 CZP Plasma concentrations 
For subjects who began treatment on the original CZP dose regimen, geometric mean plasma 
concentrations will be summarized separately for the plasma samples obtained during the 
period of exposure to (1) the original CZP dose (all results before and through the dose 
reduction visit), and (2) the reduced CZP dose (all results from the initial dose reduction visit 
onward); plasma concentrations at the dose reduction visit will be included in both 
summaries for purposes of comparison.  For the summarization of geometric mean 
concentrations on the reduced CZP dose, visits will be identified as number of weeks relative 
to the dose reduction visit, regardless of the actual visit at which the dose reduction occurred.  
Subjects that reduce dose are thus expected to have plasma concentration results at the dose 
reduction visit, 4 weeks after dose reduction (identified as Week 4), 8 weeks after dose 
reduction (identified as Week 8), and 12 weeks after dose reduction (identified as Week 12).  
Any subsequent concentration results for the reduced dose period will also be similarly 
summarized (ie, concentration results 24 weeks after dose reduction will be summarized as 
Week 24 results).  
Summaries of concentration results will be provided by Baseline weight group, as well as 
Baseline age group. In addition, summaries will be provided by anti-CZP antibody titer and 
concomitant MTX use in combination with Baseline weight group.  
Geometric mean plasma concentration time curves will be provided separately for subjects 
enrolled on the original CZP dose regimen vs. the reduced CZP dose regimen. For subjects 
enrolled on the original CZP dose regimen, geometric mean plasma concentrations will be 
plotted separately for the plasma samples obtained during the period of exposure to (1) the 
original CZP dose (all results before and through the dose reduction visit),  and (2) the 
reduced CZP dose (all results from the initial dose reduction visit onward). As described 
above for the tabular summary, plots of geometric mean plasma concentrations at and 
following dose reduction visits will be identified as number of weeks relative to the dose 
reduction visit, regardless of the actual visit at which the dose reduction occurred.  Plots of 
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geometric mean plasma concentrations will be provided overall and by Baseline age stratum, 
Baseline weight group, anti-CZP antibody titer, and concomitant MTX use.    
In addition, observed plasma concentrations over time will be plotted for individual subjects, 
separately for each dose regimen, which will also identify weight group per subject. For 
subjects who began treatment according to the original CZP dose regimen, plasma 
concentrations will be plotted separately for the plasma samples obtained during the period of 
exposure to (1) the original CZP dose (all results before and through the dose reduction visit),  
and (2) the reduced CZP dose (all results from the initial dose reduction visit onward). As 
described above, plots of plasma concentrations at and following dose reduction visits will be 
identified as number of weeks relative to the dose reduction visit, regardless of the actual visit 
at which the dose reduction occurred.  Plots of individual plasma concentrations will be 
provided by Baseline age stratum, Baseline weight group, anti-CZP antibody titer, and 
concomitant MTX use. 
For purposes of comparison between pediatric and adult subjects, adult CZP plasma 
concentration data for subjects from the Safety Population on the CZP 200mg arm from adult 
study C87050 will be used to derive reference boundaries for all of the plots described in this 
section.  The plots of plasma concentrations will have reference lines of the adult 5th and 
95th CZP concentration percentiles at Week 12 superimposed on to them, as well as the 
upper and lower limits of the 95% CI of the geometric mean plasma concentrations from the 
C87050 study at Week 12. In addition, for the plots of the geometric means, the minimum 
and maximum range of the pediatric concentrations at each time point will be included.  All 
plots of CZP concentration data described in this section will be presented on a linear scale. 
Values below the limit of quantification of 0.41μg/mL will be set to half the limit of 
quantification for the summaries. The geometric mean and CV% was derived when at least 
two-thirds of the concentrations at a certain visit were above the limit of quantification 
(LoQ).If that criteria was not met, only the maximum and minimum values were shown. 
Similarly, the 95% CI of the geometric mean was only calculated if at least 5 samples were 
available at that time point. Note that a separate partial PK exclusion regarding concentration 
calculation is detailed in section 5.2. 
Has been changed to: 
For study participants enrolled prior to Amendment 9, who began treatment on the original 
CZP dose regimen, and whose PK samples are analyzed with the ECLIA method, plasma 
CZP concentrations will be summarized separately for samples obtained during the period of 
exposure to (1) the original CZP dose (all results before and through the dose reduction visit), 
and (2) the reduced CZP dose (all results from the initial dose reduction visit onward). 
Plasma concentrations at the visit where dose reduction was to be initiated will be included in 
summary (1) only. Concentrations from participants enrolled after Amendment 9 will be 
included in Summary (1).  
For the summarization of geometric mean concentrations on the reduced CZP dose, visits will 
be identified as number of weeks relative to the dose reduction visit, regardless of the actual 
visit at which the dose reduction occurred.  Study participants that reduce dose are thus 
expected to have plasma concentration results at the dose reduction visit, 4 weeks after dose 
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reduction (identified as Week 4), 8 weeks after dose reduction (identified as Week 8), and 12 
weeks after dose reduction (identified as Week 12).  Any subsequent concentration results for 
the reduced dose period will also be similarly summarized (ie, concentration results 24 weeks 
after dose reduction will be summarized as Week 24 results).  
Summaries of concentration results will be provided by Baseline weight group, as well as 
Baseline age group. In addition, summaries will be provided by TE ADAb status with titer 
classification (see 8.2) and concomitant MTX use in combination with Baseline weight 
group.  
Geometric mean plasma concentration time curves will be provided separately for study 
participants according to the ECLIA assay and dosing scenarios outlined above for the 
tabular summaries. Geometric mean plots will be provided overall and by Baseline age 
stratum, Baseline weight group, TE ADAb status with titer classification (see 8.2), and 
concomitant MTX use.    
In addition, observed plasma concentrations over time will be plotted for individual study 
participants, separately for each dose regimen whose samples have been analyzed with the 
ECLIA method. Plots of individual plasma concentrations will be provided by Baseline age 
stratum, Baseline weight group, TE ADAb status with titer classification (see 8.2), and 
concomitant MTX use. 
Concentrations below the limit of quantification of 32.0 ng/mL (0.032μg/mL) (BLQ) will be 
replaced by the LLOQ divided by 2 for the calculation of descriptive statistics. The geometric 
mean and CV% will be derived when at least two-thirds of the concentrations at a certain 
visit are above the LLOQ. If that criteria are not met, only the maximum and minimum 
values will be shown. Similarly, the 95% CI of the geometric mean will be calculated if at 
least 5 samples are available at a time point.  
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Change #30 
Section 8.2 Anti-CZP Antibodies 
Anti-CZP antibody concentrations are measured at Baseline, Weeks 1, 4, 12, 16, 17, 24, 
32, 40, 48, every 24 weeks thereafter, the Early Discontinuation/EOT Visit, and the 
Final Visit. Summaries of anti-CZP antibody status will include the frequency and 
percentage of subjects who are AB- and AB+ for each visit where samples were taken. 
At each visit: 
 
• Values ≤2.4units/mL are defined as AB- 
 
• Values >2.4units/mL are defined as AB+ 
 
In addition, overall antibody status will be summarized: 
 
• Overall AB+ is defined as having a value > 2.4units/mL at any time in the 
treatment period (Note: All post-baseline data will be included except for the safety 
follow-up visit). 
 
• Overall AB- is defined as having no values > 2.4units/mL during the treatment period. 
 
Anti-CZP antibody status will be summarized for the Reduced, Original, and Any CZP Dose 
Regimen groups. For subjects who began treatment on the original CZP dose regimen, anti-
CZP antibody status will be summarized combining results prior to and following dose 
reduction.  In addition, summaries of antibody status will be produced separately for the 
antibody results obtained during the period of exposure to (1) the original CZP dose (all 
results before and through the dose reduction visit),  and (2) the reduced CZP dose (all results 
after the initial dose reduction visit).  As described above for plasma concentration results, for 
the summarization of antibody status after dose reduction, visits will be identified as number 
of weeks relative to the dose reduction visit regardless of the actual visit at which the dose 
reduction occurred. 
Summaries of anti-CZP antibody titer will be provided by Baseline weight group, as well as 
Baseline age group. In addition, summaries will be provided by concomitant MTX use in 
combination with Baseline weight group. Each subgroup summary will be provided for the 
Reduced, Original (overall, and prior to and following dose reduction), and Any CZP Dose 
Regimen groups. 
These summaries will be provided for the PK-PP Set. All anti-CZP antibody data will be 
listed. In addition, graphical presentation of cumulative percentage of positive Anti-CZP 
antibody status will be presented by Reduced CZP Dose Regimen, Original CZP Dose 
Regimen Prior to Dose Reduction, and Original CZP Dose Regimen Following Dose 
Reduction respectively. 
Has been changed to: 
Immunogenicity will be assessed through listing of individual results by study participant and 
summary tables for data generated with the ECLIA method only. Immunogenicity data will 
be related to PK and efficacy readouts.  
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Anti-drug antibodies will be assessed by a three-tiered approach: screening (positive or 
negative screen), confirmatory (positive or negative immunodepletion) and titer assays, using 
ECLIA methods. Cut points will be determined during assay validation and used by the 
bioanalytical laboratory to determine the status of ADAb in the test samples. 
 
The following definitions will be applied regarding classification of test samples: 
 
·       An ADAb status will be confirmed as positive for any sample with an ADAb level that 
is positive screen and positive immunodepletion.  
 
·       An ADAb status of negative will be concluded for any sample with an ADAb level that 
is either negative screen or positive screen and negative immunodepletion. 
 
Confirmed positive samples will be titrated and the titer will be reported. The ADAb titer is 
presented in the listings and summaries including the minimum required dilution. 
If the titer for an ADAb level that is positive screen and positive immunodepletion is missing, 
then a conservative approach will be used and ADAb status will be considered as positive. 
No imputation rules apply for the missing titer. 
 
If the ADAb level is positive screen but no confirmatory result could be determined, then 
then a conservative approach will be used and ADAb status will be considered as positive. 
 
Anomalous values will not be included in summaries/analysis but they will be reviewed and 
flagged by the study Clinical Pharmacologist. 
 
Study participants will receive a treatment-emergent (TE) ADAb status and will be classified 
as follows based on the ADAb assay results: 
 
·       TE ADAb status positive is defined as either (i) baseline ADAb negative study 
participants having at least one ADAb confirmed positive sample post baseline or ii) baseline 
ADAb positive study participants with at least one post baseline sample with ≥minimum 
significant ratio (MSR) -fold increase from baseline on CZP treatment. The MSR will be 
defined during the process of sample analysis and is disease-specific. 
 
·       TE ADAb status negative is defined as having no samples either ADAb positive or with 
values ≥MSR -fold increase from baseline.  
 
Once determined positive, a study participant’s highest titer is used to categorize (“titer 
classification”) the study participant as follows:  
 
·       Positive ≤32 
 
·       Positive >32 - ≤128 
 
·       Positive >128 - ≤512. 
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·       Positive >512 - ≤1024 
 
·       Positive >1024 - ≤4096 
 
·       Positive >4096. 
 
 
All ADAb summaries will be provided for the SS Set. All ADAb data will be listed. 
 
Summary of shift from Baseline ADAb status with titer classification to TE ADAb Status 
with titer classification for all study participants will be presented during the entire study, by 
visit. Summaries of ADAb data will be provided by Baseline weight group, as well as 
Baseline age group. In addition, summaries will be provided by concomitant MTX use in 
combination with Baseline weight group.  
 
TE ADAbs will be presented separately (per ADAb status and titer classification) for the 
Original and Reduced Dose periods (using the study Visit nomenclature previously outlined 
for PK concentrations), including the Final visit.  
 
The time to achieving TE ADAb for all study participants will be analyzed based on Kaplan-
Meier methods. Study participants will be considered to have an event at the time where 
treatment-emergent ADAb positive is first achieved during treatment period excluding 
Baseline/pre-treatment. Study participants classified as treatment-emergent ADAb negative 
will be censored at the time of last available ADAb result. The median and 95% CI based on 
the Kaplan-Meier estimation will also be presented. A plot of time to first ADAb positivity 
will be presented.  
 
A scatter plot of CZP plasma concentrations and ADAb titer, separated by concomitant MTX 
use, will be presented. This plot will be repeated for separation by concomitant MTX use as 
well as Baseline body Weight group 
Change #31 
Section 8.3 CZP Plasma concentrations, anti-CZP antibody titers, and PedACR response 
Individual subject plots displaying CZP plasma concentrations, anti-CZP antibody 
concentrations, JADAS-71 score and maximum PedACR response (the highest PedACR 
response at a given visit) will be produced by visit on the same plot. Plasma concentrations 
and antibody concentrations will be plotted on a log scale.  At each time point, the JADAS-71 
score and maximum PedACR response at that visit will be plotted on a linear scale.  A 
vertical line will be drawn at the time point of dose reduction (when applicable).  Individual 
subject plots will be provided separately for overall AB+ and overall AB- subjects. 
Has been changed to: 
Individual subject plots displaying log CZP plasma concentrations, log2 ADAb titers, 
JADAS-71 score and maximum PedACR response (the highest PedACR response at a given 
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visit) will be produced by visit on the same plot. At each time point, the JADAS-71 score and 
maximum PedACR response at that visit will be plotted on a linear scale.  A vertical line will 
be drawn at the time point of dose reduction (when applicable).   
Spaghetti plots of ADAb titer on a log2 scale by week from CZP first dosing separated by 
concomitant MTX use and ADAb titer classification will be presented for study participants 
with PedACR0/30/50/70/90 at Week 16 as separate graphs. 
Change #32 
Section 9.1 Extent of exposure 
Subject time at risk will also be calculated. Subject time at risk represents the time a subject 
is at risk for having an AE. Subject time (in days) at risk will generally be calculated as (date 
of the last dose of study medication – date of the first dose of study medication + 70 days) 
(70 days = 5 CZP half-lives).  The calculation of subject time at risk will be modified for 
original CZP dose regimen subjects that reduce dose; for the period of exposure prior to dose 
reduction, subject time at risk ends on the date of dose reduction (ie, do not add 70 days).  
Subject years at risk will be calculated as subject time at risk (in days) divided by 365.25. 
Duration of exposure and subject time at risk will be calculated as appropriate for each of the 
following CZP dose regimen groups: 
• Reduced CZP Dose Regimen: includes period of exposure to all CZP doses for all 
subjects enrolled on the reduced CZP dose regimen 
• Original CZP Dose Regimen: includes period of exposure to all CZP doses for all 
subjects enrolled on the original CZP dose regimen regardless of dose or subsequent 
dose reduction 
• Original CZP Dose Regimen Prior to Dose Reduction: includes period of exposure to 
original CZP dose regimen only (ie, exposure period ends on the date of dose 
reduction) 
• Original CZP Dose Regimen Following Dose Reduction: includes period of exposure 
to reduced CZP dose regimen only (ie, exposure period begins on the date of dose 
reduction) 
• Any CZP Dose Regimen: includes all CZP doses for all treated subjects 
Study drug exposure will be summarized for the Reduced, Original, and Any CZP Dose 
Regimen groups. For subjects on the original CZP dose regimen, exposure will be 
summarized combining results prior to and following dose reduction.  In addition, for 
subjects on the original CZP dose regimen, summaries of exposure will be produced 
separately for the period of exposure to (1) the original CZP dose (all exposure before the 
dose reduction visit), and (2) the reduced CZP dose (all exposure after the initial dose 
reduction visit). 
Has been changed to: 
Subject time at risk will also be calculated. Subject time at risk represents the time a subject 
is at risk for having an AE. Subject time (in days) at risk will generally be calculated as (date 
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of the last dose of study medication – date of the first dose of study medication + 70 days) 
(70 days = 5 CZP half-lives).  However, the calculation of subject time at risk will be 
modified for study participants who change from original CZP dose regimen to reduced CZP 
dose regimen, or who dose escalate from reduced CZP dose regimen to the original CZP dose 
regimen. For the period of exposure prior to a dose change, subject time at risk ends on the 
date of dose change (ie, do not add 70 days).  For the period of exposure on the final  CZP 
dose regimen for a study participant, time at risk should include the additional 70 days.  
Subject years at risk will be calculated as subject time at risk (in days) divided by 365.25. 
Duration of exposure and subject time at risk will be calculated as appropriate for each of the 
following CZP dose regimens: 
• Reduced CZP Dose Regimen Overall: includes period of exposure to all CZP doses 
for all study participants enrolled on the reduced CZP dose regimen regardless to dose 
escalation 
o Reduced CZP Dose Regimen Prior to or without Dose Escalation: includes 
period of exposure to reduced CZP dose regimen only (ie, exposure period 
ends on the date of dose escalation) 
• Original CZP Dose Regimen Overall: includes period of exposure to all CZP doses 
for all study participants enrolled on the original CZP dose regimen regardless of dose 
or subsequent dose reduction 
o Original CZP Dose Regimen Prior to or without Dose Reduction: includes 
period of exposure to original CZP dose regimen only (ie, exposure period 
ends on the date of dose reduction) 
o Original CZP Dose Regimen Following Dose Reduction: includes period of 
exposure to reduced CZP dose regimen only (ie, exposure period begins on the 
date of dose reduction) 
• Any CZP Dose Regimen: includes all CZP doses for all treated study participants 
• Escalation CZP Dose Regimen: includes period of exposure to an escalation CZP 
dose regimen only (ie, exposure period begins on the date of dose escalation for study 
participants from Reduced CZP Dose Regimen as well as Original CZP Dose 
Regimen Following Dose Reduction) 
Study drug exposure will be summarized for the Reduced - Overall, Original - Overall, and 
Any CZP Dose Regimen groups. For study participants on the original CZP dose regimen, 
exposure will be summarized combining results prior to and following dose reduction.  In 
addition, for study participants on the original CZP dose regimen, summaries of exposure 
will be produced separately for the period of exposure to (1) the original CZP dose (all 
exposure before the dose reduction visit or all exposure for study participants with no dose 
reduction), and (2) the reduced CZP dose (all exposure after the initial dose reduction visit). 
For study participants who dose escalate, exposure will be summarized. 
Change #33 
The following was inserted in Section 9.2 Adverse Events: 
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Any TEAE leading to permanent withdrawal of IMP 
Change #34 
Section 9.2 Adverse Events 
Overall summaries of TEAEs will be provided for the Reduced, Original, and Any CZP Dose 
Regimen groups. For subjects on the original CZP dose regimen, summaries will be provided 
combining results prior to and following dose reduction.  In addition, overall TEAE 
summaries for the original CZP dose regimen will be produced separately for TEAEs 
occurring during the period of exposure to (1) the original CZP dose (all results before the 
dose reduction visit),  and (2) the reduced CZP dose (all results after the initial dose reduction 
visit).  TEAEs occurring on the day of dose reduction will be reviewed by the study physician 
in order to assign events to the most appropriate time period (before or after dose reduction). 
Has been changed to: 
Overall summaries of TEAEs will be provided for the Reduced Overall, Original Overall, and 
Any CZP Dose Regimen groups. For study participants on the reduced CZP dose regimen 
overall, summaries will be provided for the TEAEs occurring during the period of exposure 
to reduced CZP dose only.  For study participants on the original CZP dose regimen, 
summaries will be provided combining results prior to and following dose reduction.  In 
addition, overall TEAE summaries for the original CZP dose regimen will be produced 
separately for TEAEs occurring during the period of exposure to (1) the original CZP dose 
(all results before the dose reduction visit or all results for study participants with no dose 
reduction),  and (2) the reduced CZP dose (all results after the initial dose reduction visit). 
For study participants on either Reduced Overall or Original Overall, overall TEAE 
summaries will be produced for TEAEs occurring during the period of exposure to (3) the 
escalated CZP dose (all results after the initial dose escalation visit).  TEAEs occurring on the 
day of dose reduction or dose escalation, respectively, will be reviewed by the study 
physician in order to assign events to the most appropriate time period (before or after dose 
reduction or dose escalation, respectively). 
Change #35 
Section 9.2 Adverse Events 
For all of the summaries in the above list (except for the ones flagged with an asterisk (*) or 
double asterisks (**)), TEAEs will be summarized for the Reduced, Original, and Any CZP 
Dose Regimen groups. For the above summaries flagged with double asterisks (**), only the 
Any CZP Dose Regimen will be presented. For the above summaries flagged with an asterisk 
(*), TEAEs for the Original CZP Dose Regimen group will also be summarized separately 
for events occurring during the period of exposure to (1) the original CZP dose (all results 
before the dose reduction visit), and (2) the reduced CZP dose (all results after the initial dose 
reduction visit).  As indicated above, TEAEs occurring on the day of dose reduction will be 
reviewed by the study physician in order to assign events to the most appropriate time period 
(before or after dose reduction). 
Has been changed to: 
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For all of the summaries in the above list (except for the ones flagged with an asterisk (*) or 
double asterisks (**)), TEAEs will be summarized for the Reduced Overall, Original Overall, 
and Any CZP Dose Regimen groups. For the above summaries flagged with double asterisks 
(**), only the Any CZP Dose Regimen will be presented. For the above summaries flagged 
with an asterisk (*), TEAEs for the Original CZP Dose Regimen Overall group will also be 
summarized separately for events occurring during the period of exposure to (1) the original 
CZP dose (all results before the dose reduction visit or all results for study participants with 
no dose reduction), and (2) the reduced CZP dose (all results after the initial dose reduction 
visit); the Reduced Overall will summarize separately events occurring during the period of 
exposure to Reduced CZP Dose regimen; and study participants from either Reduced Overall 
and Original Overall will summarize separately events occurring during the period of the 
escalated CZP dose (all results after the initial dose escalation visit).  As indicated above, 
TEAEs occurring on the day of dose reduction or dose escalation, respectively, will be 
reviewed by the study physician in order to assign events to the most appropriate time period 
(before or after dose reduction or dose escalation, respectively). 
Change #36 
Section 9.2 Adverse Events 
Data displayed will include the number of AEs, number of subjects experiencing the AEs and 
percentage of subjects with the AE (all occurrences of the same event will be counted under 
the number of AEs but the subject will only be counted once). Summaries of all TEAEs, 
serious TEAEs, TEAEs leading to death, and TEAEs leading to study discontinuation will 
also include the exposure-adjusted incidence rate (EAIR) with associated 95% confidence 
interval, and the exposure-adjusted event rate (EAER). 
Has been changed to: 
Data displayed will include the number of TEAEs, number of study participants experiencing 
the TEAEs and percentage of study participants with the TEAE (all occurrences of the same 
event will be counted under the number of TEAEs but the subject will only be counted once). 
Summaries of all TEAEs, serious TEAEs, TEAEs leading to death, TEAEs leading to 
permanent withdrawal of IMP, and TEAEs leading to study discontinuation will also include 
the exposure-adjusted incidence rate (EAIR) with associated 95% confidence interval, and 
the exposure-adjusted event rate (EAER).  
Change #37: 
Section 9.2 Adverse events, the following were updated: 
3) Congestive heart failure.  These will be manually identified by the study physician from 
the previously described All TEAEs table.  No separate table is planned.   In addition, major 
adverse cardiac events (MACE) will be presented in a table using UCB-defined search 
criteria and will include fatal and serious non-fatal myocardial infarction, cerebrovascular 
events and congestive heart failure.     
4) Demyelinating-like disorders.   These will be manually identified by the study physician 
from the previously described All TEAEs table.  No separate table is planned.   
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7) Lupus and lupus-like illness.  These will be manually identified by the study physician 
from the previously described All TEAEs table.  No separate table is planned. 
8) Serious skin reactions (eg, Stevens-Johnson Syndrome, toxic epidermal necrosis, 
anderythema multiforme).   These will be manually identified by the study physician from the 
previously described All SAEs table.  No separate table is planned. 
Has been changed to: 
3) Congestive heart failure.  These will be manually identified by the study physician from 
the previously described All TEAEs table.  In addition, major adverse cardiac events 
(MACE) will be presented in a table using UCB-defined search criteria and will include fatal 
and serious non-fatal myocardial infarction, cerebrovascular events and congestive heart 
failure.     
4) Demyelinating-like disorders.   These will be manually identified by the study physician 
from the previously described All TEAEs table.   
7) Lupus and lupus-like illness.  These will be manually identified by the study physician 
from the previously described All TEAEs table.   
8) Serious skin reactions (eg, Stevens-Johnson Syndrome, toxic epidermal necrosis, 
anderythema multiforme).   These will be manually identified by the study physician from the 
previously described All SAEs table.   
Change #38 
Section 9.2 Adverse Events 
The following is an AE of special interest for this study; the associated analysis will be 
described in the PDILI paragraph in Section 9.3: 
Potential Hy’s Law, defined as ≥3xULN alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the absence of ≥2xULN 
alkaline phosphatase (ALP), with no alternative explanation for the biochemical abnormality 
(ie, without waiting for any additional etiologic investigations to have been concluded). 
Follow-up information should be reported if an alternative etiology is identified during 
investigation and monitoring of the participant. 
Further information regarding search criteria and algorithms is provided in the guidance 
document “AEs of Interest – Cimzia Program”.  
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Change #39 
Section 9.2 Adverse events 
The tables for 1, 2, 3, 5, and 6 above will be summarized by SOC, HLT, and PT and will 
include the number of events, the number and percentage of subjects with an event, the EAIR 
with associated 95% CIs and the EAER.  AEs of interest tables will be provided for the 
Reduced CZP Dose Regimen, the Original CZP Dose Regimen Overall, the Original CZP 
Dose Regimen Prior to Dose Reduction, the Original CZP Dose Regimen Following Dose 
Reduction, and the Any CZP Dose Regimen. 
Has been changed to: 
The tables for 1, 2, 3, 5, and 6 above will be summarized by SOC, HLT, and PT and will 
include the number of events, the number and percentage of study participants with an event, 
the EAIR with associated 95% CIs and the EAER.  TEAEs of interest tables will be provided 
for the Reduced CZP Dose Regimen, the Original CZP Dose Regimen Overall, the Original 
CZP Dose Regimen Prior to Dose Reduction or without Dose Reduction, the Original CZP 
Dose Regimen Following Dose Reduction, the Any CZP Dose Regimen, and the Dose 
Escalation Dose Regimen.  
Change #40 
Section 9.3 Clinical laboratory evaluations 
Hematology, biochemistry, and urinalysis samples will be collected at Screening, Baseline, 
Weeks 4, 8, 12, 16, 20, 24, 32, every 8 weeks thereafter, the Early Discontinuation/End of 
Treatment Visit, and the Final Visit 12 weeks after the last dose of study medication. 
All laboratory summaries described in this section will be provided overall (ie, Any CZP 
Dose Regimen) and by Baseline weight group only; no additional summarized by CZP dose 
regimen will be provided. 
Has been changed to: 
All laboratory summaries described in this section will be provided overall (ie, Any CZP 
Dose Regimen) and by Baseline weight group; laboratory summaries will also be provided by 
the Dose Escalation Dose Regimen and by Baseline weigh group. 
Change #41 
Section 9.3 Clinical laboratory evaluations – the following paragraph was added: 
PDILI IMP discontinuation criteria as outlined in the Appendix of Protocol Amendment 9 
will be evaluated at all laboratory assessments, for all study participants. The number and 
percentage of study participants with elevated liver function tests and meeting PDILI criteria 
will be presented. Any data that meets the PDILI criteria or is captured regarding PDILI will 
be listed.  
Change #42 
Section 9.4.1 Vital Signs 
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Vital signs will be measured at Screening, Baseline, every visit through the Early 
Discontinuation/End of Treatment Visit, and the Final Visit 12 weeks after the last dose of 
study medication. 
Descriptive statistics for observed values, and change from pre-dose to post-dose pulse and 
blood pressure when available, will be presented for each visit for each vital sign parameter. 
Vital signs summaries will be provided overall (ie, for  the Any CZP Dose Regimen) and by 
Baseline weight group only; no additional summaries by CZP dose regimen will be provided. 
Has been changed to: 
Descriptive statistics for observed values and change from pre-dose to post-dose pulse and 
blood pressure when available, will be presented for each visit for each vital sign parameter. 
Vital signs summaries will be provided overall (ie, for the Any CZP Dose Regimen) and by 
Baseline weight group; vital sign summaries will also be provided by the Dose Escalation 
Dose Regimen and by Baseline weigh group. 
Change #43 
Section 9.4.2.1 Height and weight 
Height will be collected at Screening, Baseline, Weeks 24 and 48, every 24 weeks thereafter, 
and the Early Discontinuation/EOT Visit. Weight will be collected at Screening, Baseline, 
and every visit through the Final Visit. Pre-study height and weight measurements will be 
collected at Screening for a period of up to 12 months prior to study entry, including up to 3 
sets of measurements for the 6-month period prior to study entry, and up to 3 sets of 
measurements for the period of time >6 to 12 months prior to study entry.  Where possible, 
pre-study measurements as close as possible to 6 and 12 months prior to study entry will be 
collected. 
Has been updated to: 
At Screening, change in height and weight over the last 6 months and over the last year will 
be collected via parent-/self-report, if not available from medical records. 
Change #44 
Section 9.4.2.2 Tanner stages 
Assessments of subjects’ developmental stages on external genitalia and pubic hair (boys) 
and on breast and pubic hair (girls) will be performed to determine Tanner stages. Tanner 
stages will be assessed at Baseline, Weeks 24 and 48, every 24 weeks thereafter, and the 
Early Discontinuation/EOT Visit. A summary of shift table of Tanner stages from baseline to 
relevant post-treatment visit(s) (eg., 48 week) by age and gender will be provided for the Any 
CZP Dose Regimen. Overall Tanner stage at each visit is derived as the minimum stage of 
the 2 components. If one component is missing at a visit, then the overall stage will be set to 
missing for that visit. 
Has been changed to: 
Assessments of study participants’ developmental stages on external genitalia and pubic hair 
(boys) and on breast and pubic hair (girls) will be performed to determine Tanner stages, for 
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those who have not reached Tanner stage V. A summary of shift table of Tanner stages from 
baseline to relevant post-treatment visit(s) (eg., 48 week) by age and gender will be provided 
for the Any CZP Dose Regimen. Overall Tanner stage at each visit is derived as the 
minimum stage of the 2 components. If one component is missing at a visit, then the overall 
stage will be set to missing for that visit. 
Change #45 
Section 9.4.2.4 Reproductive potential and birth control 
The reproductive potential of all subjects will be assessed by clinical questioning at 
Screening, Baseline, Weeks 4, 8, 12, 16, 20, 24, 32, every 8 weeks thereafter, the Early 
Discontinuation/EOT Visit, and the Final Visit. If the subject is not of reproductive potential, 
the reason will be recorded. If the subject is of reproductive potential and is sexually active, 
the method of birth control used will be recorded. Reproductive potential and birth control 
information will be listed by visit for each subject. 
Has been changed to: 
The reproductive potential of all study participants will be assessed by clinical questioning at 
Screening, Baseline, and every visit thereafter except at Visits 3 and 4 and at Unscheduled 
Visits. If the subject is not of reproductive potential, the reason will be recorded. If the 
subject is of reproductive potential and is sexually active, the method of birth control used 
will be recorded. Reproductive potential and birth control information will be listed by visit 
for each subject. 
Change #46 
Section 9.4.2.5 Autoantibodies 
All autoantibodies summaries will be provided overall (ie, for the Any CZP Dose Regimen) 
and by Baseline weight group only; no additional summaries by CZP dose regimen will be 
provided. 
Has been changed to: 
All autoantibodies summaries will be provided overall (ie, for the Any CZP Dose Regimen) 
and by Baseline weight group; all autoantibody summaries will also be provided by the Dose 
Escalation Dose Regimen and by Baseline weigh group. 
Change #47 
Section 10 Efficacy Analyses 
Efficacy will be analyzed using the FAS.  All efficacy results will be provided for the 
Reduced CZP Dose Regimen, the Original CZP Dose Regimen, and the Any CZP Dose 
Regimen. For subgroup efficacy analyses, summaries by Baseline age group, concomitant 
MTX use, and anti-CZP antibody status will be presented pooling across all weight groups 
unless otherwise specified. In addition, selected summaries will also be presented by gender 
and race. 
Has been changed to: 
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Efficacy will be analyzed using the FAS.  All efficacy results will be summarized overall and 
by Baseline weight group and will be provided for the Reduced CZP Dose Regimen Overall, 
the Original CZP Dose Regimen Overall, and the Any CZP Dose Regimen. For subgroup 
efficacy analyses, summaries by Baseline age group, concomitant MTX use, and anti-CZP 
antibody status will be presented pooling across all weight groups unless otherwise specified. 
In addition, selected summaries will also be presented by gender and race. 
Change #48 
The following sentence was updated in Section 10.3.8 Juvenile Arthritis Disease Activity 
Score 71-joint: 
Descriptive statistics of the observed composite scores and change from Baseline will be 
presented by visit (except at Final Visit). 
13.4 
AMENDMENT 4 
Rationale for the amendment 
The primary reasons for this SAP amendment was to: 
• Update the analyses for the CZP plasma concentrations, 
• Update the analyses for the anti-CZP antibodies, 
• Clarify the definitions for the dose group presentations used in the analyses, 
• Slightly modify the definition for FAS at the suggestion of FDA, 
• Removal of the LOCF methodology at the suggestion of FDA, 
• Clarify the CTCAE criteria for laboratory markedly abnormal criteria, 
• Update the subgroup variables used in the analyses, 
• Specify the markedly abnormal criteria for vital signs,  
• Specify sensitivity analyses of TEAEs in regards to covid vaccination in the Treatment 
Period, and  
• Describe the analyses of PK data that will be done with RA0138 data for comparison to 
RA0043 analyses. 
Modifications and changes 
Global changes 
The reference to polyarticular-source JIA has been changed to pJIA throughout the SAP. 
Three dose groups are now referenced for analysis: Original CZP Dose, Reduced CZP Dose 
and Any CZP Dose. For Original CZP Dose and Reduced CZP Dose, the data captured from 
when the study participant takes their first dose until the day before their dose is changed, is 
what is presented in those analyses. For Any CZP Dose, all data captured from first CZP 
through the last CZP dose is presented, for completeness. 
Specific changes 
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Change #1 
SAP/Amendment  
Date 
Final SAP 
23 Jun 2015 
SAP Amendment 1 
29 Sep 2015 
SAP Amendment 2 
24 Jun 2016 
SAP Amendment 3 
30 Jun 2021 
Has been changed to: 
SAP/Amendment  
Date 
Final SAP 
23 Jun 2015 
SAP Amendment 1 
29 Sep 2015 
SAP Amendment 2 
24 Jun 2016 
SAP Amendment 3 
30 Jun 2021 
SAP Amendment 4 
8 Dec 2022 
Change #2 
Section 2, Protocol Summary, the following was added: 
Below is the list of protocol amendments, dates and rationales for key updates: 
Table 13‒1: Protocol, Amendments, Dates and Rationales 
RA0043 
Protocol/Amendment 
Number 
Date 
Rationale for Key Updates 
Protocol 
10 Jan 2010 
NA 
Amendment 1 
26 Aug 2011 
The primary purpose of this substantial protocol amendment is 
to revise the protocol in line with change requests from health 
authorities following discussions on the CZP pediatric arthritis 
development program. Key updates include adding 
effectiveness as a secondary objective, defining the study 
population as polyarticular-course JIA, setting minimum 
number of enrolled participants by body weight and age and 
adding the study stopping rule. 
Amendment 2 
02 Jul 2012 
The primary purpose of this nonsubstantial amendment is to 
change in the participating countries, including removal of 
Western Europe. RA0043 will not be included in the European 
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Table 13‒1: Protocol, Amendments, Dates and Rationales 
Paediatric Investigational Plan and will therefore not be 
conducted in Western Europe. 
Amendment 2.1  
21 Aug 2012 
Amendment 2 adapted for Russia. The primary purpose of this 
substantial amendment is to change the age range for 
enrollment from 2-17 years to 6-17 years of age which is in 
response to comments received from the Ministry of Health 
and Social Development of the Russian Federation. 
Amendment 3 
06 May 2013 
The primary purpose of this substantial amendment is to update 
the exclusion criteria and guidelines related to TB detection 
and monitoring in order to comply with the revised UCB TB 
Task Force policy. 
Amendment 3.1 
06 May 2013 
Amendment 3 adapted for Russia as per Amendment 2.1. 
Amendment 4 
01 Aug 2013 
The primary purpose of this substantial amendment is for the 
dose for study participants already enrolled in RA0043 to be 
reduced (enrollment into RA0043 was suspended, effective 17 
Jul 2013). An overall dose reduction for pediatric study 
participants of 50% of the dose currently used in RA0043 is 
proposed to provide a pragmatic dosing regimen that will yield 
a closer match to the adult plasma concentration range 
achieved in adults with the approved label for RA (CZP 400mg 
at Weeks 0, 2, and 4 followed by CZP 200mg Q2W thereafter).  
Amendment 4.1 
01 Aug 2013 
Amendment 4 adapted for Russia as per Amendment 2.1. 
Amendment 5 
20 Jan 2014 
The primary purpose of this substantial amendment is to 
reopen enrollment under the new reduced CZP dose regimen 
and to update the statistical analysis to account for the changes 
in the CZP dose regimen. 
Amendment 5.1 
20 Jan 2014 
Amendment 5 adapted for Russia as per Amendment 2.1. 
Amendment 5.2 
23 Feb 2015 
The primary purpose of this nonsubstantial amendment is to lift 
the enrollment cap per site in Russia to allow further 
enrollment in the weight group of 15 to <20kg for sites that 
have enrolled the maximum number of 12 study participants.  
Amendment 6 
17 Sep 2015 
The primary purpose of this administrative amendment is to 
update the packaging and labeling sections of the protocol to 
account for a new presentation of the prefilled syringe (PFS). 
Amendment 6.1 
17 Sep 2015 
Amendment 6 adapted for Russia as per Amendment 2.1. 
Amendment 7 
22 Sep 2016 
The primary purpose of this substantial amendment is to update 
the protocol in accordance with current UCB TB detection 
procedures, including the introduction of yearly TB testing and 
the extension of the prophylactic TB treatment duration from 
4 to 8 weeks. Furthermore, it has been clarified that long-term 
efficacy data from study participants who withdraw from the 
study after Week 56 or initiate any rescue medication use after 
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Table 13‒1: Protocol, Amendments, Dates and Rationales 
Week 56 will be analyzed “as observed” and will no longer be 
imputed as nonresponse or missing. 
Amendment 7.1 
22 Sep 2016 
Amendment 7 adapted for Russia as per Amendment 2.1. 
Amendment 8 
24 Jun 2019 
The primary purpose of this substantial amendment is to reduce 
the study participants’ burden by limiting the frequency of on-
site visits, safety sampling, and efficacy assessments.  
The frequency of on-site visits will be reduced from every 8 
weeks to every 16 weeks in this long-term study. At the time of 
implementing Protocol Amendment 8, all ongoing study 
participants have at least completed the visit for Week 180. As 
before, on-site CZP administration between scheduled visits is 
offered as needed. 
Amendment 8.1 
18 Jul 2019 
Amendment 8 adapted for Russia as per Amendment 2.1 
Amendment 9 
27 Apr 2020 
The primary purpose of this substantial amendment is to enroll 
an additional 30 study participants on the original CZP dose 
regimen in order to adequately assess the exposure levels and 
clinical experience of CZP in pJIA at both the reduced and 
original CZP dose regimens and also adequately support the 
safety assessment of the original CZP dosing regimen. More of 
the safety data collected in the study to date has been on the 
reduced dose, and which of these dose regimens to be included 
in the marketing application for CZP in pJIA is still to be 
determined.  
Amendment 9.1 
28 Jul 2020 
Amendment 9 adapted for Russia as per Amendment 2.1 
Amendment 9.2 
30 Jul 2021 
The primary purpose of this nonsubstantial amendment is to 
increase the enrollment cap per site in Russia to allow further 
enrollment on the original dose regimen for sites that have 
enrolled the maximum number of 16 study participants. 
 
Results of a planned interim PopPK analysis conducted suggested that while observed CZP 
plasma concentrations with the original dose regimen administration remained in the adult 
range, they were at the upper end of the distribution. Based on these findings, the dosing 
regimen was changed with Protocol Amendments 4 and 5, and the doses to be administered 
were reduced by 50% for all weight groups. This dose change was intended to achieve 
plasma concentrations that were similar to the effective concentrations observed in previous 
studies in adult study participants with RA. Based on interactions with FDA, Amendment 9 
re-introduced the original dose regimen for 30 new participants and the option to increase to 
this dose for ongoing participants that had been receiving the reduced dose. 
The following graphic illustrates the study conduct once study participants taking original 
dose regimen were allowed to reduce their dose: 
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OD=Original CZP Dose, RD=Reduced CZP Dose 
Change #3 
Section 2, Protocol Summary 
In order to adequately assess the exposure levels and clinical experience of CZP in JIA at 
both the reduced and original CZP dose regimen and also to adequately support the safety 
assessment of the original CZP dosing regimen, as more of the safety data collected in the 
study to date has been on the reduced dose, 30 additional study participants will be enrolled 
on the original CZP dose regimen following Protocol Amendment 9. 
All study participants enrolled under Protocol Amendment 9 or later will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using electrochemiluminescence 
immunoassay (ECLIA) methods that meets current regulatory standards. In addition, PK and 
ADA samples (for which sufficient volume is available) collected in this study prior to 
Protocol Amendment 9 will be analyzed with the ECLIA methods. The collective ECLIA-
based PK data for this study will form the basis of any future CZP modeling and simulation 
Was changed to: 
In order to adequately assess the exposure levels and clinical experience of CZP in pJIA at 
both the Reduced and Original CZP Dose and also to further support the safety assessment of 
the Original CZP Dose, 30 additional study participants will be enrolled on the Original CZP 
Dose following Protocol Amendment 9. 
All study participants enrolled under Protocol Amendment 9 or later will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using electrochemiluminescence 
immunoassay (ECLIA) methods that meets current regulatory standards (versus those 
previously analyzed using ELISA methods for the prior Week 24 interim analysis). In 
addition, PK and ADAb samples (for which sufficient volume is available) collected in this 
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study for participants enrolled prior to Protocol Amendment 9 will be re-analyzed with the 
ECLIA methods. The collective ECLIA-based PK data for this study will form the basis of 
any future CZP modeling and simulation work. 
Change #4 
Section 2.2.3.4, Additional other variables was added 
Additional variables that were covered under other variables that will be specifically analyzed 
and intended to be used for comparison purposes to support the regulatory submission 
include: 
• CZP plasma concentrations at Weeks 12 and 24 
• Anti-CZP antibody levels up to and including Week 24 
• CZP plasma concentration from study RA0138 at Weeks 12 and 24 
• Anti-CZP antibody levels from study RA0138 up to and including Week 24 
Change #5 
Section 2.3, Study design and conduct 
The table below shows the data collection schedule prior to Protocol Amendment 8 and after 
implementing Protocol Amendment 8. For the study participants who switch to the 16 week 
schedule, the date of the first visit of this schedule will be captured on the “Study 
Participation” CRF module. 
Was changed to: 
The table below shows the data collection schedule prior to Protocol Amendment 8 and after 
implementing Protocol Amendment 8. For the study participants who switch to the 16-week 
schedule, the date of the first visit of this schedule will be captured on the “Study 
Participation” CRF module. Of note, the participants enrolled after Protocol Amendment 9 
(the new 30 study participants on Original CZP Dose) will remain on the original visit 
schedule throughout the study. 
Change #6 
Section 2.3, Study design and conduct 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 followed by maintenance doses 
Q2W. The original minimum and maximum loading doses in the study are CZP 100mg Q2W 
and CZP 400mg Q2W, respectively, and the original minimum and maximum maintenance 
doses are CZP 50mg Q2W and CZP 200mg Q2W, respectively.  
Based on interim PopPK analysis of RA0043 data, the minimum and maximum loading doses 
in the study were adjusted to CZP 50mg Q2W and CZP 200mg Q2W, respectively, and the 
minimum and maximum maintenance doses were adjusted to CZP 50mg Q4W and CZP 
100mg Q2W, respectively, following implementation of Protocol Amendments 4 and 5. 
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPK analysis and 
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simulations that informed the dose reduction in Protocol Amendments 4 and 5 unusable from 
a regulatory standpoint. Accordingly, PK samples were no longer collected for study 
participants on the reduced CZP dose regimen following implementation of Protocol 
Amendment 8. 
An ECLIA method, for which selectivity had previously been assessed in the RA matrix, has 
now been validated to meet the standards set in the regulatory guidance for analytical 
procedures and methods validations for drugs and biologics. 
Based on 24-week interim results from the first 163 study participants enrolled in RA0043, 
both the original and reduced dose regimens showed safety profiles similar to the approved 
CZP dose regimen in the adult RA population.  The overall clinical response in this analysis 
(taking both dose regimens into account) was PedACR30 and PedACR50 responses of 77.3% 
and 67.5%, respectively at Week 12. The response from the original dose regimen was 75.6% 
for PedACR30 and 64.1% for PedACR50.  PedACR50 response demonstrates a highly 
clinically relevant decrease in disease activity. 
Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
JIA at both the reduced and original CZP dose regimens and also to adequately support the 
safety assessment of the original CZP dose regimen, as more of the safety data collected in 
the study to date has been on the reduced dose, 30 additional study participants will be 
enrolled on the original CZP dose regimen following Protocol Amendment 9. All study 
participants enrolled following Protocol Amendment 9 will have plasma concentrations of 
CZP and anti-CZP antibodies analyzed using the ECLIA method. In addition, PK and ADA 
samples (for which sufficient volume is available) collected in this study prior to Protocol 
Amendment 9 will be analyzed with the ECLIA method. The collective ECLIA-based PK 
data for this study will form the basis of any future CZP modeling and simulation work. 
Full interim analyses were performed in 2016 after all active study participants completed the 
Week 24 (Visit 10) assessments.  Week 24 full interim analyses were completed as described 
in SAP Amendment 1. SAP Amendment 3 comprises the analyses to be completed for an 
Updated Week 24 (Visit 10) interim, Week 56 (Visit 14) interim and the final analysis of the 
study. 
Was changed to: 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 followed by maintenance doses 
Q2W (except the 10 to < 20kg group on the reduced dose will be administered 50mg Q4W). 
The doses are explained in the following table: 
 
 
 
 
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Table 13‒2: Dosing administration of CZPa  
Weight range 
Loading dose – Weeks 0, 2, and 
4 
(mg/kg dose range) 
IMP Description 
Maintenance – Week 6 and onwards 
(mg/kg dose range) 
IMP Description 
Original CZP regimen 
10 to <20kg 
(22 to <44lb) 
100mg Q2W 
(5-10mg/kg) 
1 x 0.5mL inj 
50mg Q2W 
(2.5-5mg/kg) 
1 x 0.25 mL inj 
20 to <40kg 
(44 to <88lb) 
200mg Q2W 
(5-10mg/kg) 
1 x 1mL inj 
100mg Q2W 
(2.5-5mg/kg) 
1 x 0.5mL inj 
≥40kg 
(≥88lb) 
400mg Q2W 
(<10mg/kg) 
2 x 1mL inj 
200mg Q2W 
(<5mg/kg) 
1 x 1mL inj 
Reduced CZP regimen 
10 to <20kg 
(22 to <44lb) 
50mg Q2W 
(2.5-5mg/kg) 
1 x 0.25mL inj  
50mg Q4W 
(2.5-5mg/kg) 
1 x 0.25mL inj  
20 to <40kg 
(44 to <88lb) 
100mg Q2W 
(2.5-5mg/kg) 
1 x 0.5mL inj  
50mg Q2W 
(1.25-2.5mg/kg) 
1 x 0.25mL inj  
≥40kg 
(≥88lb) 
200mg Q2W 
(<5mg/kg) 
1 x 1mL inj  
100mg Q2W 
(<2.5mg/kg) 
1 x 0.5mL inj  
CZP=certolizumab pegol; inj=injection; Q2W=every 2 weeks; Q4W=every 4 weeks 
Note: A study participant should change dosing category during the course of the study if their weight crosses 
the 40kg/88lb boundary or crosses the 20kg/44lb boundary. 
a Note that the original CZP regimen describes the dosing administration of CZP prior to the implementation 
of Protocol Amendments 4 and 5 and for study participants enrolled following the implementation of 
Protocol Amendment 9. The reduced CZP regimen describes the dosing administration of CZP after 
implementation of Protocol Amendments 4 and 5.  
Based on interim PopPK analysis of RA0043 data, the minimum and maximum loading doses 
in the study were adjusted to CZP 50mg Q2W and CZP 200mg Q2W, respectively, and the 
minimum and maximum maintenance doses were adjusted to CZP 50mg Q4W and CZP 
100mg Q2W, respectively, following implementation of Protocol Amendments 4 and 5. 
However, it was later determined that there were deficiencies with the bioanalytical assays 
used for RA0043, which rendered the PK data unreliable. Accordingly, PK samples were no 
longer collected for study participants on the Reduced CZP Dose following implementation 
of Protocol Amendment 8, in addition to reducing the burden on participants who had already 
been in the study for a number of years. 
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A validated ECLIA method that meets the standards set in the regulatory guidance for 
analytical procedures and methods validations for drugs and biologics will be used for any 
new analyses, including re-analysis of archived samples collected before Protocol 
Amendment 9 and for the analysis of bio-samples collected from the additional 30 study 
participants after Protocol Amendment 9. 
Based on 24-week interim results from the first 163 study participants enrolled in RA0043, 
both the original and reduced doses showed safety profiles similar to the approved CZP dose 
regimen in the adult RA population.  The overall clinical response in this analysis (taking 
both doses into account) was PedACR30 and PedACR50 responses of 77.3% and 67.5%, 
respectively at Week 12. The response from the original dose was 75.6% for PedACR30 and 
64.1% for PedACR50; the response from the reduced dose was 78.8% for PedACR30 and 
70.6% for PedACR50.  PedACR50 response demonstrates a highly clinically relevant 
decrease in disease activity. 
Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
pJIA at both the reduced and Original CZP Doses and support the safety for the Original CZP 
Dose, as more of the safety data collected in the study to date has been on the reduced dose, 
30 additional study participants will be enrolled on the Original CZP Dose following Protocol 
Amendment 9.  
All study participants enrolled following Protocol Amendment 9 will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using the ECLIA method. In 
addition, PK and ADAb samples (for which sufficient volume is available) collected in this 
study prior to Protocol Amendment 9 will be analyzed with the ECLIA method. The 
collective ECLIA-based PK data for this study will form the basis of any future CZP 
modeling and simulation work. 
Full interim analyses were performed in 2016 after all active study participants completed the 
Week 24 (Visit 10) assessments.  Week 24 full interim analyses were completed as described 
in SAP Amendment 1. SAP Amendment 4 comprises the analyses to be completed for an 
Updated Week 24 (Visit 10) interim analysis including the 30 new study participants enrolled 
after Protocol Amendment 9, any interim analyses to support marketing applications and the 
final analysis of the study. 
Change #7 
Section 2.5, Study RA0138 was added 
RA0138 is an open-label study in 30 adult study participants with RA.  This study was 
conducted to generate PK and ADAb data using the same ECLIA assay as used in RA0043 to 
form the basis of “PK-matching” for CZP approval. The PK and ADAb data from RA0138 
will be analyzed and displayed in the same manner as data from RA0043 so that comparisons 
and conclusions can be made.  Those details will be presented in the Appendix, Section 12.1. 
Change #8 
Section 3.1, General presentation of summaries and analyses 
SAS® Version 9.3 (or later) will be used to perform all summaries and analyses, unless 
specified otherwise. 
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All study participants received CZP and are grouped by their Baseline weight group in the 
summary tables.  Generally, data summaries will be organized by CZP dosing regimen, and 
will include the following CZP dose regimen groups with results presented in this order: 
• Reduced CZP Dose Regimen Overall: includes all study participants who began treatment 
in accordance with the reduced CZP dosing regimen defined for the study (3 loading 
doses of CZP at Weeks 0, 2, and 4 [minimum=50mg Q2W, maximum=200mg Q2W] 
followed by a maintenance dose for the duration of the study [minimum=50mg Q4W, 
maximum=100mg Q2W]). This subgroup includes all study participants who began the 
study with this CZP dose regimen and received 1 or more doses of this regimen, 
regardless of any subsequent switch to the original CZP dose regimen. 
o Under Protocol Amendment 9, study participants are allowed to escalate to the 
Original CZP Dose  
• Original CZP Dose Regimen Overall: includes all study participants who began treatment 
in accordance with the original CZP dosing regimen defined for the study (3 loading 
doses of CZP at Weeks 0, 2, and 4 [minimum=100mg Q2W, maximum=400mg Q2W] 
followed by a maintenance dose for the duration of the study [minimum=50mg Q2W, 
maximum=200mg Q2W]). This subgroup includes all study participants who began the 
study with this CZP dose regimen and received 1 or more doses of this regimen, 
regardless of any subsequent switch to the reduced CZP dose regimen. 
• Any CZP Dose Regimen: includes all study participants in the reduced and original CZP 
dosing regimens. 
For the Original CZP Dose Regimen Overall group, selected data will be further subdivided 
into events and assessments occurring prior to or without and following dose reduction - 
namely Original CZP Dose Regimen Prior to or Without Dose Reduction vs. Original CZP 
Dose Regimen Following Dose Reduction. Original CZP Dose Regimen study participants 
whose CZP dose was not reduced prior to study discontinuation will be excluded from 
summaries of data following CZP dose reduction; this will include the 30 study participants 
enrolled under Protocol Amendment 9 who do not dose reduce. Summaries of data following 
dose reduction for study participants who began treatment on the original CZP dose regimen 
will be restricted to study participants whose CZP dose was actually reduced and for the time 
that the dose was reduced.  If study participants escalate their dose after reduction (allowed 
after Protocol Amendment 9), that data may be summarized or listed separately.   
Summaries of data that have been subdivided as prior to or without dose reduction vs. 
following dose reduction vs following dose escalation will generally assign data associated 
with the dose reduction visit to the “prior to or without dose reduction” category and data 
associated with the dose escalation visit to the “dose reduction” category.  The only 
exceptions to this rule will be for AEs occurring on the same date as the dose reduction 
whereby the classification of AEs occurring on the date of dose reduction will be based upon 
review and classification by the study physician and for AEs on the same date as the dose 
escalation, whereby the classification of the AEs occurring on the date of dose escalation will 
also be based upon review and classification by study physician.  
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Generally, data will be summarized by the Reduced Overall, Original Overall, and Any CZP 
Dose Regimen groups with selected outputs further summarized by the Original CZP Dose 
Regimen Prior to or Without Dose Reduction vs. the Original CZP Dose Regimen Following 
Dose Reduction. Selected outputs will further summarize the data occurring during the 
Escalation CZP Dose Regimen. 
Note that for efficacy data, summaries will be presented by the Reduced CZP Dose Regimen 
Overall (regardless of dose escalation), the Original CZP Dose Regimen Overall (regardless 
of dose reduction or dose escalation), and the Any CZP Dose Regimen (regardless of dose 
reduction or dose escalation). 
Further details regarding these displays based upon dose regimen can be found in the 
respective PK, safety and efficacy analysis sections below. 
Categorical data will be presented as summary tables. A missing category will be included as 
applicable.   
Continuous variables will be summarized with the mean, standard deviation, median, 
minimum, and maximum. For CZP plasma concentrations and CRP, the geometric mean and 
geometric coefficient of variation (CV) will be presented.     
Mean, standard deviation, and median will be displayed to 1 more decimal place than 
collected in the case report form (CRF). Minimum and maximum values will be displayed to 
the same level of precision as collected in the CRF. Percentages will be calculated using the 
number of study participants in the relevant population or subgroup as the denominator. 
Presentation of percentages will be to 1 decimal place. Percentages will not be presented if 
the frequency count is 0. 
No formal statistical hypothesis testing will be performed. Ninety-five percent confidence 
intervals (CIs) for the percentage of responders will be calculated using the exact binomial 
method. 
In addition, for other subgroup analyses (Baseline age group, concomitant MTX use, ERA 
status and overall anti-CZP antibody status), data will be generally presented by the specified 
subgroups pooling across all weight groups (with the exception of PK analyses which are 
specified in the corresponding sections).  
In some listings, study participants who started on the original CZP dose regimen will be 
divided into two subgroups as listed below: 
Original CZP Dose with Dose Reduction: includes all study participants who started with the 
original CZP dose regimen and then subsequently switched to the reduced dose. 
Original CZP Dose without Dose Reduction: includes all study participants who started with 
the original CZP dose regimen without switching to reduced dose (for example, discontinued 
study drug prior to dose reduction visit). 
Was changed to: 
SAS® Version 9.3 (or later) will be used to perform all summaries and analyses, unless 
specified otherwise. 
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All study participants received CZP and in most cases, are grouped by their Baseline weight 
group in the summary tables.  Generally, data summaries will be organized by CZP dose, and 
will include the following CZP dose groups: 
• Original CZP Dose: includes all study participants who began treatment in accordance 
with the Original CZP Dose defined for the study (3 loading doses of CZP at Weeks 0, 2, 
and 4 [minimum=100mg Q2W, maximum=400mg Q2W] followed by a maintenance 
dose for the duration of the study [minimum=50mg Q2W, maximum=200mg Q2W]). 
Only data obtained prior to their first change in dosage will be included in summaries of 
the Original CZP Dose. 
• Reduced CZP Dose: : includes all study participants who began treatment in accordance 
with the Reduced CZP Dose defined for the study (3 loading doses of CZP at Weeks 0, 2, 
and 4 [minimum=50mg Q2W, maximum=200mg Q2W] followed by a maintenance dose 
for the duration of the study [minimum=50mg Q4W, maximum=100mg Q2W]). Only 
data obtained prior to a dose change will be included in summaries of the Reduced CZP 
Dose. 
• Any CZP Dose: includes all data from all study participants while being treated with the 
Original CZP Dose or the Reduced CZP Dose at any time in the study, regardless of dose 
switching.  
Generally, data will be summarized by the Original CZP Dose, Reduced CZP Dose, and Any 
CZP Dose groups.  For PK and ADA analyses, data will be summarized by Original CZP 
Dose and Reduced Dose only.  
Further details regarding these displays based upon dose groups can be found in the 
respective PK, safety and efficacy analysis sections below. 
Categorical data will be presented as summary tables. A missing category will be included as 
applicable.   
Continuous variables will be summarized with the mean, standard deviation, median, 
minimum, and maximum. For CZP plasma concentrations and CRP, the geometric mean and 
geometric coefficient of variation (CV) will be presented.     
Mean, standard deviation, and median will be displayed to 1 more decimal place than 
collected in the case report form (CRF). Minimum and maximum values will be displayed to 
the same level of precision as collected in the CRF. Percentages will be calculated using the 
number of study participants in the relevant population or subgroup as the denominator. 
Presentation of percentages will be to 1 decimal place. Percentages will not be presented if 
the frequency count is 0. 
No formal statistical hypothesis testing will be performed. Ninety-five percent confidence 
intervals (CIs) for the percentage of responders will be calculated using the exact binomial 
method. 
For certain laboratory parameter results that are collected as either “<XX.X” or “>XX.X”, if 
descriptive statistics are calculated for the parameter, the XX.X will be used in the calculation 
but the data listing will reflect the actual reported result. 
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The classification of AEs occurring on the same date as a dose change will belong to the 
period of the dose change. 
In addition, for other subgroup analyses (e.g. Baseline age group, concomitant MTX use, 
etc.), data will be generally presented by the specified subgroups pooling across all weight 
groups (with the exception of PK analyses which are specified in the corresponding sections).  
Change #9 
Section 3.2.1, Analysis time points 
For study participants who withdraw prior to the last time point for the particular analysis 
being conducted (ie, Week 16, Week 24, Week 56, Final), data recorded at the Early 
Discontinuation/EOT Visit will be assigned to what would have been the next scheduled 
visit, unless unavailable or otherwise specified, dependent on which visit schedule the study 
participant is following. These data will be included in the summaries of the assigned visit 
and the “Early Discontinuation/EOT” Visit if applicable. For efficacy data, the Early 
Discontinuation/EOT Visit will not be summarized and only the re-assigned visit will be 
included in the summary tables. Note that data from the Early Discontinuation Visit or EOT 
will be listed as “Visit X (Week Y)/ED” or “Visit X (Week Y)/EOT” where the X was the 
re-assigned visit number and Y was the re-assigned week number in all safety and efficacy 
data listings as applicable. 
Was changed to: 
For study participants who withdraw prior to the last time point for the particular analysis 
being conducted (ie, Week 16, Week 24, other interim analysis, Final), data recorded at the 
Early Discontinuation/EOT Visit will be assigned to what would have been the next 
scheduled visit, unless unavailable or otherwise specified, dependent on which visit schedule 
the study participant is following. This re-assignment should be based upon the study day 
(relative to the baseline visit date) and also keeping in mind the +/- 3-day window into which 
visits fall. These data will be included in the summaries of the assigned visit and the “Early 
Discontinuation/EOT” Visit if applicable. For efficacy data, the Early Discontinuation/EOT 
Visit will not be summarized and only the re-assigned visit will be included in the summary 
tables. Note that data from the Early Discontinuation Visit or EOT will be listed as “Visit X 
(Week Y)/ED” or “Visit X (Week Y)/EOT” where the X was the re-assigned visit number 
and Y was the re-assigned week number in all safety and efficacy data listings as applicable. 
Change #10 
Section 3.4, Protocol deviations 
Important protocol deviations will be predefined and data cleaning meetings will be held on 
an ongoing basis to review the important protocol deviations. 
In addition, protocol deviations related to the impact of the global pandemic of coronavirus 
disease 2019 (COVID-19) will be documented. 
Was changed to: 
Important protocol deviations will be pre-defined and data cleaning meetings will be held on 
an ongoing basis to review the important protocol deviations.  At these data cleaning 
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meetings, protocol deviations from the Clinical Trial Management System (CTMS) as well as 
those generated programmatically will be reviewed by the study team in order to flag those 
that are important. 
In addition, protocol deviations related to the impact of the global pandemic of coronavirus 
disease 2019 (COVID-19) will be documented. 
Change #11 
Section 3.4.1, PK protocol deviations was added 
Exclusion of specific PK data points will be done for that PK data presented in the subset of 
tables and figures where geometric means are calculated and displayed.  These exclusions 
will not occur in the PK data presented in spaghetti plots or individual profile figures.  The 
reasons why PK data points may be excluded are the following:  
• Study participant taking an incorrect treatment or dose, 
• Study participant’s discontinuation of CZP, 
• Study participant being in Clinical remission (and not taking CZP), 
• Study participant having deviations where CZP dosings occur outside the scheduled CZP 
dosing window, and 
• Study participant is procedurally non-compliant in having PK samples taken at the 
appropriate time points. 
PK data that is excluded due to the above reasons will be flagged on the analysis PK dataset.  
The flagging will allow the data to be excluded from geometric mean calculations which 
could be more affected by instances of treatment and procedure non-compliance. 
Change #12 
Section 3.4.1.1, Rules for exclusions of specific PK samples was added 
The PK sample results taken at a specific visit will be excluded from analysis for the 
following reasons: 
• For study participants in documented clinical remission (and not taking CZP), any study 
participant’s PK sample results during clinical remission (after CZP dose is stopped) are 
excluded, 
− For study participants returning to CZP dosing after having stopped taking CZP (eg. 
when in clinical remission), a study participant’s PK sample result will be included in 
summaries if the prior 3 consecutive CZP doses are present, 
• If the study participant’s PK sample was taken at a visit where the prior 2 consecutive 
CZP doses were missed, then the study participant’s PK sample is excluded, 
• If in the 168 days prior to the study participant’s PK sample, there were >3 CZP doses 
missed, then that study participant’s PK sample is excluded, 
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• If the PK sample is taken following the study participant’s noncompliance in CZP dosing 
as indicated by an important protocol deviation, then the study participant’s affected PK 
sample (the one following that noncompliant dose) will be excluded, 
• If a study participant is on a Q2W CZP dosing interval, and the study participant’s PK 
sample is taken <9 days or >19 days from the last CZP dosing, then it is excluded, 
• If a study participant is on a Q4W CZP dosing interval, and the study participant’s PK 
sample is taken <23 days or >33 days from the last CZP dosing, then it is excluded, 
• For the Week 1 PK sample, if a study participant’s PK sample is taken (too soon) <4 days 
after or (too late) >10 days after the Week 0 CZP dose, it is excluded, or 
For the Week 17 PK sample, if a study participant’s PK sample is taken (too soon) <4 days 
after or (too late) >10 days after the Wk 16 CZP dose, it is excluded. 
Change #12 
Section 3.5.3, Full Analysis Set 
The Full Analysis Set (FAS) will consist of all study participants in the SS who have at least 
1 valid Baseline and 1 valid post-Baseline assessment for the same efficacy variable. 
Was changed to: 
The Full Analysis Set (FAS) will consist of all study participants in the SS who have no more 
than one of the 6 core components missing at baseline (count of joints with active arthritis, 
count of joints with limitation of range of motion, Physician’s Global Assessment of Disease 
Activity score, CHAQ score, Parent’s Global Assessment of Overall Well-Being score and 
CRP result) for calculating PedACR30/50/70/90. 
Change #13 
Section 3.5.5, Pharmacokinetic-Pharmacodynamic (PK-PD) Set was removed 
Change #14 
Section 3.6, Treatment assignment and treatment groups 
For PK, safety and efficacy analyses, study participants will be grouped by their Baseline 
weight group. Selected analyses will also group study participants by their Baseline age 
group, concomitant MTX use, and overall anti-CZP antibody status (as defined in Section 
8.2).  Additionally, PK and selected safety data will be presented by CZP dose regimen 
(Reduced Overall vs. Original CZP Dose Regimen Overall).  For study participants enrolled 
on the original CZP dose regimen, data will be tabulated overall, and selected data will be 
further subdivided into events and assessments occurring prior to or without and following 
dose reduction. Efficacy summaries will be presented by the Reduced CZP Dose Regimen 
Overall, the Original CZP Dose Regimen Overall, and the Any CZP Dose Regimen. 
Regardless of changes in dosing due to weight change, study participants will generally be 
analyzed by the CZP dosing regimen they received at Baseline (with the exception of study 
participants that began treatment on the original CZP dose regimen and underwent dose 
reduction, as described in Section 3.1). 
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Was changed to: 
For PK, safety and efficacy analyses, study participants will be grouped by their Baseline 
weight group. Selected analyses will also group study participants by their Baseline age 
group, concomitant MTX use, and ADAb titer (as defined in Section 8.2 ).   
Regardless of specific prescribed doses dictated by weight change during study conduct, 
study participants will be analyzed by the CZP dose group stated in Section 3.1. 
Change #15 
Section 3.8, Coding dictionaries 
Adverse events and medical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®) according to UCB standard operating procedures (SOP). 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
according to UCB SOPs.  
Was changed to: 
Adverse events and medical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA® version 18.1) according to UCB standard operating 
procedures (SOP). Medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD version dated Sep 2013) according to UCB SOPs.  
Change #16 
Section 3.9, Changes to protocol-defined analyses 
The protocol stated that vital sign abnormalities will be evaluated at every visit.  Vital signs 
are collected at every visit, not vital sign abnormalities, and observed values and changes 
from Baseline in observed values will be summarized.  
In the statistical section of the protocol, it is stated that the frequency and percentage of AEs 
reported during the first 16 weeks of study medication exposure will be summarized 
separately for the 2 CZP dose regimens (the Original CZP Dose Regimen, the Reduced CZP 
Dose Regimen), and that this analysis will be repeated, excluding any study participants who 
switched from the original to the reduced CZP dose prior to Week 16.  Given that only 1 
study participant switched from the original to the reduced CZP dose prior to Week 16 (at 
Week 12), the analysis will not be repeated with this subject excluded. Exposure-adjusted 
event rates (EAER) are added to selected TEAE tables. 
This analysis plan includes plots of CZP plasma concentrations, anti-CZP antibody 
concentrations, JADAS-71 and maximum PedACR response for individual study participants 
by visit; these plots were not pre-specified in the study protocol.  
Subgroup analyses by ERA status were not pre-specified in the protocol, but are included for 
selected outcomes. 
In the protocol it was stated that continuous efficacy endpoints would be presented using both 
last observation carried forward (LOCF) and observed case (OC) analyses. Instead, only 
LOCF summaries of continuous efficacy endpoints will be presented since efficacy is not the 
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primary objective of this study and little difference is expected between the two different 
analyses. 
For joints with limitation of motion (LOM), it was stated in the protocol that the assessment 
of LOM would be made using 69 of the 75 joints from the standard PRINTO/PRCSG 
standard joint examination; however, the assessment described in the SAP that utilized 
67 joints was conducted. This was according to an updated definition of LOM in the 
PRINTO/PRCSG assessment at the time of finalization of the original SAP. 
For CRP, summaries present the percent change from Baseline instead of the ratio to Baseline 
to aid in interpretation. 
Was changed to: 
The definition for the FAS has been clarified to the following: The Full Analysis Set (FAS) 
will consist of all study participants in the SS who have no more than one of the 6 core 
components (count of joints with active arthritis, count of joints with limitation of range of 
motion, Physician’s Global Assessment of Disease Activity score, CHAQ score, Parent’s 
Global Assessment of Overall Well-Being score and CRP result) for calculating improvement 
in PedACR30/50/70/90 missing at baseline. 
The definition for the PK-PP has been clarified that study participants in this set must have 
PK data analyzed using the ECLIA method. 
In the statistical section of the protocol, it is stated that the AEs will be summarized 
separately for the periods of exposure to Original CZP Dose and the Reduced CZP Dose, in 
addition to exposure for study participants that switched from the Reduced CZP Dose to the 
Original CZP Dose following Protocol Amendment 9.  The analysis of AEs after a study 
participant changes doses will not be separately identified and presented in the Updated 
Week 24 Interim Analysis although the AEs that occur after dose changes will be 
summarized in the Any CZP Dose group. 
In the statistical section of the protocol, it is stated that the frequency and percentage of AEs 
reported during the first 16 weeks of study medication exposure will be summarized 
separately for the 2 CZP doses (the Original CZP Dose, the Reduced CZP Dose), and that this 
analysis will be repeated, excluding any study participants who switched from the original to 
the reduced CZP dose prior to Week 16.  The protocol-specified safety Week 16 analyses 
generated for prior interim analyses will not be included in the Updated Week 24 Interim 
Analysis or any later analyses. 
Exposure-adjusted event rates (EAER) are added to selected TEAE tables. 
This analysis plan includes plots of CZP plasma concentrations, ADAb titers, JADAS-71 and 
maximum PedACR response for individual study participants by visit. Box plots of the PK 
distribution as Weeks 12 and 24 stratified by Baseline weight group, Baseline age group, 
concomitant MTX use and participant ADAb classification will be performed as a basis of 
the comparison with the adult RA PK exposures in RA0138; this comparison of observed PK 
data will be covered in Appendix Section 12.1. Plots of PK and ADAb data were not pre-
specified in the study protocol.   
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It is not planned to perform a population PKPD modeling analysis of RA0043 data to explore 
the exposure-response relationship in JIA pediatric population for the following reasons: i) 
the purpose of the RA0043 study is to support the efficacy extrapolation to the pediatric 
population by PK matching with respect to RA adult PK, and thus the main aim of the 
analysis that will be performed by nonlinear mixed effect modeling is to characterize the PK 
in JIA pediatrics with precise parameter estimates; and ii) the W24 interim analyses 
performed and submitted in 2016 (BLA 125160-275) included PedACR and JADAS-71 
graphical explorations by dose regimen which concluded that a substantial improvement of 
the PedACR and JADAS-71 responses across both dosing regimens investigated in Study 
RA0043 was observed, with no differences between these, that would support a pop-PKPD 
analysis. Hence the PK-PD Set was removed as no analysis are planned for this population. 
In the protocol it was stated that continuous efficacy endpoints would be presented using both 
last observation carried forward (LOCF) and observed case (OC) analyses. Instead, only 
observed case summaries of continuous efficacy endpoints will be presented since efficacy is 
not the primary objective of this study and little difference is expected between the two 
different analyses. 
For the Updated Week 24 Interim Analysis, the efficacy data will be summarized and plotted 
up to and including Week 24; all efficacy data will be included in listings. Efficacy analyses 
will not be submitted for the 120 Day Safety Update. 
For joints with limitation of motion (LOM), it was stated in the protocol that the assessment 
of LOM would be made using 69 of the 75 joints from the standard PRINTO/PRCSG 
standard joint examination. In all SAPs since SAP Amendment 2, the assessment now utilizes 
67 joints and this was according to an updated definition of LOM in the PRINTO/PRCSG 
assessment that was not available prior to the finalization of the protocol. 
For CRP, summaries present the percent change from Baseline instead of the ratio to Baseline 
to aid in interpretation. 
Change #17 
Section 4.2, Handling of dropouts or missing data 
For continuous efficacy endpoints, missing assessments will be imputed using an LOCF 
approach. For Week 56 and final analyses, LOCF will only be applied to study participants 
who have discontinued early prior to reaching the Week 56 visit and data will be carried 
forward up to the Week 56 visit as appropriate. Data beyond Week 56 will be analyzed as 
observed cases without any imputation. The same rule will also be applied in nonresponder 
imputation (NRI) calculations for binary efficacy outcomes. 
Unless otherwise stated, the following guidelines apply for the LOCF analyses: 
• If a Baseline value is missing, carry forward the Screening value as far as Baseline but 
no further. 
• For post-Baseline assessments, only carry forward earlier post-Baseline values. 
Baseline and pre-Baseline values do not get carried forward to the post-Baseline 
visits. 
Was changed to: 
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For continuous efficacy endpoints, missing assessments will not be imputed. For all analyses, 
the data will be analyzed as observed cases without any imputation. For the non-responder 
imputation (NRI) calculations for binary efficacy outcomes, the data beyond Week 56 will be 
analyzed as observed cases without any imputation while the data up to and including Week 
56, NRI will only be applied to study participants who have discontinued early prior to 
reaching Week 56. 
No further imputations of any other missing data are planned (eg, efficacy data missing at 
random). 
Change #18 
Section 4.2.2, Incomplete date for the last administration of study medication was added 
No imputation should be performed for missing study medication start dates. This field on the 
CRF should not be partial or missing. 
For partial or missing date of last dose of study medication, the following imputation rules 
will be applied for the purpose of calculating overall exposure: 
If the day is missing (but month and year available), impute the last dose date as the 
minimum of the last day of the month or the date of last contact reported on the Study 
Termination CRF; if day and month are both missing (only year available), impute the last 
dose date as the minimum of the last day of the year or the date of last contact on the Study 
Termination CRF. 
If a subject died and has a partial or missing last administration date, the date is to set to the 
date of death. If there is a partial date of last dose and the month/year are prior to the month 
and year of the date of death, follow partial date imputation rules. 
If the last dose date is completely missing and no information could be obtained from data 
cleaning exercises, the last dose date should be imputed as the date of last contact according 
to the Study Termination CRF. A review of the data for subjects with completely missing last 
dose dates should be performed to ensure that the imputation does not result in an unrealistic 
value for duration of exposure.  
Imputed date of last dose dates should only be used for calculation of the duration of 
exposure. The date as recorded on the CRF should be presented in subject data listings (no 
imputed dates should be included in subject data listings). 
Change #19 
Section 4.2.4, Missing adverse event intensity was added 
If the intensity of an AE is missing, then it will be counted as severe for analysis purposes. 
Change #20 
Section 4.2.5, Missing adverse event relationship to study medication was added 
If the AE relationship to study medication is missing, then it will be counted as related for 
analysis purposes. 
Change #21 
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Section 4.3, Interim analyses and data monitoring 
Based on results of this interim PopPK analysis, the dosing regimen was changed with 
Protocol Amendments 4 and 5, and the doses to be administered were reduced by 50% for all 
weight groups. This change was intended to achieve plasma concentrations similar to the 
effective concentrations observed in previous studies in adult study participants with RA. 
However, it was later determined that there were deficiencies detected with the use of the 
bioanalytical assay within RA0043, which rendered the PK data for the PopPK analysis and 
simulations that informed the dose reduction in Protocol Amendments 4 and 5 unusable from 
a regulatory standpoint.  
Interim analyses of PK, immunogenicity, safety, and efficacy endpoints 
An interim analysis of PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants that were enrolled and treated prior to implementation of 
Protocol Amendment 9 had completed the Week 24 (Visit 10) assessments, and the results 
were reported separately; this is referred to as the 2016 Week 24 interim analysis. An interim 
analysis, including all enrolled participants, for all PK, immunogenicity, safety, and efficacy 
endpoints will be performed after all active study participants, including those enrolled 
following the implementation of Protocol Amendment 9, have completed the Week 24 (Visit 
10) assessments; this will be referred to as the Updated Week 24 Interim analysis.  A Week 
56 (Visit 14) interim analysis will also be performed after all those enrolled, following the 
implementation of Protocol Amendment 9, have completed the Week 56 (Visit 14) 
assessments. 
All statistical tables, listings and figures comprising this SAP will be produced for all future 
interim and final analyses. 
Was changed to: 
Based on results of this interim PopPK analysis, the doses was changed with Protocol 
Amendments 4 and 5, and the doses to be administered were reduced by 50% for all weight 
groups. This change was intended to achieve plasma concentrations similar to the effective 
concentrations observed in the previous study in adult study participants with RA (study  
C87050). However, it was later determined that there were deficiencies detected with in the 
bioanalytical assay used within RA0043, which rendered the PK data for the PopPK analysis 
and simulations that informed the dose reduction in Protocol Amendments 4 and 5 were not 
up to current standards and FDA guidelines; therefore, those data were not able to support the 
regulatory filing.  
Interim analyses of PK, immunogenicity, safety, and efficacy endpoints 
An interim analysis of PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants that were enrolled and treated prior to implementation of 
Protocol Amendment 9 had completed the Week 24 (Visit 10) assessments, and the results 
were reported separately; this is referred to as the 2016 Week 24 interim analysis. An interim 
analysis, including all enrolled participants, for all PK, immunogenicity, safety, and efficacy 
endpoints will be performed after all active study participants, including those enrolled 
following the implementation of Protocol Amendment 9, have completed the Week 24 (Visit 
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10) assessments; this will be referred to as the Updated Week 24 Interim analysis to be used 
in support of the re-submission of BLA 125160-275.   
All statistical tables, listings and figures comprising this SAP will be produced for all future 
interim and final analyses. Interim data from RA0043 may be summarized to support 
regulatory submissions, regular safety signal detection monitoring, publications and annual 
reports to regulatory agencies.  For any interim data summary, all available data as of the 
time of the clinical cut-off date will be included.  Subjects ongoing at the time of an interim 
data summary will be assumed to be treated (ie exposed) up to and including the date of the 
clinical data cut-off; efficacy data will not be imputed for the closest visit to the clinical 
snapshot date if the visit is not currently in the clinical database; composite variables will not 
be calculated if one or more components are unavailable for the visit closest to the clinical 
snapshot date. 
Change #22 
Section 4.7, Examination of subgroups 
All PK, safety and efficacy summaries will be presented by Baseline weight group (10 to 
<20kg, 20 to <40kg, and ≥40kg). For some safety and efficacy endpoints, such as 
PedACR30, PedACR50, PedACR70, PedACR90 and incidence of treatment-emergent AEs 
(TEAEs), results will also be presented by Baseline age group, overall anti-CZP antibody 
status, ERA status, and  concomitant MTX use group as listed below pooling across all 
weight groups: 
• Baseline age group:  
o 2-<6 years 
o 6-<12 years 
o 12-17 years 
• TE Anti-CZP antibody status and titer classification:  
o TE ADAb status negative 
o TE ADAb status positive <=32 
o TE ADAb status positive >32 to <=128 
o TE ADAb status positive >128 to <=512 
o TE ADAb status positive >512 to <=1024 
o TE ADAb status positive >1024 to <=4096 
o TE ADAb status positive >4096 
• ERA status:  
o presence 
o absence 
• Concomitant MTX use (distinct from Baseline MTX use presented in Section 6.1 and 
defined as any concomitant MTX use during the Treatment Period):  
o With concomitant MTX use 
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o Without concomitant MTX use 
For subgroup analyses of incidence of anti-CZP antibody formation and CZP plasma 
concentrations, results will also be presented by Baseline age group. In addition, summaries 
will be provided by overall anti-CZP antibody status, ERA status, and concomitant MTX use 
group in combination with Baseline weight group.  
As specified in Section 3.3, Baseline for all subgroup analyses will always be the original 
Baseline (ie, prior to the 1st CZP Dose in this study). 
For efficacy endpoints PedACR30, PedACR50, PedACR70, and PedACR90, results will also 
be presented by gender and race. 
In addition, selected outputs will only be summarized for the Any CZP Dose Regimen as 
specified in each relevant section. 
Was changed to: 
Most PK, safety and efficacy summaries will be presented by Baseline weight group (10 to 
<20kg, 20 to <40kg, and ≥40kg). For some safety and efficacy endpoints, such as 
PedACR30, PedACR50, PedACR70, PedACR90 and incidence of treatment-emergent AEs 
(TEAEs), results will also be presented by the subgroups as listed below (at times, pooling 
across all baseline weight groups): 
• Baseline age group:  
− 2-<6 years 
− 6-<12 years 
− 12-17 years 
• ADAb titer classification (defined in Section 8.2 using RA0043 data): ):  
− >= 0 to <= Quartile 1 
− > Quartile 1 to <= Quartile 2 (Median) 
− > Quartile 2 (Median) to <= Quartile 3 
− > Quartile 3 
− Missing 
• Concomitant MTX use (distinct from Baseline MTX use presented in Section 6.1 and 
defined as any concomitant MTX use during the Treatment Period):  
− With concomitant MTX use 
− Without concomitant MTX use 
• Gender 
− Female 
− Male 
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• Race 
− White 
− Non-white 
For subgroup analyses of incidence of ADAb formation and CZP plasma concentrations, 
results will also be presented by Baseline age group. In addition, summaries will be provided 
by ADAb titer classification, ADAb participant status classification (defined in Section 8.2 ), 
and concomitant MTX use group in combination with Baseline weight group.  
As specified in Section 3.3, Baseline for all subgroup analyses will always be the original 
Baseline (ie, prior to the 1st CZP Dose in this study). 
In addition, selected outputs will only be summarized for the Any CZP Dose as specified in 
each relevant section. 
Change #23 
Section 5.1, Subject disposition 
The number of screened study participants, and reasons for screen failure, will be 
summarized for all screened study participants. 
The number and percentage of study participants who were treated, who completed the study, 
and who discontinued from the study, along with the discontinuation reasons, will be 
summarized for the Safety Set.  For the Week 16, Week 24 and Week 56 interim analyses, 
number of study participants completing Week 16, Week 24 and Week 56 (respectively) will 
be added in addition to the number completing the study as appropriate. The number of study 
participants in each analysis set will be presented. Summaries will be provided for the 
Reduced Overall, Original Overall, and Any CZP Dose Regimen groups. 
Discontinuations due to AEs will be summarized separately for the SS, and will be provided 
for the Reduced Overall, Original Overall, and Any CZP Dose Regimen groups. 
The number and percentages of subjects impacted by COVID-19 will be presented for each 
visit, overall and by impact category, for each relationship to COVID-19 as well as any 
relationship, overall and by country, for all subjects in the SS.  This data will be presented in 
subject data listings. 
Was changed to: 
The number of screened study participants, and reasons for screen failure, will be 
summarized for all screened study participants. 
The number and percentage of study participants who were treated, who completed the study, 
and who discontinued from the study, along with the discontinuation reasons, will be 
summarized for the Safety Set by CZP Dose Regimen (Reduced, Original and Any) and 
Baseline weight group as well as by CZP Dose Regimen and ADAb titer classification.  For 
the Week 16, Week 24 and other interim analyses, number of study participants completing 
Week 16, Week 24 and Week 48 (respectively) will be added in addition to the number 
completing the study as appropriate. The disposition of study participants in their initial 
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dosing phase, reduction phase and escalation dosing phase of the study will also be presented. 
The number of study participants in each analysis set will be presented.  
Discontinuations due to AEs will be summarized separately for the SS, and will be provided 
for the Reduced CZP Dose, Original CZP Dose, and Any CZP Dose groups. 
The number and percentages of subjects impacted by COVID-19 will be presented for overall 
and by impact visit, for any reason for all subjects in the SS.  This data will be presented in 
subject data listings. 
Change #24 
Section 5.2, Protocol deviations 
The number and percentage of study participants with important protocol deviations will be 
summarized by type for the SS for the Any CZP Dose Regimen. All important protocol 
deviations will also be listed. 
Note that partial PK data exclusion is implemented due to certain protocol deviations (eg, 
incorrect treatment or dose, procedural noncompliance related to PK sampling), minor 
deviations from the planned treatment schedule (eg, delays or missing doses not considered 
as important protocol deviations), CZP interruption or CZP discontinuation due to AEs, 
TB prophylactic treatment, or clinical remission. These exclusions will be reviewed and 
identified at data cleaning meetings and are only applicable for group PK summary tables and 
graphs where the geometric mean for plasma concentration are calculated and displayed. 
However, all PK data will be included in listings and individual graphs. Study participants 
with at least one PK data exclusion are summarized and listed. 
Was changed to: 
The number and percentage of study participants with important protocol deviations will be 
summarized by type for the SS for the Reduced CZP Dose, Original CZP Dose, and Any CZP 
Dose. All important protocol deviations will also be listed. 
Note that PK sample exclusion will be implemented due to certain protocol deviations; see 
Section 3.5. Study participants with at least one PK data exclusion are summarized and listed. 
Change #25 
Section 6.6, Rescue medications 
Use of the following medications only results in efficacy data at the next scheduled visit 
being treated as missing/nonresponse: 
• Higher than Baseline dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and 
cyclooxygenase-2 (COX-2) inhibitors, including as needed (PRN) use within 72 hours 
prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
• Higher than Baseline dose of analgesics or opioids including PRN use within 48 hours 
prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
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• Any increase in dose of oral corticosteroids within 7 days prior to scheduled study visit 
(Note: The increase has to be higher than baseline). 
In all cases, any medications recorded in the database will be classified as rescue medication 
only when JIA is listed as the indication for that medication. Rescue medication use and date 
of first usage will be confirmed during the data cleaning meetings prior to the database lock. 
Generally, the +1 day rule was applied to the first usage date when considering its impact on 
efficacy endpoints. Therefore, only efficacy data with dates after the first usage date of the 
rescue medication were impacted (using the nonresponder imputation (NRI) or LOCF 
imputation methods). Exceptions are nonsteroidal anti-inflammatory drugs (NSAIDs), 
cyclooxygenase-2 (COX-2) inhibitors, analgesics or opioids, or oral corticosteroids as 
specified above. The number and percentage of study participants of who used rescue 
medication up to the Week 16 visit and after the Week 16 visit will be summarized 
separately. 
All summaries of rescue medications will be provided for the SS for the Reduced CZP Dose 
Regimen Overall, the Original CZP Dose Regimen Overall and the Any CZP Dose Regimen. 
All rescue medication will be listed. 
Was changed to: 
In all cases, any medications recorded in the database will be classified as rescue medication 
only when pJIA is listed as the indication for that medication. Rescue medication use and 
date of first usage will be confirmed during the data cleaning meetings prior to the database 
lock. Generally, the +1 day rule was applied to the first usage date when considering its 
impact on efficacy endpoints. Therefore, only efficacy data with dates after the first usage 
date of the rescue medication were impacted (using the non-responder imputation (NRI) 
method). The number and percentage of study participants of who used rescue medication up 
to the Week 16 visit and after the Week 16 visit will be summarized separately. 
All summaries of rescue medications will be provided for the SS for the Reduced CZP Dose, 
the Original CZP Dose and the Any CZP Dose. All rescue medication will be listed.  
Use of the following medications, which are not rescue medications, only results in efficacy 
data at the next scheduled visit being treated as missing/non-response: 
• Higher than Baseline dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and 
cyclooxygenase-2 (COX-2) inhibitors, including as needed (PRN) use within 72 hours 
prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
• Higher than Baseline dose of analgesics or opioids including PRN use within 48 hours 
prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
• Any increase in dose of oral corticosteroids within 7 days prior to scheduled study visit 
(Note: The increase has to be higher than baseline). 
All medication data resulting in efficacy data being treated as missing/non-response will be 
flagged in the concomitant medication listing. 
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Change #26 
Section 7, Measurements of treatment compliance 
In addition, a study participant could change dose (or frequency of dosing if in 10-20kg 
group) if a study participant crossed into a new weight group, which is not considered in the 
above expected calculations of number of CZP administration since all expectations are based 
on baseline weight group dosing regimen regardless of weight change. This specifically 
applies to the change of dose frequency from Q4W to Q2W if a subject crossed into the 20 to 
<40kg weight group, which is not considered in the expected calculations. Note that the dose 
reduction of ongoing study participants following Protocol Amendment 4 is considered in the 
calculations. Note also the dose escalation of ongoing study participants following Protocol 
Amendment 9 is considered in the calculations. 
Treatment compliance is provided for the SS for the Reduced CZP Dose Regimen Overall, 
Reduced CZP Dose Regimen, Original CZP Dose Regimen Prior to Dose Reduction or 
without Dose Reduction, Original CZP Dose Regimen Following Dose Reduction, Original 
CZP Dose Regimen Overall and Escalation CZP Dose Regimen. 
Was changed to: 
In addition, a study participant could change dose (or frequency of dosing if in 10-20kg 
group) if a study participant crossed into a new weight group, which is not considered in the 
above expected calculations of number of CZP administration; study participants are assigned 
dose groups (Reduced CZP Dose and Original CZP Dose) and Baseline weight group at 
baseline and do not change either for the entire analysis  regardless of weight change and 
dose adjustments. This specifically applies to the change of dose frequency from Q4W to 
Q2W if a subject crossed into the 20 to <40kg weight group, which is not considered in the 
expected calculations. Note that the dose reduction of ongoing study participants following 
Protocol Amendment 4 is considered in the calculations. Note also the dose escalation of 
ongoing study participants following Protocol Amendment 9 is considered in the calculations.  
For the Original CZP Dose and Reduced CZP Dose groups, treatment compliance is 
calculated from the first dose of CZP, for the entire time the study participant is taking study 
medication up to the dose change. For the results presented for Any CZP Dose, treatment 
compliance is calculated for the entire time the study participant is taking CZP from first dose 
until the last dose. Treatment compliance is summarized for the SS for the Reduced CZP 
Dose, Original CZP Dose, and Any CZP Dose. 
Change #27 
Section 8.1, CZP plasma concentriations 
CZP plasma concentrations are measured at Baseline, Weeks 1, 4, 12, 16, 17, 24, 32, 40, 48, 
every 24 weeks thereafter, the Early Discontinuation/EOT Visit, and the Final Visit; for study 
participants enrolled prior to Protocol Amendment 8, samples were not collected after 
implementation of Protocol Amendment 8. CZP plasma concentrations will be summarized 
by CZP dose regimen (Original CZP Dose Regimen or Reduced CZP Dose Regimen) using 
geometric means, 95% CIs for the geometric mean, geometric CV, and the median, minimum 
and maximum concentrations.  
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The geometric CV will be calculated using the following formula: 
, 
where SD=standard deviation from the log-transformed data. 
For study participants enrolled prior to Amendment 9, who began treatment on the original 
CZP dose regimen, and whose PK samples are analyzed with the ECLIA method, plasma 
CZP concentrations will be summarized separately for samples obtained during the period of 
exposure to (1) the original CZP dose (all results before and through the dose reduction visit), 
and (2) the reduced CZP dose (all results from the initial dose reduction visit onward). 
Plasma concentrations at the visit where dose reduction was to be initiated will be included in 
summary (1) only. Concentrations from participants enrolled after Amendment 9 will be 
included in Summary (1).  
For the summarization of geometric mean concentrations on the reduced CZP dose, visits will 
be identified as number of weeks relative to the dose reduction visit, regardless of the actual 
visit at which the dose reduction occurred.  Study participants that reduce dose are thus 
expected to have plasma concentration results at the dose reduction visit, 4 weeks after dose 
reduction (identified as Week 4), 8 weeks after dose reduction (identified as Week 8), and 12 
weeks after dose reduction (identified as Week 12).  Any subsequent concentration results for 
the reduced dose period will also be similarly summarized (ie, concentration results 24 weeks 
after dose reduction will be summarized as Week 24 results).  
Summaries of concentration results will be provided by Baseline weight group, as well as 
Baseline age group. In addition, summaries will be provided by TE ADAb status with titer 
classification (see 8.2) and concomitant MTX use in combination with Baseline weight 
group.  
Geometric mean plasma concentration time curves will be provided separately for study 
participants according to the ECLIA assay and dosing scenarios outlined above for the 
tabular summaries. Geometric mean plots will be provided overall and by Baseline age 
stratum, Baseline weight group, TE ADAb status with titer classification (see 8.2), and 
concomitant MTX use.    
In addition, observed plasma concentrations over time will be plotted for individual study 
participants, separately for each dose regimen whose samples have been analyzed with the 
ECLIA method. Plots of individual plasma concentrations will be provided by Baseline age 
stratum, Baseline weight group, TE ADAb status with titer classification (see 8.2), and 
concomitant MTX use. 
Concentrations below the limit of quantification of 32.0 ng/mL (0.032μg/mL) (BLQ) will be 
replaced by the LLOQ divided by 2 for the calculation of descriptive statistics. The geometric 
mean and CV% will be derived when at least two-thirds of the concentrations at a certain 
visit are above the LLOQ. If that criteria are not met, only the maximum and minimum 
values will be shown. Similarly, the 95% CI of the geometric mean will be calculated if at 
least 5 samples are available at a time point.  
100
*
1
)
exp(
(%)
2 −
=
SD
geoCV
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All summaries will be provided for the PK-PP Set.  All plasma concentration data will be 
listed. 
Was changed to: 
Only CZP plasma results analyzed using the ECLIA method will be summarized using the 
participants in the PK-PP set. CZP plasma concentrations are measured at Baseline, Weeks 1, 
4, 12, 16, 17, 24, 32, 40, 48, every 24 weeks thereafter, the Early Discontinuation/EOT Visit, 
and the Final Visit; for study participants enrolled prior to Protocol Amendment 8, samples 
were not collected after implementation of Protocol Amendment 8. CZP plasma 
concentrations will be summarized by CZP dose (Original CZP Dose, Reduced CZP Dose) 
using geometric means, 95% CIs for the geometric mean, geometric CV, and the median, 
minimum and maximum concentrations.  
The geometric CV will be calculated using the following formula: 
, 
where SD=standard deviation from the log-transformed data. 
For the two CZP Dose groups, summaries at all available visits and plots of plasma 
concentration results will be produced separately by Baseline weight group, Baseline age 
group, ADAb participant status classification, ADAb titer classification (see Section 8.2) and, 
concomitant MTX use in combination with Baseline weight group.  
Line-plots will be produced to summarize geometric mean (+/- 95% CI) plasma concentration 
over time.  On each plot there will be separate plot lines for each subgroup category as 
described above.  Plasma concentration will be plotted on both linear and semi-logarithmic 
scales.  
In addition, spaghetti plots of CZP plasma concentrations over time will be produced for 
individual study participants, separately for each CZP dose group. Plots will be provided by 
Baseline age group, Baseline weight group, concomitant MTX use in combination with 
Baseline weight group. In each plot, different symbols/colours will be used to identify 
subgroup categories.   
Box plots of the PK concentrations at Weeks 12 and 24 will be presented by CZP dose group 
for Baseline weight group, Baseline age group, ADAb participant status classification, ADAb 
titer classification, and concomitant MTX use in combination with Baseline weight group.  
Concentrations below the limit of quantification of 32.0 ng/mL (0.032μg/mL) (BLQ) will be 
replaced by the LLOQ divided by 2 for the calculation of descriptive statistics. The geometric 
mean and CV% will be derived when at least two-thirds of the concentrations at a certain 
visit are above the LLOQ. If the criteria are not met, only the maximum and minimum values 
will be shown. Similarly, the 95% CI of the geometric mean will be calculated if at least 
5 samples are available at a time point.  
All summaries will be provided for the PK-PP Set.  All plasma concentration data will be 
listed. 
Change #28 
100
*
1
)
exp(
(%)
2 −
=
SD
geoCV
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Section 8.2, Anti-ACZP antibodies 
Immunogenicity will be assessed through listing of individual results by study participant and 
summary tables for data generated with the ECLIA method only. Immunogenicity data will 
be related to PK and efficacy readouts.  
Anti-drug antibodies will be assessed by a three-tiered approach: screening (positive or 
negative screen), confirmatory (positive or negative immunodepletion) and titer assays, using 
ECLIA methods. Cut points will be determined during assay validation and used by the 
bioanalytical laboratory to determine the status of ADAb in the test samples. 
 
The following definitions will be applied regarding classification of test samples: 
 
·       An ADAb status will be confirmed as positive for any sample with an ADAb level that 
is positive screen and positive immunodepletion.  
 
·       An ADAb status of negative will be concluded for any sample with an ADAb level that 
is either negative screen or positive screen and negative immunodepletion. 
 
Confirmed positive samples will be titrated and the titer will be reported. The ADAb titer is 
presented in the listings and summaries including the minimum required dilution. 
• If the titer for an ADAb level that is positive screen and positive immunodepletion is 
missing, then a conservative approach will be used and ADAb status will be 
considered as positive. No imputation rules apply for the missing titer. 
 
If the ADAb level is positive screen but no confirmatory result could be determined, 
then then a conservative approach will be used and ADAb status will be considered as 
positive. 
Anomalous values will not be included in summaries/analysis but they will be reviewed and 
flagged by the study Clinical Pharmacologist. 
Study participants will receive a treatment-emergent (TE) ADAb status and will be classified 
as follows based on the ADAb assay results: 
• TE ADAb status positive is defined as either (i) baseline ADAb negative study 
participants having at least one ADAb confirmed positive sample post baseline or ii) 
baseline ADAb positive study participants with at least one post baseline sample with 
≥minimum significant ratio (MSR) -fold increase from baseline on CZP treatment. The 
MSR will be defined during the process of sample analysis and is disease-specific. 
• TE ADAb status negative is defined as having no samples either ADAb positive or with 
values ≥MSR -fold increase from baseline.  
 
Once determined positive, a study participant’s highest titer is used to categorize (“titer 
classification”) the study participant as follows:  
• Positive ≤32 
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• Positive >32 - ≤128 
• Positive >128 - ≤512 
• Positive >512 - ≤1024 
• Positive >1024 - ≤4096 
• Positive >4096. 
 
All ADAb summaries will be provided for the SS Set. All ADAb data will be listed. 
 
Summary of shift from Baseline ADAb status with titer classification to TE ADAb Status 
with titer classification for all study participants will be presented during the entire study, by 
visit. Summaries of ADAb data will be provided by Baseline weight group, as well as 
Baseline age group. In addition, summaries will be provided by concomitant MTX use in 
combination with Baseline weight group.  
 
TE ADAbs will be presented separately (per ADAb status and titer classification) for the 
Original CZP Dose Regimen Overall and Reduced CZP Dose Regimen Overall (using the 
study Visit nomenclature previously outlined for PK concentrations), including the Final 
visit.  
 
The time to achieving TE ADAb for all study participants will be analyzed based on Kaplan-
Meier methods. Study participants will be considered to have an event at the time where 
treatment-emergent ADAb positive is first achieved during treatment period excluding 
Baseline/pre-treatment. Study participants classified as treatment-emergent ADAb negative 
will be censored at the time of last available ADAb result. The median and 95% CI based on 
the Kaplan-Meier estimation will also be presented. A plot of time to first ADAb positivity 
will be presented.  
 
A scatter plot of CZP plasma concentrations and ADAb titer, separated by concomitant MTX 
use, will be presented. This plot will be repeated for separation by concomitant MTX use as 
well as Baseline body Weight group. 
Was changed to: 
Immunogenicity will be assessed through listing of individual results by study participant and 
summary tables and graphs for data generated with the ECLIA method only for the SS. 
Immunogenicity data will be related to PK (using the PK-PP set), efficacy (using the FAS) 
and safety (using the SS). All data including those results at the Final Visit will be used for 
analyses for the entire study. 
Anti-drug antibodies will be assessed by a three-tiered approach: screening (positive or 
negative screen), confirmatory (positive or negative immuno-depletion) and titer assays, 
using ECLIA methods. Cut points will be determined during assay validation and used by the 
bioanalytical laboratory to determine the status of ADAb in the test samples as described in 
the table below. 
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Table 13‒3: ADAb status at sample level 
ADAb positive 
(ADAb+) 
Sample values that are ‘positive screen’ and ‘positive immuno-
depletion.’ 
ADAb negative 
(ADAb-) 
Sample values that are either ‘negative screen’ or ‘positive screen’ and 
‘negative immuno-depletion’ if corresponding drug levels are equal or 
below the validated drug tolerance limit of the assay allowing detection 
of 100 ng/ml ADAb positive control or limit dictated by the ADAb assay 
and project needs (e.g. 250 ng/ml positive control). 
ADAb 
inconclusive 
Sample values that are either ‘negative screen’ or ‘positive screen’ and 
‘negative immuno-depletion’ but with corresponding drug levels above 
the validated drug tolerance limit of the assay allowing detection of 100 
ng/ml ADAb positive control or limit dictated by the ADAb assay and 
project needs (e.g. 250 ng/ml positive control). 
Missing  
Samples that were not collected per schedule or that could not be tested 
for ADAb status due to inadequate sample volume, mishandling, or 
errors in sample collection, processing, storage, etc. 
Confirmed positive samples will be titrated and the titer will be reported including the 
minimum required dilution (MRD) of the assay.    
• If the titer, for an ADAb level that is 'positive screen' and 'positive immunodepletion' 
status, is missing, then ADAb status will be considered as positive and no imputation 
rules apply for the missing titer. 
If the ADAb level is 'positive screen' but no confirmatory result could be determined, then a 
conservative approach will be used and ADAb status will be considered as positive.  No 
imputation rules apply for the missing titer. 
Change #29 
Section 8.2.1, Participant ADAb classification was added 
Study participants from the SS will be classified based on their pre and treatment ADAb 
status (see the table below). Classification will be done separately two ways: using the study 
participants’ data for the entire study treatment period and using the study participants’ data 
up to and including Week 24 (to facilitate comparison with adult RA data from study 
RA0138). Pre ADAb values are defined as the latest (not missing, not inconclusive and not 
anomalous) measurements up to and including the date of administration of first CZP 
treatment.  
 
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Table 13‒4: ADAb status classification at participant level 
1. 
Pre ADAb negative and treatment 
emergent ADAb negative  
Study participants who were negative at Baseline and 
negative at all sampling points post treatment until the time 
point of interest (eg. Data up to/including Week 24, data for 
the entire treatment period) 
 
[Note: study participants with baseline samples missing and 
negative ADAb status at all sampling points post treatment 
are included in this category because participants who are 
pre ADAb positive are expected to have ADAb positive 
samples post-dosing]  
 
2. 
Pre ADAb negative and treatment-
(emergent) induced ADAb 
positive 
Study participants who were negative at Baseline and 
positive at any sampling point post treatment until the 
timepoint of interest (eg. Data up to/including Week 24, 
data for the entire treatment period). This group also 
included study participants who had a missing Baseline 
sample with 1 or more positive post treatment samples. 
3. 
Pre ADAb positive and treatment-
emergent reduced ADAb  
Study participants who were positive at Baseline, and 
negative at all sampling points post treatment until the 
timepoint of interest (eg. Data up to/including Week 24, 
data for the entire treatment period). 
4. 
Pre ADAb positive and treatment-
emergent unaffected ADAb 
positive 
Study participants who were positive at Baseline and were 
positive at any sampling point post treatment with titer 
values of the same magnitude as Baseline (i.e., less than or 
equal to a predefined fold difference from the Baseline 
value of 2.10 which is defined with the validaton of the 
assay). 
5. 
Pre ADAb positive and treatment-
emergent ADAb boosted positive 
Study participants who were positive at Baseline and were 
positive at any sampling point post treatment with increased 
titer values compared to Baseline (greater than a predefined 
fold difference increase of 2.10 from Baseline value which 
is defined within the validation of the assay). 
6. 
ADAb inconclusive 
Study participants who were positive at Baseline and some 
post-treatment samples were missing or inconclusive, while 
other post-treatment samples were negative.  
7. 
Treatment emergent ADAb 
positive 
Study participants that were classified as 2 or 5. 
8. 
Pre-treatment ADAb positive  
Study participants who are positive ADAb at baseline, so 
those classified as 3, 4, 5 or 6. 
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Table 13‒4: ADAb status classification at participant level 
9. 
Missing 
Study participants who were negative at Baseline or 
missing their Baseline assessment, were not positive at any 
post-Baseline visit, and have at least one missing/or 
inconclusive post-treatment scheduled assessment.  
10 
ADAb positive 
Study participants who have a positive ADA sample status 
at any timepoint (either Baseline or post dose). 
 
Change #30 
Section 8.2.2, ADAb Titer Classification was added 
To further evaluate the impact of ADAb on PK, efficacy and safety, grouped ADAb titer 
categories will be defined based on ADAb quartiles (see Section 4.7) observed in the study.  
Quartiles will be calculated separately for the entire treatment period, and then for the period 
up to and including Week 24, using each study participant’s highest post-treatment ADAb 
titer (ADAb negative participants will be deemed to have zero titer levels for calculation 
purposes).   
If interpretation of the grouped titer summaries is inconclusive or results from other studies 
suggest other groupings, additional post-hoc analyses may be conducted to further 
investigate. 
Immunogenicity will be assessed through summary tables and figures and listing of 
individual results by study participant on the SS. Summaries will be by CZP dose (Reduced 
CZP Dose, Original CZP Dose) and each of Baseline weight group, Baseline age group, and 
concomitant MTX use, unless specified otherwise.  
• All individual study participant-level ADAb results will be listed for all study 
participants. This will include the screening assay, confirmatory assay, and titer (if 
applicable). A separate listing showing CZP plasma concentrations, ADAb sample status 
classification, ADAb participant classification, ADAb titer, and ADAb titer 
classifications will be produced showing concentration and ADAb data in adjacent 
columns.  
• Number and percentage of study participants with positive, negative, inconclusive or 
missing ADAb sample status (see Table 4) will be summarized at each visit and overall 
and by dose (Original CZP dose, Reduced CZP Dose).  
• The number and percentage of study participants in each of the ADAb participant status 
categories (overall and up to Week 24 as defined according to Table 5) will be 
summarized. Percentages for the denominator will include all the participants that have 
been classified as per Table 5, so including missing /inconclusive participants.   
Prevalence and incidence: 
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• Prevalence of pre ADAb positivity: number and percentage of study participants that have 
Baseline positive ADAb sample status, with the denominator for percentages defined as 
all participants having an evaluable (not missing, not inconclusive and not anomalous) 
Baseline ADAb sample.  
• Incidence of treatment-emergent ADAb positivity: number and percentage of study 
participants with either treatment boosted ADAb or treatment induced ADAb, with the 
denominator for percentages all participants except those categorized as inconclusive or 
missing (overall for the entire treatment period and then up to and including Week 24). 
Change #31 
Section 8.2.3, Time to first occurrence of treatment-emergent ADAb positivity was added 
Study participants will be considered to have an event at the first ADAb sampling time point 
with ADAb positive status if the participant is pre-ADAb negative or first ADAb sampling 
time point with fold difference increase from Baseline > 2.1 if participant is pre-ADAb 
positive. Study participants who are never treatment-emergent ADAb positive will be 
censored at the date of the last evaluable (not missing, not inconclusive and not anomalous) 
ADAb sample or on date of first CZP if no evaluable post-treatment ADAb samples. In case 
of pre-ADAb present in more than 10% of the study participants, the table will be produced 
separately for ADAb participant category 2 (induced) and 5 (boosted).   
• Summary tables based on Kaplan-Meier (KM) estimates will be produced.   
Kaplan-Meier plots of time to first treatment-emergent ADAb positivity will also be 
produced separately for the CZP doses (Original CZP dose, Reduced CZP dose). All 
available data timepoints will be included. 
Change #32 
Section 8.3, CZP plasma concentrations, anti-CZP antibody titers and PedACR response 
Individual subject plots displaying log CZP plasma concentrations, log2 ADAb titers, 
JADAS-71 score and maximum PedACR response (the highest PedACR response at a given 
visit) will be produced by visit on the same plot. At each time point, the JADAS-71 score and 
maximum PedACR response at that visit will be plotted on a linear scale.  A vertical line will 
be drawn at the time point of dose reduction (when applicable).   
Spaghetti plots of ADAb titer on a log2 scale by week from CZP first dosing separated by 
concomitant MTX use and ADAb titer classification will be presented for study participants 
with PedACR0/30/50/70/90 at Week 16 as separate graphs. A listing of the corresponding 
data by visit, including CZP dose, will also be provided. 
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Individual participants plots displaying CZP plasma concentrations, ADAb titers, JADAS-71 
score and maximum PedACR response (the highest PedACR response at a given visit) will be 
produced by visit on the same plot. At each time point, the JADAS-71 score and maximum 
PedACR response at that visit will be plotted on a linear scale.  CZP plasma concentration 
will be plotted on a (natural) log scale and ADAb titer will be plotted on a log 2 scale.  CZP 
dosing and ADAb inconclusive values will be flagged in this plot. A vertical line will be 
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plotted when dose was changed for the participant. For each study participant, the category of 
ADAb participant status and demographic information at baseline (body weight and age) will 
be displayed.  
Multi-panel spaghetti plots of individual participant (natural) log CZP plasma concentration 
by visit will be produced separately for each CZP dose (Original CZP dose, Reduced CZP 
dose) and ADAb titer classification and ADAb participant classification. Concomitant MTX 
use will be shown in different line colors and CZP concentrations for which ADAb positive 
samples were positive will be plotted with a red dot.  These individual plots will be repeated 
replacing CZP plasma concentration with maximum PedACR response (linear scale). 
Scatter plots of the plasma CZP concentration at each visit with different colors/symbols 
depending on ADAb participant classification and ADAb titer classification will be produced 
separately for the doses (Original CZP Dose, Reduced CZP Dose). 
Change #33 
Section 8.4, PopPK and PK-PD analyses 
Plasma concentrations will be used to build a PopPK model using either a Bayesian approach 
with the Winbugs software or meta-analysis with the nonlinear mixed-effect modeling 
(NONMEM) software. A graphical analysis of the relationship between PK and the clinical 
effect will be performed, and if data merits, a more formal modeling exercise will be 
performed. Details of the PopPK and PK-PD modeling procedures will be described in a 
separate data analysis plan. 
Was changed to: 
Plasma concentrations will be used to build a PopPK model with the nonlinear mixed-effect 
modeling (NONMEM) software. Details of the PopPK modeling procedures will be 
described in a separate data analysis plan. 
Change #34 
Section 9.1, Extent of exposure 
The extent of exposure to study drug will be evaluated by summarizing the total amount of 
CZP received in mg and the total duration of exposure in days. Total duration of exposure 
will be calculated as the date of last dose of study medication – date of first dose of study 
medication + 14 if administration of CZP is Q2W, +28 if administration of CZP is Q4W. 
Subject time at risk will also be calculated. Subject time at risk represents the time a subject 
is at risk for having an AE. Subject time (in days) at risk will generally be calculated as (date 
of the last dose of study medication – date of the first dose of study medication + 70 days) 
(70 days = 5 CZP half-lives).  However, the calculation of subject time at risk will be 
modified for study participants who change from original CZP dose regimen to reduced CZP 
dose regimen, or who dose escalate from reduced CZP dose regimen to the original CZP dose 
regimen. For the period of exposure prior to a dose change, subject time at risk ends on the 
date of dose change (ie, do not add 70 days).  For the period of exposure on the final  CZP 
dose regimen for a study participant, time at risk should include the additional 70 days.  
Subject years at risk will be calculated as subject time at risk (in days) divided by 365.25. 
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Duration of exposure and subject time at risk will be calculated as appropriate for each of the 
following CZP dose regimens: 
• Reduced CZP Dose Regimen Overall: includes period of exposure to all CZP doses 
for all study participants enrolled on the reduced CZP dose regimen regardless to dose 
escalation 
o Reduced CZP Dose Regimen Prior to or without Dose Escalation: includes 
period of exposure to reduced CZP dose regimen only (ie, exposure period 
ends on the date of dose escalation) 
• Original CZP Dose Regimen Overall: includes period of exposure to all CZP doses 
for all study participants enrolled on the original CZP dose regimen regardless of dose 
or subsequent dose reduction 
o Original CZP Dose Regimen Prior to or without Dose Reduction: includes 
period of exposure to original CZP dose regimen only (ie, exposure period 
ends on the date of dose reduction) 
o Original CZP Dose Regimen Following Dose Reduction: includes period of 
exposure to reduced CZP dose regimen only (ie, exposure period begins on the 
date of dose reduction) 
• Any CZP Dose Regimen: includes all CZP doses for all treated study participants 
• Escalation CZP Dose Regimen: includes period of exposure to an escalation CZP 
dose regimen only (ie, exposure period begins on the date of dose escalation for study 
participants from Reduced CZP Dose Regimen as well as Original CZP Dose 
Regimen Following Dose Reduction) 
Study drug exposure will be summarized for the Reduced - Overall, Original - Overall, and 
Any CZP Dose Regimen groups. For study participants on the original CZP dose regimen, 
exposure will be summarized combining results prior to and following dose reduction.  In 
addition, for study participants on the original CZP dose regimen, summaries of exposure 
will be produced separately for the period of exposure to (1) the original CZP dose (all 
exposure before the dose reduction visit or all exposure for study participants with no dose 
reduction), and (2) the reduced CZP dose (all exposure after the initial dose reduction visit). 
For study participants who dose escalate, exposure will be summarized. 
Was changed to: 
The extent of exposure to study drug will be evaluated by summarizing the total amount of 
CZP received in mg and the total duration of exposure in days. Total duration of exposure 
will be calculated as the date of last dose of study medication – date of first dose of study 
medication + 14 days if administration of CZP is Q2W, +28 days if administration of CZP is 
Q4W. 
Subject time at risk will also be calculated. Subject time at risk represents the time a subject 
is at risk for having an AE. Subject time (in days) at risk will generally be calculated as (date 
of the last dose of study medication – date of the first dose of study medication + 70 days) 
(70 days = 5 CZP half-lives).  However, the calculation of subject time at risk will be 
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modified for study participants who change from Original CZP Dose to Reduced CZP Dose, 
or who dose escalate from Reduced CZP Dose to the Original CZP Dose. For the period of 
exposure prior to a dose change, subject time at risk ends on the date of dose change (ie, do 
not add 70 days).  For the period of exposure on the final CZP dose for a study participant, 
time at risk should include the additional 70 days.  Subject years at risk will be calculated as 
subject time at risk (in days) divided by 365.25. 
Duration of exposure and subject time at risk will be calculated as appropriate for each of the 
following CZP dose groups: 
• Reduced CZP Dose: includes period of exposure to the Reduced CZP Dose for all 
study participants enrolled on the Reduced CZP Dose; the exposure ends on the date 
of dose escalation or last dose of Reduced CZP Dose.  The exposure calculation is 
Date of Dose Escalation or Last Dose of Reduced CZP – Date of First Dose + 14 or 
28 days depending on administration of CZP. 
• Original CZP Dose: includes period of exposure to the Original CZP Dose for all 
study participants enrolled on the Original CZP Dose; the exposure ends on the date 
of dose reduction or Last Dose of Original CZP.  The exposure calculation is Date of 
Dose Reduction or Last Dose of Original CZP – Date of First Dose of CZP +14 or 28 
days depending on administration of CZP.  
• Any CZP Dose: includes the exposure to all CZP doses for all treated study 
participants; the exposure period is calculated using the formulas above depending on 
whether the subject took a Q2W or Q4W dose. 
Study drug exposure will be summarized for the Reduced CZP Dose, Original CZP Dose, and 
Any CZP Dose groups. Exposure will be presented as follows: >0 months, ≥6 months, ≥12 
months, ≥24 months, ≥36 months, ≥48 months and ≥60 months. 
Change #35 
Section 9.1.1, Updated Week 24 Interim Analysis and other interim analyses was added 
For interim analyses such as for the SSD, DMC and the Updated Week 24, the following 
modifications will be made to more accurately calculate exposure and time at risk. 
For an interim analysis with a database cutoff date,  
• if the study participant is ongoing, the exposure calculation is database cutoff date – 
date of first dose of study medication + 1 day.  No data is presented in the analyses 
that is dated after the database cutoff date 
• if the study participant is ongoing, the time at risk calculation is database cutoff date – 
date of first dose of study medication + 1 day.    
• if the study participant has discontinued from the study >28 days before the database 
cutoff date and has Q4W dosing at the time of study discontinuation, then the 
exposure is date of last dose of study medication – date of first dose of study 
medication + 28 days 
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• if the study participant has discontinued from the study ≤28 days before the database 
cutoff date and has Q4W dosing at the time of study discontinuation, then the 
exposure is database cutoff date – date of first dose of study medication + 1 day 
• if the study participant has discontinued from the study >14 days before the database 
cutoff date and has Q2W dosing at the time of study discontinuation, then the 
exposure is date of last dose of study medication – date of first dose of study 
medication + 14 days 
• if the study participant has discontinued from the study ≤14 days before the database 
cutoff date and has Q2W dosing at the time of study discontinuation, then the 
exposure is database cutoff date – date of first dose of study medication + 1 day 
• if the study participant has discontinued from the study >70 days before the database 
cutoff date, then the time at risk is date of last dose of study medication – date of first 
dose of study medication + 70 days 
if the study participant has discontinued from the study ≤70 days before the database cutoff 
date, then the time at risk is the database cutoff date – date of first dose of study medication + 
1 day. 
Change #36 
Section 9.2, Adverse events 
Only treatment emergent adverse events (TEAE) will be included in the summary tables. 
Treatment emergent AEs are defined as AEs starting on or after the first administration of 
CZP and up to 70 days after the last dose of study medication. AEs that are pre-treatment or 
that start more than 70 days after the last dose of study medication will be flagged in the 
listing but excluded from summaries. 
All AEs will be classified by SOC, HLT and PT according to the version of MedDRA® that is 
current to the sponsor at the time of data capture. A glossary for the TEAE listing will detail 
the verbatim terms that are coded to each SOC, HLT, and PT. 
Treatment-related TEAEs are those with relationship to study medication of “Related” or 
“Possibly related” or those with a missing relationship.  Severe TEAEs are those with an 
intensity of “Severe” or those with a missing intensity. 
An overall summary of TEAEs overall and by Baseline weight group (10 to <20kg, 20 to 
<40kg, and ≥40kg) will include the number of events and number of study participants and 
percentage of study participants with: 
• Any TEAE 
• Any serious TEAE 
• Any treatment-related TEAE 
• Any severe TEAE 
• Any TEAE leading to permanent withdrawal of IMP 
• Any TEAE leading to discontinuation 
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• All deaths 
• Any TEAE leading to death 
Overall summaries of TEAEs will be provided for the Reduced Overall, Original Overall, and 
Any CZP Dose Regimen groups. For study participants on the reduced CZP dose regimen 
overall, summaries will be provided for the TEAEs occurring during the period of exposure 
to reduced CZP dose only.  For study participants on the original CZP dose regimen, 
summaries will be provided combining results prior to and following dose reduction.  In 
addition, overall TEAE summaries for the original CZP dose regimen will be produced 
separately for TEAEs occurring during the period of exposure to (1) the original CZP dose 
(all results before the dose reduction visit or all results for study participants with no dose 
reduction),  and (2) the reduced CZP dose (all results after the initial dose reduction visit). 
For study participants on either Reduced Overall or Original Overall, overall TEAE 
summaries will be produced for TEAEs occurring during the period of exposure to (3) the 
escalated CZP dose (all results after the initial dose escalation visit).  TEAEs occurring on the 
day of dose reduction or dose escalation, respectively, will be reviewed by the study 
physician in order to assign events to the most appropriate time period (before or after dose 
reduction or dose escalation, respectively). 
The overall summary of TEAEs will also be presented by Baseline age group (2 to 5 years, 6 
to 11 years, and 12 to 17 years), concomitant MTX use, ERA status (only for the Any CZP 
Dose Regimen), and anti-CZP antibody status pooling across all weight groups.  
The following AE summaries will also be presented:   
• All TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight group* 
• All TEAEs by primary SOC, HLT, and PT by Baseline age group 
• All TEAEs by primary SOC, HLT, and PT by concomitant MTX use* 
• All TEAEs by primary SOC, HLT, and PT by ERA status** 
• All TEAEs by primary SOC, HLT, and PT by overall anti-CZP antibody status* 
• All serious TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight 
group* 
• All TEAEs leading to study drug discontinuation by primary SOC, HLT, and PT, overall 
and by Baseline weight group* 
• All TEAEs leading to death by primary SOC, HLT, and PT, overall and by Baseline 
weight group 
• Injection reaction TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight 
group, further subdivided into injection site reactions and systemic reactions, with 
systemic reactions further subdivided into acute vs. delayed systemic reactions 
• All TEAEs by primary SOC, PT, and maximum intensity, overall and by Baseline weight 
group 
• All TEAEs by primary SOC, PT, and relationship, overall and by Baseline weight group 
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• All serious TEAEs by primary SOC, PT, and relationship, overall and by Baseline weight 
group 
• All non-serious TEAEs by primary SOC, PT, and relationship, overall and by Baseline 
weight group 
• All fatal TEAEs by primary SOC, PT, and relationship, overall and by Baseline weight 
group  
• Individual study participant numbers experiencing a given adverse event, grouped by 
SOC, PT, intensity, and relation to study drug** 
• TEAEs occurring in at least 5% of study participants by primary SOC, HLT, and PT, 
overall and by Baseline weight group* 
• Non-serious TEAEs occurring in more than 5% of study participants by primary SOC and 
PT, overall and by Baseline weight group** 
• Non-serious TEAEs occurring in more than 5% of study participants by primary SOC, 
PT, and relationship, overall and by Baseline weight group** 
• All non-serious TEAEs by primary SOC and PT, overall and by Baseline weight group** 
For all of the summaries in the above list (except for the ones flagged with an asterisk (*) or 
double asterisks (**)), TEAEs will be summarized for the Reduced Overall, Original Overall, 
and Any CZP Dose Regimen groups. For the above summaries flagged with double asterisks 
(**), only the Any CZP Dose Regimen will be presented. For the above summaries flagged 
with an asterisk (*), TEAEs for the Original CZP Dose Regimen Overall group will also be 
summarized separately for events occurring during the period of exposure to (1) the original 
CZP dose (all results before the dose reduction visit or all results for study participants with 
no dose reduction), and (2) the reduced CZP dose (all results after the initial dose reduction 
visit); the Reduced Overall will summarize separately events occurring during the period of 
exposure to Reduced CZP Dose regimen; and study participants from either Reduced Overall 
and Original Overall will summarize separately events occurring during the period of the 
escalated CZP dose (all results after the initial dose escalation visit).  As indicated above, 
TEAEs occurring on the day of dose reduction or dose escalation, respectively, will be 
reviewed by the study physician in order to assign events to the most appropriate time period 
(before or after dose reduction or dose escalation, respectively). 
In addition, to assess TEAEs by duration of exposure, the frequency and percentage of 
TEAEs reported during the first 16 weeks of study medication exposure will be summarized 
separately for the 2 CZP dose regimens (original CZP dose regimen overall, reduced CZP 
dose regimen overall).  
Data displayed will include the number of TEAEs, number of study participants experiencing 
the TEAEs and percentage of study participants with the TEAE (all occurrences of the same 
event will be counted under the number of TEAEs but the subject will only be counted once). 
Summaries of all TEAEs, serious TEAEs, TEAEs leading to death, TEAEs leading to 
permanent withdrawal of IMP, and TEAEs leading to study discontinuation will also include 
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the exposure-adjusted incidence rate (EAIR) with associated 95% confidence interval, and 
the exposure-adjusted event rate (EAER).  
For EAIR, the numerator will be the total number of study participants experiencing a 
particular TEAE. The denominator will be 100 subject-years, ie, the total summation of 
individual subject-years at risk up to the first occurrence of the given TEAE for study 
participants with that TEAE, plus the total subject-years at risk for those study participants 
not experiencing that TEAE, divided by 100.  Details regarding calculation of subject-years 
at risk are described in Section 9.1.  EAIR will be presented with exact 95% confidence 
intervals based on the link between the chi-square distribution and the Poisson distribution 
(Ulm, 1990). 
For EAER, the numerator will be the number of TEAEs including repeat occurrences in 
individual study participants. The denominator will be in 100 subject-years (total summation 
of individual subject-years at risk divided by 100). No confidence interval will be computed. 
The following are TEAEs of interest for this study and will be summarized as described 
below: 
1) Serious infections, including opportunistic infections.   Serious infections will be 
summarized using the previously described All SAEs table.  No separate table is planned.  In 
addition, opportunistic infections (including tuberculosis) will be presented in a table using 
UCB-defined search criteria.     
2) Malignancies, including lymphoma. These will be presented in 2 tables using the criteria 
SMQ = “Malignant or unspecified tumours” and SMQ=”Malignant tumours”, respectively. 
3) Congestive heart failure.  These will be manually identified by the study physician from 
the previously described All TEAEs table.  In addition, major adverse cardiac events 
(MACE) will be presented in a table using UCB-defined search criteria and will include fatal 
and serious non-fatal myocardial infarction, cerebrovascular events and congestive heart 
failure.     
4) Demyelinating-like disorders.   These will be manually identified by the study physician 
from the previously described All TEAEs table.   
5) Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leucopenia.   These 
will be presented in a table using the criteria SMQ = “Haematopoietic cytopenias” in the 
subset of SAEs. 
6) Serious bleeding events.  These will be presented in a table using the criteria SMQ = 
“Haemorrhages” in the subset of SAEs. 
7) Lupus and lupus-like illness.  These will be manually identified by the study physician 
from the previously described All TEAEs table.   
8) Serious skin reactions (eg, Stevens-Johnson Syndrome, toxic epidermal necrosis, 
anderythema multiforme).   These will be manually identified by the study physician from the 
previously described All SAEs table.   
The following is an AE of special interest for this study; the associated analysis will be 
described in the PDILI paragraph in Section 9.3: 
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Potential Hy’s Law, defined as ≥3xULN alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the absence of ≥2xULN 
alkaline phosphatase (ALP), with no alternative explanation for the biochemical abnormality 
(ie, without waiting for any additional etiologic investigations to have been concluded). 
Follow-up information should be reported if an alternative etiology is identified during 
investigation and monitoring of the participant. 
Further information regarding search criteria and algorithms is provided in the guidance 
document “AEs of Interest – Cimzia Program”.  
The tables for 1, 2, 3, 5, and 6 above will be summarized by SOC, HLT, and PT and will 
include the number of events, the number and percentage of study participants with an event, 
the EAIR with associated 95% CIs and the EAER.  TEAEs of interest tables will be provided 
for the Reduced CZP Dose Regimen Overall, Reduced CZP Dose Regimen, the Original CZP 
Dose Regimen Overall, the Original CZP Dose Regimen Prior to Dose Reduction or without 
Dose Reduction, the Original CZP Dose Regimen Following Dose Reduction, the Any CZP 
Dose Regimen, and the Escalation CZP Dose Regimen.  
Was changed to: 
Only treatment emergent adverse events (TEAE) will be included in the summary tables. 
Treatment emergent AEs are defined as AEs starting on or after the first administration of 
CZP and up to 70 days after the last dose of study medication. AEs that are pre-treatment or 
that start more than 70 days after the last dose of study medication will be flagged in the 
listing but excluded from summaries. 
All AEs will be classified by SOC, HLT and PT according to the version of MedDRA® that is 
current to the sponsor at the time of data capture. A glossary for the TEAE listing will detail 
the verbatim terms that are coded to each SOC, HLT, and PT. 
Treatment-related TEAEs are those with relationship to study medication of “Related” or 
“Possibly related” or those with a missing relationship.  Severe TEAEs are those with an 
intensity of “Severe” or those with a missing intensity. 
All TEAE summaries will be provided for the Reduced CZP Dose, Original CZP Dose, and 
Any CZP Dose groups. TEAEs occurring on the day of dose reduction or dose escalation, 
respectively, will be reviewed by the study physician in order to assign events to the most 
appropriate time period (before or after dose reduction or dose escalation, respectively). 
The overview of the incidence of TEAEs, overall and by Baseline weight group (10 to <20kg, 
20 to <40kg, and ≥40kg), will include the number of events and number of study participants 
and percentage of study participants with: 
• Any TEAE 
• Any serious TEAE 
• Any treatment-related TEAE 
• Any severe TEAE 
• Any TEAE leading to permanent withdrawal of IMP 
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• Any TEAE leading to discontinuation 
• All deaths 
• Any TEAE leading to death 
The overview of the incidence of TEAEs will also be presented by the following subgroups: 
• Baseline age group (2 to 5 years, 6 to 11 years, and 12 to 17 years),  
• concomitant MTX use,  
• gender, 
race,   
• ADAb participant status classification, and 
• ADAb titer classification pooling across all Baseline weight groups.  
The incidence and event rate (per 100 subject-years) of TEAEs will be presented as follows:   
• All TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight group 
• All TEAEs by primary SOC, HLT, and PT by Baseline age group 
• All TEAEs by primary SOC, HLT, and PT by concomitant MTX use 
• All TEAEs by primary SOC, HLT, and PT by ADAb titer classification 
• All TEAEs by primary SOC, HLT and PT by ADAb participant status classification 
• All serious TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight group 
• All TEAEs leading to study drug discontinuation by primary SOC, HLT, and PT, overall 
and by Baseline weight group 
• All TEAEs leading to death by primary SOC, HLT, and PT, overall and by Baseline 
weight group 
The incidence of TEAEs will be presented as follows: 
• Injection reaction TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight 
group, further subdivided into injection site reactions and systemic reactions, with 
systemic reactions further subdivided into acute vs. delayed systemic reactions 
• All TEAEs by primary SOC, PT, and intensity, overall and by Baseline weight group 
• All TEAEs by primary SOC, PT, and relationship, overall and by Baseline weight group 
• All serious TEAEs by primary SOC, PT, and relationship, overall and by Baseline weight 
group 
• All non-serious TEAEs by primary SOC, PT, and relationship, overall and by Baseline 
weight group 
• All fatal TEAEs by primary SOC, PT, and relationship, overall and by Baseline weight 
group  
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• TEAEs occurring in at least 5% of study participants by primary SOC, HLT, and PT, 
overall and by Baseline weight group 
• Non-serious TEAEs occurring in more than 5% of study participants by primary SOC and 
PT, overall and by Baseline weight group 
 
Incidence tables summarizing TEAEs will include the number of TEAEs, number of study 
participants experiencing the TEAEs and percentage of study participants with the TEAE (all 
occurrences of the same event will be counted under the number of TEAEs but the subject 
will only be counted once).  
Incidence and event rate tables will include the descriptive statistics on the incidence table 
but also include the exposure-adjusted incidence rate (EAIR) with associated 95% confidence 
interval, and the exposure-adjusted event rate (EAER).  
For EAIR, the numerator will be the total number of study participants experiencing a 
particular TEAE. The denominator will be 100 subject-years, ie, the total summation of 
individual subject-years at risk up to the first occurrence of the given TEAE for study 
participants with that TEAE, plus the total subject-years at risk for those study participants 
not experiencing that TEAE, divided by 100.  Details regarding calculation of subject-years 
at risk are described in Section 9.1.  EAIR will be presented with exact 95% confidence 
intervals based on the link between the chi-square distribution and the Poisson distribution 
(Ulm, 1990). 
For EAER, the numerator will be the number of TEAEs including repeat occurrences in 
individual study participants. The denominator will be in 100 subject-years (total summation 
of individual subject-years at risk divided by 100). No confidence interval will be computed. 
Listings: 
Individual study participant numbers experiencing a given adverse event, grouped by SOC, 
PT, intensity, and relation to study drug 
Change #37 
Section 9.2.1, TEAEs of interest was added 
The following are TEAEs of interest for this study and will be summarized in incidence and 
event rate tables (ie will include the number of events, the number and percentage of study 
participants with an event, the EAIR with associated 95% CIs and the EAER) as described 
below: 
1) Serious infections, including opportunistic infections.   Serious infections will be 
summarized using the previously described All SAEs table.  No separate table is planned.  In 
addition, opportunistic infections (including tuberculosis) will be presented in a table using 
UCB-defined search criteria.     
2) Malignancies, including lymphoma. These will be presented in 2 tables using the criteria 
SMQ = “Malignant or unspecified tumours” and SMQ=”Malignant tumours”, respectively. 
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3) Congestive heart failure.  These will be manually identified by the study physician from 
the previously described All TEAEs table.  In addition, major adverse cardiac events 
(MACE) will be presented in a table. using UCB-defined search criteria and will include fatal 
and serious non-fatal myocardial infarction, cerebrovascular events and congestive heart 
failure.     
4) Demyelinating-like disorders.   These will be presented in a table based on the 
SMQ=”Demyelination” in the TEAEs.   
5) Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leucopenia.   These 
will be presented in a table using the criteria SMQ = “Haematopoietic cytopenias” in the 
subset of SAEs. 
6) Serious bleeding events.  These will be presented in a table using the criteria SMQ = 
“Haemorrhage terms (excl laboratory terms)” in the subset of SAEs. 
7) Lupus and lupus-like illness.  These will be manually identified by the study physician 
from the previously described All TEAEs table and not tabulated separately.   
8) Serious skin reactions (eg, Stevens-Johnson Syndrome, toxic epidermal necrosis, 
anderythema multiforme).   These will be manually identified by the study physician from the 
previously described All SAEs table and not tabulated separately.   
9) Hepatic events. These will be summarized in a table that includes all TEAEs in the 
following SMQs: Cholestasis and jaundice of hepatic origin; hepatic failure, fibrosis and 
cirrhosis and other liver damage-related conditions; hepatitis, noninfectious; liver-related 
investigations, signs and symptoms; liver-related coagulation and bleeding disturbances. 
10)Hypersensitivity reactions. These will be determined from all TEAEs that either emerged 
on the same day as or next day after the administration of study medication injection and 
summarized in a table.  The PTs are: administration site hypersensitivity, documented 
hypersensitivity to administered product, drug hypersensitivity, hypersensitivity, 
hypersensitivity vasculitis, infusion site hypersensitivity, injection site hypersensitivity, 
medical device site hypersensitivity, type II hypersensitivity, type IV hypersensitivity. 
reaction. 
11) Anaphylactic reactions. These will be determined from all TEAEs that either emerged on 
the same day as or next day after the administration of study medication injection. 
Anaphylactic reactions will be summarized in a table using UCB-defined search criteria. 
Further information regarding search criteria and algorithms is provided in the guidance 
document “AEs of Interest – Cimzia Program”. 
Change #38 
Section 9.2.2, AE of special interest was added 
Potential Hy’s Law is an AE of special interest for this study; the definition is below.  The 
occurrence of this AE of special interest is dependent upon laboratory parameters, given that, 
the associated analysis of these AEs will be described in the Clinical laboratory evaluations 
section, PDILI paragraph in Section 9.3: 
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Potential Hy’s Law, defined as ≥3xULN alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the absence of ≥2xULN 
alkaline phosphatase (ALP), with no alternative explanation for the biochemical abnormality 
(ie, without waiting for any additional etiologic investigations to have been concluded). 
Follow-up information should be reported if an alternative etiology is identified during 
investigation and monitoring of the participant. 
Change #39 
Section 9.2.3, Covid vaccine sensitivity analysis was added 
A summary of the incidence and event rate (per 100 subject-years) of TEAEs by primary 
SOC, HLT, and PT, overall and by Baseline weight group will be presented which will 
exclude TEAEs occurring up to and including 7 days from the date of covid vaccination.  The 
list of TEAEs to be excluded if reported with Mild or Moderate intensity are: 
Table 13‒5: Covid vaccination related adverse events for sensitivity analysis 
 
ARTHRALGIA 
INJECTION SITE INDURATION 
AXILLARY SWELLING 
INJECTION SITE PAIN 
AXILLARY TENDERNESS 
INJECTION SITE WARMTH 
BACKACHE 
MYALGIA 
BODY TEMPERATURE INCREASED 
NAUSEA 
CHILLS 
PRURITUS 
DIARRHOEA 
RASH 
FEVER 
TENDERNESS 
HEAD DISCOMFORT 
URTICARIA 
HEADACHE 
VOMITING 
INJECTION SITE ERYTHEMA 
 
Change #40 
Section 9.3, Clinical laboratory evaluations 
PDILI IMP discontinuation criteria as outlined in the Appendix of Protocol Amendment 9 
will be evaluated at all laboratory assessments, for all study participants. The number and 
percentage of study participants with elevated liver function tests and meeting PDILI criteria 
will be presented. Any data that meets the PDILI criteria or is captured regarding PDILI will 
be listed.  
Was changed to: 
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PDILI IMP discontinuation criteria as outlined in the Appendix of Protocol Amendment 9 
will be evaluated at all laboratory assessments, for all study participants. The number and 
percentage of study participants meeting PDILI criteria will be presented.  The following 
criteria will be presented: 
• AST or ALT ≥ 3xULN and Total Bilirubin < 2xULN 
• AST or ALT ≥ 3xULN and Total Bilirubin ≥ 2xULN 
• AST or ALT ≥ 3xULN and Total Bilirubin ≥ 2xULN and Alkaline Phosphatase < 2xULN 
(Hy’s Law if all criteria met at the same visit) 
• AST or ALT ≥ 5xULN 
Any data that meets the PDILI criteria or is captured regarding PDILI will be listed. 
Change #41 
Section 9.4.1, Vital signs 
Vital signs will be measured within approximately 15 minutes prior to dosing, and in addition 
(following implementation of Protocol Amendment 3), pulse and blood pressure only will be 
measured approximately 30 minutes after dosing with study medication. Study participants 
should be sitting for at least 5 minutes prior to and during the collection of blood pressure and 
pulse rate measurements. Vital signs to be collected are pulse, systolic/diastolic blood 
pressure measurement, and temperature. 
Descriptive statistics for observed values and change from pre-dose to post-dose pulse and 
blood pressure when available, will be presented for each visit for each vital sign parameter. 
Vital signs summaries will be provided overall (ie, for the Any CZP Dose Regimen) and by 
Baseline weight group. 
Was changed to: 
Vital signs will be measured within approximately 15 minutes prior to dosing, and in addition 
(following implementation of Protocol Amendment 3), pulse and blood pressure only will be 
measured approximately 30 minutes after dosing with study medication. Study participants 
should be sitting for at least 5 minutes prior to and during the collection of blood pressure and 
pulse rate measurements. Vital signs to be collected are pulse, systolic/diastolic blood 
pressure measurement, and temperature. 
For pre-dose measurements, if more than one results appears for a specific visit, then the pre-
dose results are averaged.  The same will occur for post dose measurements.  All data will be 
listed, including the averages. If measurements are labeled as pre-dose in the CRF, but when 
compared to dosing, it is actually post-dose, the analysis label will reflect a post dose 
measurement. The same will occur for post-dose measurements.  
Descriptive statistics for observed values and change from pre-dose to post-dose pulse and 
blood pressure when available, will be presented for each visit for each vital sign parameter. 
Vital signs summaries will be provided for the Reduced CZP Dose, Original CZP Dose, and 
Any CZP Dose) and by Baseline weight group. 
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A summary of the incidence of markedly abnormal vital signs results by visit will be 
presented for temperature, blood pressure, and pulse rate parameters.  Details of markedly 
abnormal values will be listed by subject and parameter for which there is at least 1 markedly 
abnormal result recorded. Definitions of markedly abnormal values are given below in the 
table below. 
Markedly abnormal high temperature is >40.0 degrees Celsius (>104.0 degrees Fahrenheit) 
while a markedly abnormal low temperature is 32 – 35 degrees Celsius (89.6 – 95 degrees 
Fahrenheit). 
Table 13‒6: Definitions of Markedly Abnormal Vital Signs Values 
 
Parameter 
Age 
Range 
Abnormality 
Criteria 
Pulse Rate 
(beats/minute) 
  
  
3y - 
<12y 
<60 
>130 
12y - 
<17y 
<50 
>120 
≥17y 
<60 
 >100  
Systolic Blood 
Pressure 
(mmHg) 
3y - 
<12y 
<80 
>140 
12y - 
<17y 
<90 
>160 
≥17y 
<90 
>140 
>160 
Diastolic Blood 
Pressure 
(mmHg) 
3y - 
<12y 
<50 
>80 
12y - 
<17y 
<50 
>105 
≥17y 
<50 
>90 
>100 
Change #42 
Section 10, Efficacy Analyses  
Efficacy will be analyzed using the FAS.  All efficacy results will be summarized overall and 
by Baseline weight group and will be provided for the Reduced CZP Dose Regimen Overall, 
the Original CZP Dose Regimen Overall, and the Any CZP Dose Regimen. For subgroup 
efficacy analyses, summaries by Baseline age group, concomitant MTX use, and anti-CZP 
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antibody status will be presented pooling across all weight groups unless otherwise specified. 
In addition, selected summaries will also be presented by gender and race. 
In addition to the efficacy summaries described below, all efficacy results will be listed by 
subject. However, some listings for study participants in Original CZP Dose Regimen may be 
grouped by study participants with dose reduction and study participants without dose 
reduction within each weight group. 
Was changed to: 
Efficacy will be analyzed using the FAS.  All efficacy results will be summarized overall and 
by Baseline weight group and will be provided for the Original CZP Dose, Reduced CZP 
Dose, and the Any CZP Dose. For subgroup efficacy analyses, summaries by Baseline age 
group, concomitant MTX use, and ADAb status will be presented pooling across all weight 
groups unless otherwise specified. In addition, selected summaries will also be presented by 
gender and race. 
In addition to the efficacy summaries described below, all efficacy results will be listed by 
subject data listings.  
In Section 10, the analyses described will be generated for the final analysis.  For the Updated 
Week 24 Interim analysis, only efficacy data up to and including Week 24 will be presented 
in the analyses described in Section 10 for the following variables:  
• PedACR30/50/70, 90 
• Number of joints with active arthritis 
• Number of joints with limitation of range of motion 
• Physician’s Global Assessment of Disease Activity 
• Childhood Health Assessment Questionnaire 
• Parent’s Global Assessment of Overall Well-Being 
• C-Reactive protein 
• Juvenile Arthritis Disease Activity Score 71-joint 
For the Updated Week 24 Interim analysis, all reported data for other efficacy variables will 
be listed only; any calculations described for the final analysis will not be performed. These 
include the following variables: 
• Clinically Inactive Disease 
• Clinical remission on medication 
• Duration of Morning Stiffness 
• Parent’s Assessment of Arthritis Pain 
• Faces Pain Scale Revised 
• JIA Pain 
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• Fatigue Assessment Scale, and 
• Juvenile Arthritis School Attendance and Caregiver Work Productivity Survey. 
 
Change #43 
Section 10.2, Statistical analysis of the secondary efficacy variables 
The frequency and percentage of study participants achieving a PedACR30, PedACR50, 
PedACR70, and PedACR90 response and associated 95% exact binomial CIs will be 
summarized for Week 16 as compared to Baseline. Results will be presented overall and by 
Baseline weight group (10 to <20kg, 20 to <40kg, and ≥40kg), as well as by Baseline age 
group (2 to 5 years, 6 to 11 years, and 12 to 17 years), concomitant MTX use, overall anti-
CZP antibody status, gender and race.   
Was changed to: 
The frequency and percentage of study participants achieving a PedACR30, PedACR50, 
PedACR70, and PedACR90 response and associated 95% exact binomial CIs will be 
summarized for Week 16. Results will be presented overall and by Baseline weight group (10 
to <20kg, 20 to <40kg, and ≥40kg), as well as by Baseline age group (2 to 5 years, 6 to 11 
years, and 12 to 17 years), concomitant MTX use, ADAb titer classification, gender and race 
pooling across all Baseline weight groups.   
 
Plots will be produced to show the percentage of PedACR30/50/70/90 responders by visit 
and ADAb titer classification. 
Change #44 
Section 10.3, Analysis of other efficacy variables 
Continuous endpoints will be summarized using LOCF for missing values, unless otherwise 
specified, as for the Juvenile Arthritis School Attendance and Caregiver Work Productivity 
Survey.  
Was changed to: 
Continuous endpoints will be summarized using observed case, as for the Physician’s Global 
Assessment of Disease Activity.  
Change #45 
Section 10.3.1, PedACR30, PedACR50, PedACR70, and PedACR90, the following was 
added 
Plots will be produced to show the percentage of PedACR30/50/70/90 responders by visit 
and ADAb titer classification. 
Change #46 
Section 10.3.5, Parent’s Assessment of Arthritis Pain VAS 
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This section was updated to indicate that for the Updated Week 24 Interim Analysis, the data 
for this efficacy parameter would only be listed (not summarized). 
Change #47 
Section 10.3.9, Clinically Inactive Disease 
This section was updated to indicate that for the Updated Week 24 Interim Analysis, the data 
for this efficacy parameter would only be listed (not summarized). 
Change #48 
Section 10.3.10, Clinical Remission on Medication 
This section was updated to indicate that for the Updated Week 24 Interim Analysis, the data 
for this efficacy parameter would only be listed (not summarized). 
Change #49 
Section 10.3.11, Duration of morning stiffness 
This section was updated to indicate that for the Updated Week 24 Interim Analysis, the data 
for this efficacy parameter would only be listed (not summarized). 
Change #50 
Section 10.3.12, Faces Pain Scale - Revised 
This section was updated to indicate that for the Updated Week 24 Interim Analysis, the data 
for this efficacy parameter would only be listed (not summarized). 
Change #51 
Section 10.3.13, Patient’s Assessment of Arthritis Pain VAS 
This section was updated to indicate that for the Updated Week 24 Interim Analysis, the data 
for this efficacy parameter would only be listed (not summarized). 
Change #52 
Section 10.3.14, FASCA – Fatigue Assessment Analysis 
This section was updated to indicate that for the Updated Week 24 Interim Analysis, the data 
for this efficacy parameter would only be listed (not summarized). 
Change #53 
Section 10.3.15, Juvenile Arthritis School Attendance and Caregiver Work Productivity 
Survey 
This section was updated to indicate that for the Updated Week 24 Interim Analysis, the data 
for this efficacy parameter would only be listed (not summarized). 
Change #54 
Section 12.1, Comparisons with RA0138 data was added 
Comparisons between RA0043 and RA0138 data will focus on common timepoints (Weeks 
12 and 24).  
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Separate boxplots will be performed for Week 12 and Week 24 showing plasma CZP 
concentrations for the two CZP dose groups (Original or Reduced) for RA0043 and the single 
CZP dose group for RA0138 in the same plot. The plots will be repeated separately by 
Baseline weight group, Baseline age group and concomitant MTX use. 
Separate plots of individual participant (natural) log CZP plasma concentration versus log2 
ADAb titer will be produced for Week 12 and Week 24 data for both studies. In these plots, 
participants study (RA0043 or RA0138) and CZP dose group (Original or Reduced) will be 
shown as a different symbol/color to aid comparison. In addition, for RA0138 only, plots of 
individual participant area under the plasma concentration curve over the 2-week dosing 
interval (AUC0-tau) versus log2 ADAb titer at Week 12 will be produced. 
If there are signs that higher titer levels are associated with lower plasma concentrations, 
further investigations will be performed to attempt to determine at which titer levels 
differences are observed and to assess the impact on efficacy and safety. 
Further analyses may be defined in the integrated summary of immunogenicity including 
comparisons of ADAb titer levels between studies (no pooling of studies across indications 
are planned) allowing us to put the pJIA/RA data in context of the AS and PSO indications. 
 
13.5 
AMENDMENT 5 
Rationale for the amendment 
The primary reasons for this SAP amendment were to: 
• Include additional exposure, CZP plasma concentration, ADAb and treatment-emergent 
adverse event analyses on Complete Reduced CZP and Complete Original CZP doses, in 
line with 
 response, 
• Update analysis concepts in regards to the PK and ADAb analyses, and  
• Clarify and update other analysis concepts. 
Modifications and changes 
Global changes 
Three dose groups are now referenced for analysis: Original CZP Dose, Reduced CZP Dose 
and Any CZP Dose. The FDA has requested two additional dose groups – Complete Reduced 
CZP dose (which will show data captured at the time a study participant was taking Reduced 
CZP dose, regardless of dose switching) and Complete Original CZP dose (which will show 
data captured while a study participant was taking Original CZP dose, regardless of dose 
switching).  Only specific tables for exposure, PK, ADAb and adverse events will present 
data summarized using these two new treatment groups. 
Specific changes 
Change #1 
SAP/Amendment  
Date 
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Final SAP 
23 Jun 2015 
SAP Amendment 1 
29 Sep 2015 
SAP Amendment 2 
24 Jun 2016 
SAP Amendment 3 
30 Jun 2021 
SAP Amendment 4 
8 Dec 2022 
Has been changed to: 
SAP/Amendment  
Date 
Final SAP 
23 Jun 2015 
SAP Amendment 1 
29 Sep 2015 
SAP Amendment 2 
24 Jun 2016 
SAP Amendment 3 
30 Jun 2021 
SAP Amendment 4 
8 Dec 2022 
SAP Amendment 5 
21 Jun 2023 
Change #2 
List of abbreviations include ED and ELISA. 
Change #3 
Section 2, Protocol Summary 
Results of a planned interim PopPK analysis conducted suggested that while observed CZP 
plasma concentrations with the original dose regimen administration remained in the adult 
range, they were at the upper end of the distribution. Based on these findings, the dosing 
regimen was changed with Protocol Amendments 4 and 5, and the doses to be administered 
were reduced by 50% for all weight groups. This dose change was intended to achieve 
plasma concentrations that were similar to the effective concentrations observed in previous 
studies in adult study participants with RA. Based on interactions with FDA, Amendment 9 
re-introduced the original dose regimen for 30 new participants and the option to increase to 
this dose for ongoing participants that had been receiving the reduced dose. 
Was changed to: 
Study participants, prior to Protocol Amendment 4, were enrolled on the Original CZP Dose. 
Results of a planned interim PopPK analysis conducted suggested that while observed CZP 
plasma concentrations with the Original Dose administration remained in the adult range, 
they were at the upper end of the distribution. Based on these findings, the dosing was 
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changed with Protocol Amendments 4 and 5, and the doses to be administered were reduced 
by 50% for all weight groups, Reduced CZP Dose, see Table 2‒3. This dose change was 
intended to achieve plasma concentrations that were similar to the effective concentrations 
observed in previous studies in adult study participants with RA. Based on interactions with 
FDA, Amendment 9 allowed 30 new participants to be enrolled taking Original CZP Dose; 
for the study participants who were taking Reduced CZP Dose, it introduced the option to 
increase to the Original CZP Dose. 
Study participants will be summarized by the following 5 dose groups:  
• Any CZP Dose – includes all data from all study participants while being treated in the 
study 
• Original CZP Dose – includes all data for study participants enrolled on Original CZP 
Dose prior to the first change in dosage 
• Reduced CZP Dose – includes all data for study participants enrolled on Reduced CZP 
Dose prior to the first change in dosage 
• Complete Original CZP Dose – includes all data for study participants who took Original 
CZP Dose prior to the first change in dosage as well as the data from when study 
participants increased their dosage to Original CZP after taking Reduced CZP Dose 
• Complete Reduced CZP Dose – includes all data for study participants who took Reduced 
CZP Dose prior to the first change in dosage as well as the data from when study 
participants took Reduced CZP Dose after taking Original CZP Dose  
Change #4 
Section 2.3 Study design and conduct 
In order to further support the safety assessment of the original CZP dose, as more of the 
safety data collected in the study to date has been on the reduced dose, an additional 30 study 
participants will be enrolled on the original dose with the aim to enroll at least 5 study 
participants in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 to <88lb), 
and >40kg (>88lb) following Protocol Amendment 9. 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 followed by maintenance doses 
Q2W (except the 10 to < 20kg group on the reduced dose will be administered 50mg Q4W). 
Was changed to: 
In order to further support the safety assessment of the Original CZP Dose, as more of the 
safety data collected in the study to date has been on the reduced dose, an additional 30 study 
participants are intended to be enrolled on the Original CZP Dose with the aim to enroll at 
least 5 study participants in each weight range of 10 to <20kg (22 to <44lb), 20 to <40kg (44 
to <88lb), and >40kg (>88lb) following Protocol Amendment 9. 
Certolizumab pegol will be administered as a fixed dose based on weight throughout the 
study consisting of 3 loading doses at Weeks 0, 2, and 4 followed by maintenance doses 
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Q2W (except the 10 to < 20kg group on the Reduced CZP Dose will be administered 50mg 
Q4W). 
Change #5 
Section 2.4 Determination of sample size 
With Protocol Amendment 9, an additional 30 study participants will be enrolled on the 
original dose with the aim to enroll at least 5 study participants in each weight range of 10 to 
<20kg (22 to <44lb), 20 to <40kg (44 to <88lb), and >40kg (>88lb). 
Was changed to: 
With Protocol Amendment 9, an additional 30 study participants will be enrolled with the 
aim to enroll at least 5 study participants in each weight range of 10 to <20kg (22 to <44lb), 
20 to <40kg (44 to <88lb), and >40kg (>88lb). 
Change #6 
Section 2.5 Study RA0138 
RA0138 is an open-label study in 30 adult study participants with RA.  This study was 
conducted to generate PK and ADAb data using the same ECLIA assay as used in RA0043 to 
form the basis of “PK-matching” for CZP approval. The PK and ADAb data from RA0138 
will be analyzed and displayed in the same manner as data from RA0043 so that comparisons 
and conclusions can be made.  Those details will be presented in the Appendix, Section 12.1. 
Was changed to: 
RA0138 is an open-label study in 33 adult study participants with RA who took 400mg 
loading dose (Weeks 0, 2, and 4), followed by 200mg CZP Q2W.  This study was conducted 
to generate PK and ADAb data using the same ECLIA assay as used in RA0043 to form the 
basis of “PK-matching” for CZP approval. The PK and ADAb data from RA0138 will be 
analyzed and displayed in the same manner as data from RA0043 so that comparisons and 
conclusions can be made.  Those details will be presented in the Appendix, Section 12.1. 
Change #7 
Section 3.1 General presentation of summaries and analyses 
Generally, data will be summarized by the Original CZP Dose, Reduced CZP Dose, and Any 
CZP Dose groups.  For PK and ADA analyses, data will be summarized by Original CZP 
Dose and Reduced Dose only.  
Further details regarding these displays based upon dose groups can be found in the 
respective PK, safety and efficacy analysis sections below. 
Was changed to: 
The planned data summaries using dose groups of Original CZP Dose and Reduced CZP 
Dose are designed to allow for the most relevant comparison of PK data and PK extrapolation 
using only data collected from study participants while receiving one consistent dosing 
regimen of CZP. This assignment of treatment groups will allow for a pure comparison of PK 
of the Original CZP Dose and the Reduced CZP Dose between pediatrics and adults without 
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the potential of confounding differences in CZP plasma concentrations due to dose switching. 
Additionally, these dose groupings allow for the continuity of safety, immunogenicity, and 
open label efficacy analyses for the Original CZP Dose and Reduced CZP Dose. 
 
Generally, data will be summarized by the Original CZP Dose, Reduced CZP Dose, and Any 
CZP Dose groups.  For PK and ADAb analyses, data will be summarized by Original CZP 
Dose and Reduced CZP Dose only.  
Following recommendations received from 
 
, a few data summaries will be organized by "Complete" CZP dose groups defined 
below, which will allow assessment of exposure and safety for all time that study participants 
were receiving the specified dose regardless of dose switching: 
• Complete Original CZP Dose: includes all study participants who began treatment in 
accordance with the Original CZP Dose, as well as study participants who began 
treatment in accordance with the Reduced CZP Dose and then later dose escalated to the 
Original CZP Dose. 
 
Only data obtained while the study participant was receiving the Original CZP Dose will 
be included in summaries of the Complete Original CZP Dose. For study participants who 
began treatment with the Original CZP Dose, this includes time on the Original CZP 
Dose prior to first change in dosage, as well as time after returning to Original CZP Dose 
after a previous dose reduction. For study participants who began treatment with the 
Reduced CZP Dose, this includes only time after dose escalation to the Original CZP 
Dose. 
• Complete Reduced CZP Dose: includes all study participants who began treatment in 
accordance with the Reduced CZP Dose, as well as study participants who began 
treatment in accordance with the Original CZP Dose and later dose reduced to the 
Reduced CZP Dose. 
 
Only data obtained while the study participant was receiving the Reduced CZP Dose will 
be included in summaries of the Complete Reduced CZP Dose. For study participants 
who began treatment with the Reduced CZP Dose, this includes time on the Reduced 
CZP Dose prior to first change in dosage. For study participants who began treatment 
with the Original CZP Dose, this includes only time after dose reduction to the Reduced 
CZP Dose, and prior to any potential later dose escalation back to the Original CZP Dose. 
 
Selected exposure and TEAE summaries will be produced on Complete Original CZP Dose 
and Complete Reduced CZP Dose in order to answer specific agency questions. Similarly, 
summaries of the proportion of PK and ADAb samples and participants that have been 
reanalyzed with the ECLIA assay will also be produced with this treatment association. 
Further details regarding these displays based upon dose groups can be found in the 
respective PK, safety and efficacy analysis sections below. 
Change #8 
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Section 3.2.5 Week 24 was added: 
Week 24 is defined as the visit labeled as Week 24 or Visit 10 in the data. 
Change #9 
Section 3.2.6 Entire treatment period was added: 
The entire treatment period is the same as the entire exposure period which includes all data 
while the study participant is taking study medication. 
Change #10 
Section 3.4.1 PK protocol deviations was renamed to Exclusion of PK data points 
Exclusion of specific PK data points will be done for that PK data presented in the subset of 
tables and figures where geometric means are calculated and displayed.  These exclusions 
will not occur in the PK data presented in spaghetti plots or individual profile figures.  The 
reasons why PK data points may be excluded are the following:  
• Study participant taking an incorrect treatment or dose, 
• Study participant’s discontinuation of CZP, 
• Study participant being in Clinical remission (and not taking CZP), 
• Study participant having deviations where CZP dosings occur outside the scheduled CZP 
dosing window, and 
• Study participant is procedurally non-compliant in having PK samples taken at the 
appropriate time points. 
PK data that is excluded due to the above reasons will be flagged on the analysis PK dataset.  
The flagging will allow the data to be excluded from geometric mean calculations which 
could be more affected by instances of treatment and procedure non-compliance.   
Was changed to: 
Exclusion of specific PK data points will be done for that CZP plasma concentration data 
presented in the subset of tables and figures where geometric means are calculated and 
displayed.  These exclusions will not occur in the CZP plasma concentration data presented 
in spaghetti plots or individual profile figures.  The reasons why CZP plasma concentration 
data points may be excluded are the following:  
• Study participant taking an incorrect treatment or dose, 
• Study participant’s discontinuation of CZP, 
• Study participant being in Clinical remission (and not taking CZP), 
• Study participant having deviations where CZP dosings occur outside the scheduled CZP 
dosing window, and 
• Study participant is procedurally non-compliant, in not having plasma concentration 
samples taken at the appropriate time points. 
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 CZP plasma concentration data that is excluded due to the above reasons will be flagged on 
the analysis PK dataset.  The flagging will allow the data to be excluded from geometric 
mean calculations which could be more affected by instances of treatment and procedure 
non-compliance.   
Change #11 
Section 3.4.1.1 Rules for exclusions of specific PK samples 
The PK sample results taken at a specific visit will be excluded from analysis for the 
following reasons: 
• For study participants in documented clinical remission (and not taking CZP), any study 
participant’s PK sample results during clinical remission (after CZP dose is stopped) are 
excluded, 
− For study participants returning to CZP dosing after having stopped taking CZP (eg. 
when in clinical remission), a study participant’s PK sample result will be included in 
summaries if the prior 3 consecutive CZP doses are present, 
• If the study participant’s PK sample was taken at a visit where the prior 2 consecutive 
CZP doses were missed, then the study participant’s PK sample is excluded, 
• If in the 168 days prior to the study participant’s PK sample, there were >3 CZP doses 
missed, then that study participant’s PK sample is excluded, 
• If the PK sample is taken following the study participant’s noncompliance in CZP dosing 
as indicated by an important protocol deviation, then the study participant’s affected PK 
sample (the one following that noncompliant dose) will be excluded, 
• If a study participant is on a Q2W CZP dosing interval, and the study participant’s PK 
sample is taken <9 days or >19 days from the last CZP dosing, then it is excluded, 
• If a study participant is on a Q4W CZP dosing interval, and the study participant’s PK 
sample is taken <23 days or >33 days from the last CZP dosing, then it is excluded, 
• For the Week 1 PK sample, if a study participant’s PK sample is taken (too soon) <4 days 
after or (too late) >10 days after the Week 0 CZP dose, it is excluded, or 
• For the Week 17 PK sample, if a study participant’s PK sample is taken (too soon) <4 
days after or (too late) >10 days after the Wk 16 CZP dose, it is excluded. 
Was changed to: 
The PK sample results taken at a specific visit will be excluded from analysis for the 
following reasons: 
• If the study participant’s CZP plasma concentration sample was taken at a visit where the 
prior 2 consecutive CZP doses were missed, then the study participant’s CZP plasma 
concentration sample is excluded, 
− For study participants returning to CZP dosing, a study participant’s CZP plasma 
concentration result will be included in summaries if the prior 3 consecutive CZP 
doses are present. 
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• If in the 168 days prior to the study participant’s CZP plasma concentration sample, there 
were >3 CZP doses missed, then that study participant’s CZP plasma concentration 
sample is excluded, 
− For study participants returning to CZP dosing, a study participant’s CZP plasma 
concentration result will be included in summaries if the prior 3 consecutive CZP 
doses are present. 
• If a study participant is on a Q2W CZP dosing interval, and the study participant’s CZP 
plasma concentration sample is taken <9 days or >19 days from the last CZP dosing, then 
it is excluded, 
• If a study participant is on a Q4W CZP dosing interval, and the study participant’s CZP 
plasma concentration sample is taken <23 days or >33 days from the last CZP dosing, 
then it is excluded, 
• For the Week 1 CZP plasma concentration sample, if a study participant’s sample is taken 
(too soon) <4 days after or (too late) >10 days after the Week 0 CZP dose, it is excluded, 
or 
• For the Week 17 CZP plasma concentration sample, if a study participant’s sample is 
taken (too soon) <4 days after or (too late) >10 days after the Week 16 CZP dose, it is 
excluded. 
 
In addition, CZP plasma concentrations that have been analyzed outside the stability 
coverage of the ECLIA assay have also been excluded. In this latter case from all tables 
and figures and only will appear in the listings with a flag for out of stability.  
Change #12 
Section 3.5 Analysis sets 
The efficacy variables will be summarized using the Full Analysis Set (FAS). All safety and 
immunogenicity analyses will be based on the Safety Set (SS). Plasma concentration data and 
PK parameters will be summarized using the Pharmacokinetic Per-Protocol Set (PK-PP).  
Pharmacokinetic-pharmacodynamic modeling will be based upon the Pharmacokinetic-
Pharmacodynamic (PK-PD) Set. 
Was changed to: 
The efficacy variables will be summarized using the Full Analysis Set (FAS). All safety and 
immunogenicity analyses will be based on the Safety Set (SS). Plasma concentration data will 
be summarized using the Pharmacokinetic Per-Protocol Set (PK-PP).   
Change #13 
Section 3.5.4 Pharmacokinetic Per-Protocol (PK-PP) Set  
The Pharmacokinetic Per-Protocol (PK-PP) Set is a subset of the SS consisting of those study 
participants who took at least 1 dose of study medication, provided measurable plasma 
samples (with recorded sampling time and analyzed using the ECLIA method) on at least 1 
occasion and who had no important protocol deviations affecting the PK parameters, as 
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confirmed during data cleaning meetings prior to locking the database. The PK-PP Set will be 
used for the PopPK model that will be described in a separate data analysis plan (DAP)and 
for all presentations of plasma concentration. 
Was changed to: 
The Pharmacokinetic Per-Protocol (PK-PP) Set is a subset of the SS consisting of those study 
participants who took at least 1 dose of study medication, provided measurable plasma CZP 
concentration samples (with recorded sampling date/time or for which date/time can be 
reasonably assumed and it was analyzed using the ECLIA method) on at least 1 occasion. 
The PK-PP Set will be used for the PopPK model that will be described in a separate data 
analysis plan (DAP) and for all presentations of plasma concentration. 
Change #14 
Section 3.8 Coding dictionaries 
Adverse events and medical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA® version 18.1) according to UCB standard operating 
procedures (SOP). Medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD version dated Sep 2013) according to UCB SOPs.  
Was changed to: 
Adverse events and medical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA® version 23.1) according to UCB standard operating 
procedures (SOP). Medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD version dated Sep 2020 B3) according to UCB SOPs.  
Change #15 
Section 3.9 Changes to protocol-defined analyses 
The definition for the PK-PP has been clarified that study participants in this set must have 
PK data analyzed using the ECLIA method. 
Was changed to: 
The definition for the PK-PP has been clarified such that study participants in this set must 
have PK data analyzed using the ECLIA method. 
In line with 
 response, 
additional analyses have been added to  
• summarize exposure and treatment-emergent adverse events for when study participants 
were taking Complete Original CZP Dose and Complete Reduced CZP Dose.  
− Complete Original CZP Dose includes all data for study participants who took 
Original CZP Dose prior to the first change in dosage as well as the data from when 
study participants increased their dosage to Original CZP after taking Reduced CZP 
Dose.  
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− Complete Reduced CZP Dose includes all data for study participants who took 
Reduced CZP Dose prior to the first change in dosage as well as the data from when 
study participants took Reduced CZP Dose after taking Original CZP Dose. 
• the proportion of study participants and the proportion of PK samples with sufficient 
volume for re-analysis with the ECLIA method out of all PK samples initially analyzed 
with the ELISA method will be summarized by Original CZP Dose, Reduced CZP Dose, 
Complete Original CZP Dose, and Complete Reduced CZP Dose. 
• the proportion of study participants and the proportion of PK samples with sufficient 
volume for re-analysis with the ECLIA method out of all PK samples analyzed with the 
ECLIA method (either originally or via re-analysis) will be summarized by Original CZP 
Dose, Reduced CZP Dose, Complete Original CZP Dose, and Complete Reduced CZP 
Dose. 
• the proportion of study participants and the proportion of ADAb samples with sufficient 
volume for re-analysis with the ECLIA method out of all ADAb samples initially 
analyzed with the ELISA method will be summarized by Original CZP Dose, Reduced 
CZP Dose, Complete Original CZP Dose, and Complete Reduced CZP Dose.   
• Additionally, the proportion of study participants and the proportion of ADAb samples 
with sufficient volume for re-analysis with the ECLIA method out of all ADAb samples 
analyzed with the ECLIA method (either originally or vis re-analysis) will be summarized 
by Original CZP Dose, Reduced CZP Dose, Complete Original CZP Dose, and Complete 
Reduced CZP Dose. 
Change #16 
Section 3.9 Changes to protocol-defined analyses 
This analysis plan includes plots of CZP plasma concentrations, ADAb titers, JADAS-71 and 
maximum PedACR response for individual study participants by visit. Box plots of the PK 
distribution as Weeks 12 and 24 stratified by Baseline weight group, Baseline age group, 
concomitant MTX use and participant ADAb classification will be performed as a basis of 
the comparison with the adult RA PK exposures in RA0138; this comparison of observed PK 
data will be covered in Appendix Section 12.1. Plots of PK and ADAb data were not pre-
specified in the study protocol.   
It is not planned to perform a population PKPD modeling analysis of RA0043 data to explore 
the exposure-response relationship in JIA pediatric population for the following reasons: i) 
the purpose of the RA0043 study is to support the efficacy extrapolation to the pediatric 
population by PK matching with respect to RA adult PK, and thus the main aim of the 
analysis that will be performed by nonlinear mixed effect modeling is to characterize the PK 
in JIA pediatrics with precise parameter estimates; and ii) the W24 interim analyses 
performed and submitted in 2016 (BLA 125160-275) included PedACR and JADAS-71 
graphical explorations by dose regimen which concluded that a substantial improvement of 
the PedACR and JADAS-71 responses across both dosing regimens investigated in Study 
RA0043 was observed, with no differences between these, that would support a pop-PKPD 
analysis. Hence the PK-PD Set was removed as no analysis are planned for this population. 
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In the protocol it was stated that continuous efficacy endpoints would be presented using both 
last observation carried forward (LOCF) and observed case (OC) analyses. Instead, only 
observed case summaries of continuous efficacy endpoints will be presented since efficacy is 
not the primary objective of this study and little difference is expected between the two 
different analyses. 
For the Updated Week 24 Interim Analysis, the efficacy data will be summarized and plotted 
up to and including Week 24; all efficacy data will be included in listings. Efficacy analyses 
will not be submitted for the 120 Day Safety Update. 
Was changed to: 
This analysis plan includes plots of CZP plasma concentrations, ADAb titers, and maximum 
PedACR response for individual study participants by visit. Box plots of the PK distribution 
at Weeks 12 and 24 stratified by Baseline weight group, Baseline age group, concomitant 
MTX use and participant ADAb classification will be performed as a basis of the comparison 
with the adult RA PK exposures in RA0138; this comparison of observed PK data will be 
covered in Appendix Section 12.1. Plots of PK and ADAb data were not pre-specified in the 
study protocol.   
It is not planned to perform a population PKPD modeling analysis of RA0043 data to explore 
the exposure-response relationship in JIA pediatric population for the following reasons: i) 
the purpose of the RA0043 study is to support the efficacy extrapolation to the pediatric 
population by PK matching with respect to RA adult PK, and thus the main aim of the 
analysis that will be performed by nonlinear mixed effect modeling is to characterize the PK 
in JIA pediatrics with precise parameter estimates; and ii) the W24 interim analyses 
performed and submitted in 2016 (BLA 125160-275) included PedACR and JADAS-71 
graphical explorations by dose which concluded that a substantial improvement of the 
PedACR and JADAS-71 responses across both doses investigated in Study RA0043 was 
observed, with no differences between these, that would support a pop-PKPD analysis. Hence 
the PK-PD Set was removed as no analyses are planned for this population. 
In the protocol it was stated that continuous efficacy endpoints would be presented using both 
last observation carried forward (LOCF) and observed case (OC) analyses. Instead, only 
observed case summaries of continuous efficacy endpoints will be presented since efficacy is 
not the primary objective of this study and little difference is expected between the two 
different analyses. 
For the Updated Week 24 Interim Analysis, the efficacy data will be summarized and plotted 
up to and including Week 24; all efficacy data will be included in listings and displayed on a 
small subset of figures. 
Change #17 
Section 4.2 Handling of dropouts or missing data 
For all binary efficacy endpoints assessing response (PedACR30, PedACR50, PedACR70, 
PedACR90, CID, CRM), a subject having missing data for the time point assessed will be 
conservatively counted as a non-remitter or non-responder. This will be done whether the 
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data is missing, the subject discontinued the study prior to the time point assessed, or the data 
is considered missing due to use of prohibited or rescue medication.  
For all non-missed visits, if any of the PedACR core set measures are missing then those 
scores will be considered as not having met the criteria for improvement in the PedACR30, 
PedACR50, PedACR70 and PedACR90 response analyses. PedACR30, PedACR50, 
PedACR70, and PedACR90 responses will be derived if a single core set measure is missing.  
However, if 2 or more core set measures are missing, the corresponding PedACR30, 
PedACR50, PedACR70 and PedACR90 responses will in general be treated as missing. 
All efficacy data collected at any visits after the use of rescue medications, or prohibited 
medications that could impact efficacy, will be treated as missing for continuous endpoints 
and non-response for binary endpoints in all analyses except where specifically stated 
otherwise.  See Section 6.6  for a list of medications which would result in all efficacy data at 
only the next scheduled visit (and not all subsequent visits) being treated as missing/non-
response. Any joint receiving intra-articular corticosteroids will be treated as missing with 
respect to assessments of that joint for 3 months (91 days).   
For continuous efficacy endpoints, missing assessments will not be imputed. For all analyses, 
the data will be analyzed as observed cases without any imputation. For the non-responder 
imputation (NRI) calculations for binary efficacy outcomes, the data beyond Week 56 will be 
analyzed as observed cases without any imputation while the data up to and including Week 
56, NRI will only be applied to study participants who have discontinued early prior to 
reaching Week 56. 
No further imputations of any other missing data are planned (eg, efficacy data missing at 
random). 
Was changed to: 
For all binary efficacy endpoints assessing response (PedACR30, PedACR50, PedACR70, 
PedACR90, CID, CRM), a study participant having missing data for the time point assessed 
will be conservatively counted as a non-remitter or non-responder. This will be done whether 
the data is missing, the study participant discontinued the study prior to the time point 
assessed, or the data is considered missing due to use of prohibited or rescue medication.  
For all non-missed visits, if any of the PedACR core set measures are missing then those 
scores will be considered as not having met the criteria for improvement in the PedACR30, 
PedACR50, PedACR70 and PedACR90 response analyses. PedACR30, PedACR50, 
PedACR70, and PedACR90 responses will be derived if a single core set measure is missing.  
However, if 2 or more core set measures are missing, the corresponding PedACR30, 
PedACR50, PedACR70 and PedACR90 responses will in general be treated as missing. 
Derived binary efficacy endpoints  at visits affected by the use of rescue medications, or 
prohibited medications, will be treated as non-response.  See Section 6.7 for a list of 
medications which would result in all efficacy data at only the next scheduled visit (and not 
all subsequent visits) being treated as missing/non-response. Any joint receiving intra-
articular corticosteroids will be treated as missing with respect to assessments of that joint for 
3 months (91 days).   
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For continuous efficacy endpoints, missing assessments will not be imputed..  
For the non-responder imputation (NRI) calculations for binary efficacy outcomes,  
• the study participants who discontinued up to and including Week 56, NRI will be 
imputed up to Week 56, 
• the study participants who discontinued after Week 56, no imputation will be performed 
after the last visit,  
• for study participants who take rescue and prohibited medications (see Section 6.6),  
− for visits up to and including Week 56, the outcomes are imputed as NRI up to Week 
56 
− for visits after Week 56, the outcomes are imputed as NRI if medication initiation is 
before or on Week 56 
• for the initiation of rescue, short-acting or prohibited medications after Week 56, then the 
NRI imputation is not applied. 
No further imputations of any other missing data are planned (eg, efficacy data missing at 
random). 
Change #18 
Section 4.3 Interim analyses and data monitoring 
Based on results of this interim PopPK analysis, the doses was changed with Protocol 
Amendments 4 and 5, and the doses to be administered were reduced by 50% for all weight 
groups. This change was intended to achieve plasma concentrations similar to the effective 
concentrations observed in the previous study in adult study participants with RA (study  
C87050). However, it was later determined that there were deficiencies detected with in the 
bioanalytical assay used within RA0043, which rendered the PK data for the PopPK analysis 
and simulations that informed the dose reduction in Protocol Amendments 4 and 5 were not 
up to current standards and FDA guidelines; therefore, those data were not able to support the 
regulatory filing.  
Interim analyses of PK, immunogenicity, safety, and efficacy endpoints 
An interim analysis of PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants that were enrolled and treated prior to implementation of 
Protocol Amendment 9 had completed the Week 24 (Visit 10) assessments, and the results 
were reported separately; this is referred to as the 2016 Week 24 interim analysis. An interim 
analysis, including all enrolled participants, for all PK, immunogenicity, safety, and efficacy 
endpoints will be performed after all active study participants, including those enrolled 
following the implementation of Protocol Amendment 9, have completed the Week 24 (Visit 
10) assessments; this will be referred to as the Updated Week 24 Interim analysis to be used 
in support of the re-submission of BLA 125160-275.   
Was changed to: 
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Based on results of this interim PopPK analysis, the doses were changed with Protocol 
Amendments 4 and 5, and the doses to be administered were reduced by 50% for all weight 
groups. This change was intended to achieve plasma concentrations similar to the effective 
concentrations observed in the previous study in adult study participants with RA (study  
C87050).  
Interim analyses of PK, immunogenicity, safety, and efficacy endpoints 
An interim analysis of PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants that were enrolled and treated prior to implementation of 
Protocol Amendment 9 had completed the Week 24 (Visit 10) assessments, and the results 
were reported separately; this is referred to as the 2016 Week 24 interim analysis. However, 
it was then determined that there were deficiencies with the bioanalytical assay used within 
RA0043, which rendered the PK data for the PopPK analysis and simulations not up to 
current standards and FDA guidelines; therefore those data were not able to support the 
regulatory filing. 
At the time of Protocol Amendment 9, a new assay had been developed and would be used to 
analyze samples from the 30 new subjects enrolled on the original dose as well as any old 
samples with sufficient volume remaining. An interim analysis, including all enrolled 
participants, for all PK, immunogenicity, safety, and efficacy endpoints will be performed 
after all active study participants, including those enrolled following the implementation of 
Protocol Amendment 9, have completed the Week 24 (Visit 10) assessments; this will be 
referred to as the Updated Week 24 Interim analysis to be used in support of the re-
submission of BLA 125160-275. 
Change #19 
Section 5.2 Protocol deviations 
Note that PK sample exclusion will be implemented due to certain protocol deviations; see 
Section 3.5. Study participants with at least one PK data exclusion are summarized and listed. 
Was changed to: 
Note that PK sample exclusion will be implemented due to certain protocol deviations; see 
Section 3.5. Study participants with at least one PK data exclusion from scheduled visits are 
summarized and listed. 
Change #20 
Section Demographics, the variable ERA Status (present, absent) and the following sentence 
was added: 
Demographics information will be listed. 
Change #21 
Section 6.2 Other baseline characteristics, the following sentence was added: 
Other baseline characteristics information will be listed. 
Change #22 
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Section 6.3 Medical history and concomitant diseases, the following sentence was added: 
Medical history, JIA history and a glossary of medical history conditions will be listed. 
Change #23 
Section 6.4 Prior and concomitant medications 
All prior medications will be summarized by anatomical therapeutic chemical (ATC) 
classification level 3 (Pharmacological Subgroup) and WHO-DD generic name. In addition, 
past DMARDs will be summarized separately by ATC level 3 and WHO-DD generic name.  
These summaries will be provided for the SS for the Reduced CZP Dose, the Original CZP 
Dose and the Any CZP Dose. 
Concomitant medications will be summarized for all medications, and separately for 
DMARDs, systemic corticosteroids, and intra-articular corticosteroid injections. DMARDs 
and corticosteroids will be identified through ATC codes and medical review. Concomitant 
medications will be summarized by ATC level 3 and WHO-DD generic name. All summaries 
of concomitant medications will be provided for the SS for the Reduced CZP Dose, Original 
CZP Dose, and Any CZP Dose groups. 
Listings of all prior and concomitant medications will be provided. 
Was changed to: 
All prior medications will be summarized by anatomical therapeutic chemical (ATC) 
classification level 3 (Pharmacological Subgroup) and WHO-DD generic name. The number 
of DMARDs stopped prior to Baseline and not re-initiated during the study will be assessed 
and summarized. For those study participants with these stopped DMARDs, the WHO-DD 
generic name will be summarized.  These summaries will be provided for the SS for the 
Reduced CZP Dose, the Original CZP Dose and the Any CZP Dose. 
Concomitant medications will be summarized for all medications, and separately for 
DMARDs, systemic corticosteroids, and intra-articular corticosteroid injections. DMARDs 
and corticosteroids will be identified through ATC codes and medical review. Concomitant 
medications will be summarized by ATC level 3 and WHO-DD generic name. All summaries 
of concomitant medications will be provided for the SS for the Reduced CZP Dose, Original 
CZP Dose, and Any CZP Dose groups. 
Listings of all prior and concomitant medications will be provided as well as a glossary of the 
concomitant medications. 
 
Medications related to triamcinolone with the following WHO-DD generic names will be 
grouped and appear in summaries as "Triamcinolone" with the ATC3 level label of "UCB 
Triamcinolone ATC3": triamcinolone, triamcinolone acetonide, triamcinolone hexacetonide, 
triamcinolone acetate, triamcinolone diacetate, triamcinolone acetonide dipotassium 
phosphate. 
 
Medications related to prednisone with the following WHO-DD generic names will be 
grouped and appear in summaries as "Prednisone" with the ATC3 level label of "UCB 
Prednisone ATC3": prednisone, prednisolone, prednisolone acetate, prednisolone sodium 
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phosphate, methylprednisolone, methylprednisolone acetate. 
 
Medications related methotrexate with the following WHO-DD generic names will be 
grouped and appear in summaries as "Methotrexate" with the ATC3 level label of "UCB 
Methotrexate ATC3": methotrexate, methotrexate sodium. 
Change #24 
Section 6.5 Prohibited medications, the following sentence was added: 
Prohibited medication usage will be listed. 
Change #25 
Section 6.6 Rescue medications 
The following medications are defined as rescue medication for the remainder of the study: 
Was changed to: 
The following medications are defined as rescue medication  when initiated in the first 56 
weeks of the study: 
Change #26 
Section 6.6 Rescue medications 
The following medications are defined as rescue medication when given at any time during 
the study: 
Was changed to: 
The following medications are defined as rescue medication when initiated at any time up to 
Week 56 during the study: 
Change #27 
Section 6.6 Rescue medications 
Any joint injected with ia corticosteroids that does not satisfy the criteria for rescue 
medication (ie, isolated cases of ia corticosteroids) will be excluded from the efficacy 
analysis for a period of 3 months (91 days). 
Was changed to: 
Any joint injected with ia corticosteroids will be excluded from the efficacy analysis for a 
period of 3 months (91 days). 
Change #28 
Section 6.7 Short-acting medications was made a subsection containing the following 
unedited text: 
Use of the following medications, which are not rescue medications, only results in efficacy 
data at the next scheduled visit being treated as missing/non-response: 
• Higher than Baseline dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and 
cyclooxygenase-2 (COX-2) inhibitors, including as needed (PRN) use within 72 hours 
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prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
• Higher than Baseline dose of analgesics or opioids including PRN use within 48 hours 
prior to scheduled study visit (Note: No intake at baseline is considered equivalent to a 
baseline dose of 0). 
• Any increase in dose of oral corticosteroids within 7 days prior to scheduled study visit 
(Note: The increase has to be higher than baseline). 
All medication data resulting in efficacy data being treated as missing/non-response will be 
flagged in the concomitant medication listing. 
Change #29 
Section 6.8 Medical procedure history and concomitant medical procedures was added: 
All medical procedures, in history or concomitant, will be presented in data listings.  The 
historical procedures with no start date will be assigned to Reduced CZP dose (for those 
study participants who started the study taking Reduced CZP) or Original CZP dose (for 
those study participants who started the study taking Original CZP). 
Change #30 
Section 7 Measurements of treatment compliance 
Treatment compliance is summarized for the SS for the Reduced CZP Dose, Original CZP 
Dose, and Any CZP Dose. 
Was changed to: 
Treatment compliance will be summarized and listed for the SS for the Reduced CZP Dose, 
Original CZP Dose, and Any CZP Dose for the final analysis; for the Updated week 24 
Interim Analysis, treatment compliance will be summarized and listed for the SS for the 
Reduced CZP Dose and Original CZP Dose. 
Change #31 
Section 8 Pharmacokinetics and immunological procedures 
Data from the ECLIA methods will constitute the study’s main PK and ADAb evaluations. 
Was changed to: 
Data from the ECLIA methods, that are within the stability coverage of the assay, will 
constitute the study’s main PK and ADAb evaluations; all reported ECLIA assay results will 
be listed. 
Change #32 
Section 8 Pharmacokinetics and immunological procedures 
Box plots of the PK concentrations at Weeks 12 and 24 will be presented by CZP dose group 
for Baseline weight group, Baseline age group, ADAb participant status classification, ADAb 
titer classification, and concomitant MTX use in combination with Baseline weight group. 
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Concentrations below the limit of quantification of 32.0 ng/mL (0.032μg/mL) (BLQ) will be 
replaced by the LLOQ divided by 2 for the calculation of descriptive statistics. 
Was changed to: 
Concentrations below the limit of quantification of 320.0 ng/mL (0.32μg/mL) (BLQ) will be 
replaced by the LLOQ divided by 2 for the calculation of descriptive statistics. 
Change #33 
Section 8.1.1 ECLIA vs ELISA samples was added: 
In line with 
 response, 
the proportion of study participants and the proportion of PK samples with sufficient volume 
for re-analysis with the ECLIA method out of all PK samples initially analyzed with the 
ELISA method will be summarized. 
First, the number and percentage of study participants with at least one PK sample re-
analyzed using the ECLIA method (after previous analysis using the ELISA method) will be 
presented.  For this percentage, the denominator is the number of study participants with at 
least one non-missing PK result from the ELISA method, and the numerator is the number of 
study participants with at least one non-missing PK result from the ECLIA method that had 
also been analyzed with the ELISA method previously. (Below LLOQ is considered a non-
missing result.) 
Second, the number and percentage of post-baseline PK samples that were re-analyzed using 
the ECLIA method (after previous analysis using the ELISA method) will be presented. For 
this percentage, the denominator is the number of post-baseline PK samples with non-missing 
ELISA results. The numerator is the number of post-baseline PK samples with non-missing 
ECLIA results where the same PK sample had previously been analyzed using the ELISA 
method. (Below LLOQ is considered a non-missing result.)  
Additionally, the proportion of study participants and the proportion of PK samples with 
sufficient volume for re-analysis with the ECLIA method out of all PK samples analyzed 
with the ECLIA method (either originally or via re-analysis) will be summarized. 
First, the number and percentage of study participants with at least one PK sample re-
analyzed using the ECLIA method (after previous analysis using the ELISA method) will be 
presented.  For this percentage, the denominator is the number of study participants with at 
least one non-missing PK sample that was analyzed using the ECLIA method (either 
originally or via re-analysis).  The numerator is the number of study participants with at least 
one non-missing PK result from the ECLIA method for a sample that had also been analyzed 
with the ELISA method previously. Also, the number and percentage of study participants 
that did not have any PK sample re-analyzed with the ECLIA method will be presented. The 
denominator is the same, but the numerator is the number of study participants for whom all 
non-missing PK results obtained using the ECLIA method were on samples that had never 
been analyzed using the ELISA method. (Below LLOQ is considered a non-missing result.)  
Second, the number and percentage of post-baseline PK samples that were re-analyzed using 
the ECLIA method (after previous analysis using the ELISA method) will be presented.  For 
this percentage, the denominator is the number of non-missing post-baseline PK results that 
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were obtained using the ECLIA method (either originally or via re-analysis). The numerator 
is the number of those non-missing post-baseline PK results that were obtained by re-analysis 
with the ECLIA method, after having also been analyzed by the ELISA method previously. 
Also, the number and percentage of those post-baseline samples that were not re-analyzed 
with the ECLIA method (out of those analyzed with ECLIA method) will be presented. The 
denominator is the same, but the numerator is the number of those non-missing post-baseline 
PK results for samples that were only ever analyzed using the ECLIA method. (Below LLOQ 
is considered a non-missing result.) 
All summaries will be provided for the Safety Set and presented for Original CZP Dose, 
Reduced CZP Dose, Complete Original CZP Dose and Complete Reduced CZP Dose by 
baseline weight. 
Change #34 
Section 8.2.1 Partcipant ADAb classification 
Study participants from the SS will be classified based on their pre and treatment ADAb 
status (Table 8‒2). Classification will be done separately two ways: using the study 
participants’ data for the entire study treatment period and using the study participants’ data 
up to and including Week 24 (to facilitate comparison with adult RA data from study 
RA0138). Pre ADAb values are defined as the latest (not missing, not inconclusive and not 
anomalous) measurements up to and including the date of administration of first CZP 
treatment.  
Table 13‒7: ADAb status classification at participant level 
1. 
Pre ADAb negative and treatment-
emergent ADAb negative  
Study participants who were negative at Baseline and 
negative at all sampling points post treatment until the time 
point of interest (eg. Data up to/including Week 24, data for 
the entire treatment period) 
 
[Note: study participants with baseline samples missing and 
negative ADAb status at all sampling points post treatment 
are included in this category because participants who are 
pre ADAb positive are expected to have ADAb positive 
samples post-dosing]  
 
2. 
Pre ADAb negative and treatment-
(emergent) induced ADAb 
positive 
Study participants who were negative at Baseline and 
positive at any sampling point post treatment until the 
timepoint of interest (eg. Data up to/including Week 24, 
data for the entire treatment period). This group also 
included study participants who had a missing Baseline 
sample with 1 or more positive post treatment samples. 
3. 
Pre ADAb positive and treatment-
emergent reduced ADAb  
Study participants who were positive at Baseline, and 
negative at all sampling points post treatment until the 
timepoint of interest (eg. Data up to/including Week 24, 
data for the entire treatment period). 
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Table 13‒7: ADAb status classification at participant level 
4. 
Pre ADAb positive and treatment-
emergent unaffected ADAb 
positive 
Study participants who were positive at Baseline and were 
positive at any sampling point post treatment with titer 
values of the same magnitude as Baseline (i.e., less than or 
equal to a predefined fold difference from the Baseline 
value of 2.10 which is defined with the validation of the 
assay). 
5. 
Pre ADAb positive and treatment-
emergent ADAb boosted positive 
Study participants who were positive at Baseline and were 
positive at any sampling point post treatment with increased 
titer values compared to Baseline (greater than a predefined 
fold difference increase of 2.10 from Baseline value which 
is defined within the validation of the assay). 
6. 
ADAb inconclusive 
Study participants who were positive at Baseline and some 
post-treatment samples were missing or inconclusive, while 
other post-treatment samples were negative.  
7. 
Treatment emergent ADAb 
positive 
Study participants that were classified as 2 or 5. 
8. 
Pre-treatment ADAb positive  
Study participants who are positive ADAb at baseline, so 
those classified as 3, 4, 5 or 6. 
9. 
Missing 
Study participants who were negative at Baseline or 
missing their Baseline assessment, were not positive at any 
post-Baseline visit, and have at least one missing/or 
inconclusive post-treatment scheduled assessment.  
10 
ADAb positive 
Study participants who have a positive ADA sample status 
at any timepoint (either Baseline or post dose). 
Was changed to: 
Study participants from the SS will be classified based on their baseline and treatment-
emergent ADAb status (Table 8‒2). Classification will be done separately for two time 
periods of interest: (1) using the study participants’ data for the entire study treatment period 
and (2) using the study participants’ data up to and including Week 24 (to facilitate 
comparison with adult RA data from study RA0138). Baseline ADAb values are defined as 
the latest (not missing, not inconclusive) measurements up to and including the date of 
administration of first CZP treatment.  
Table 13‒8: ADAb status classification at participant level 
1. 
Baseline ADAb negative and 
treatment-emergent ADAb 
negative  
Study participants who were negative at Baseline and 
negative at all sampling points post treatment until the time 
point of interest  
 
[Note: study participants with Baseline samples missing 
and negative ADAb status at all sampling points post 
treatment are included in this category because participants 
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Table 13‒8: ADAb status classification at participant level 
who are pre ADAb positive are expected to have ADAb 
positive samples post-dosing]  
 
2. 
Baseline ADAb negative and 
treatment-(emergent) induced 
ADAb positive 
Study participants who were negative at Baseline and 
positive at any sampling point post treatment until the 
timepoint of interest. This group also included study 
participants who had a missing Baseline sample with 1 or 
more positive post treatment samples. 
3. 
Baseline ADAb positive and 
treatment-emergent reduced 
ADAb  
Study participants who were positive at Baseline and 
negative at all sampling points post treatment until the 
timepoint of interest. 
4. 
Baseline ADAb positive and 
treatment-emergent unaffected 
ADAb positive 
Study participants who were positive at Baseline and were 
positive at any sampling point post treatment until the 
timepoint of interest with all titer values of the same 
magnitude as Baseline (i.e., less than or equal to a 
predefined fold increase from the Baseline value of 2.10 
which is defined with the validation of the assay). 
5. 
Baseline ADAb positive and 
treatment-emergent ADAb 
boosted positive 
Study participants who were positive at Baseline and were 
positive at any sampling point post treatment until the 
timepoint of interest with any increased titer values 
compared to Baseline (greater than a predefined fold 
increase of 2.10 from Baseline value which is defined 
within the validation of the assay). 
6. 
ADAb inconclusive 
Study participants who were positive at Baseline and some 
post-treatment samples until the timepoint of interest were 
missing or inconclusive, while other post-treatment samples 
until the timepoint of interest were negative.  
[Note: study participants who were positive at Baseline and 
all post-treatment samples up to the timepoint of interest 
were missing or inconclusive are also included in this 
category.]  
7. 
Treatment emergent ADAb 
positive 
Study participants that were classified as 2 or 5. 
8. 
Baseline treatment ADAb positive  Study participants who are positive ADAb at baseline, so 
those classified as 3, 4, 5 or 6. 
9. 
Missing 
Study participants who were negative at Baseline or 
missing their Baseline assessment, were not positive at any 
post-Baseline visit, and have at least one missing/or 
inconclusive post-treatment scheduled assessment (until the 
timepoint of interest).  
10 
ADAb positive 
Study participants who have a positive ADAb sample status 
at any timepoint (either Baseline or post dose). 
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Unscheduled visits including early discontinuation visits (ED) or Final visits with missing 
results are disregarded. Thus, study participants who had missing ADAb measurements at ED 
but were ADAb negative at all other post-treatment visits will be classified in category 1 
above . Study participants who were negative at Baseline or missing their Baseline 
assessment and whose only post-treatment ADAb assessment was at ED and was missing 
will be classified in category 9 above. Study participants who were positive at Baseline and 
whose only post-treatment assessment was at ED and was missing will be classified in 
category 6 above. Only positive data at unscheduled visits will be used for classification.   
 
Table 13‒9: Aid to Programming ADAb participant status category 
ADAb Participant Status Category  
 
Post-Treatment ADAb Sample Statusa 
Baseline ADAb Sample Status 
Any Positive 
All Scheduled 
Negative 
Some/ All Scheduled 
Missingb 
Missing 
2 
1 
9 
Negative 
2 
1 
9 
Positive 
4 or 5c 
3 
6 
a  Unscheduled (including withdrawal visits) with missing data disregarded. Missing data at other (scheduled) 
visits considered. 
b  And no positive ADAb samples post-treatment (including positive in either scheduled or unscheduled). 
c  Highest ADAb titer used to determine category.  
 
Post-treatment ADAb sample status categories are mutually exclusive and applied left to right. Thus 
study participants with both positive and missing post-treatment ADAb samples are considered in the 
“Any Positive” category.  
Time point of interest is the entire treatment period including SFU and the treatment period 
up to Week 24. 
Change #35 
Section 8.2.2 ADAb Titer Classification 
To further evaluate the impact of ADAb on PK, efficacy and safety, grouped ADAb titer 
categories will be defined based on ADAb quartiles (see Section 4.7) observed in the study.  
Quartiles will be calculated separately for the entire treatment period, and then for the period 
up to and including Week 24, using each study participant’s highest post-treatment ADAb 
titer (ADAb negative participants will be deemed to have zero titer levels for calculation 
purposes).   
If interpretation of the grouped titer summaries is inconclusive or results from other studies 
suggest other groupings, additional post-hoc analyses may be conducted to further 
investigate. 
Immunogenicity will be assessed through summary tables and figures and listing of 
individual results by study participant on the SS. Summaries will be by CZP dose (Reduced 
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CZP Dose, Original CZP Dose) and each of Baseline weight group, Baseline age group, and 
concomitant MTX use, unless specified otherwise.  
• All individual study participant-level ADAb results will be listed for all study 
participants. This will include the screening assay, confirmatory assay, and titer (if 
applicable). A separate listing showing CZP plasma concentrations, ADAb sample status 
classification, ADAb participant classification, ADAb titer, and ADAb titer 
classifications will be produced showing concentration and ADAb data in adjacent 
columns.  
• Number and percentage of study participants with positive, negative, inconclusive or 
missing ADAb sample status (Table 8‒1) will be summarized at each visit and overall 
and by dose (Original CZP dose, Reduced CZP Dose).  
• The number and percentage of study participants in each of the ADAb participant status 
categories (overall and up to Week 24 as defined according to Table 8‒2) will be 
summarized. Percentages for the denominator will include all the participants that have 
been classified as per Table 8‒2, so including missing /inconclusive participants.   
Prevalence and incidence: 
• Prevalence of pre ADAb positivity: number and percentage of study participants that have 
Baseline positive ADAb sample status, with the denominator for percentages defined as 
all participants having an evaluable (not missing, not inconclusive and not anomalous) 
Baseline ADAb sample.  
Incidence of treatment-emergent ADAb positivity: number and percentage of study 
participants with either treatment boosted ADAb or treatment induced ADAb, with the 
denominator for percentages all participants except those categorized as inconclusive or 
missing (overall for the entire treatment period and then up to and including Week 24). 
Was changed to: 
To further evaluate the impact of ADAb on PK, efficacy and safety, grouped ADAb titer 
categories will be defined based on ADAb quartiles (see Section 4.7) observed in the study.  
Quartiles will be calculated separately for the entire treatment period, and then for the period 
up to and including Week 24, using each study participant’s highest post-treatment ADAb 
titer (ADAb negative participants will be deemed to have zero titer levels for calculation 
purposes). If all post-baseline scheduled visit results are Negative, then the study participant 
will be assigned to the lowest titer classification (lowest quartile); unscheduled visits with 
missing results are disregarded. If a study participant doesn’t have any positive results at 
post-baseline scheduled visits and any of the results at scheduled visits are deemed missing or 
inconclusive, then the study participant will be assigned to “Missing”. 
If interpretation of the grouped titer summaries is inconclusive or results from other studies 
suggest other groupings, additional post-hoc analyses may be conducted to further 
investigate. 
Immunogenicity will be assessed through summary tables and figures and listing of 
individual results by study participant on the SS. Summaries will be by CZP dose (Reduced 
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CZP Dose, Original CZP Dose) and each of Baseline weight group, Baseline age group, and 
concomitant MTX use, unless specified otherwise.  
• All individual study participant-level ADAb results will be listed for all study 
participants. This will include the screening assay, confirmatory assay, and titer (if 
applicable). A separate listing showing CZP plasma concentrations, ADAb sample status 
classification, ADAb participant classification, ADAb titer, and ADAb titer 
classifications will be produced showing concentration and ADAb data in adjacent 
columns.  
• Number and percentage of study participants with positive, negative, inconclusive or 
missing ADAb sample status (Table 8‒1) will be summarized at each visit and overall 
and by dose (Original CZP dose, Reduced CZP Dose).  
• The number and percentage of study participants in each of the ADAb participant status 
categories (overall and up to Week 24 as defined according to Table 8‒2) will be 
summarized. Percentages for the denominator will include all the participants that have 
been classified as per Table 8‒2, so including missing /inconclusive participants.   
Prevalence and incidence: 
• Prevalence of Baseline ADAb positivity: number and percentage of study participants 
that have Baseline positive ADAb sample status, with the denominator for percentages 
defined as all participants having an evaluable (not missing, not inconclusive) Baseline 
ADAb sample.  
Incidence of treatment-emergent ADAb positivity: number and percentage of study 
participants with either treatment boosted ADAb or treatment induced ADAb, with the 
denominator for percentages all participants except those categorized as inconclusive or 
missing (overall for the entire treatment period and then up to and including Week 24). 
Change #36 
Section 8.2.3 Time to first occurrence of treatment-emergent ADAb positivity 
Study participants will be considered to have an event at the first ADAb sampling time point 
with ADAb positive status if the participant is pre-ADAb negative or first ADAb sampling 
time point with fold difference increase from Baseline > 2.1 if participant is pre-ADAb 
positive. Study participants who are never treatment-emergent ADAb positive will be 
censored at the date of the last evaluable (not missing, not inconclusive and not anomalous) 
ADAb sample or on date of first CZP if no evaluable post-treatment ADAb samples. In case 
of pre-ADAb present in more than 10% of the study participants, the table will be produced 
separately for ADAb participant category 2 (induced) and 5 (boosted).   
Was changed to: 
Study participants will be considered to have an event at the first ADAb sampling time point 
with ADAb positive status in the entire treatment period if the participant is Baseline ADAb 
negative or first ADAb sampling time point with fold difference increase from Baseline > 2.1 
if participant is Baseline ADAb positive. Study participants who are never treatment-
emergent ADAb positive will be censored at the date of the last evaluable (not missing, not 
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inconclusive) ADAb sample or on date of first CZP if no evaluable post-treatment ADAb 
samples. In case of Baseline ADAb positivity present in more than 10% of the study 
participants, the table will be produced separately for ADAb participant category 2 (induced) 
and 5 (boosted). 
Change #37 
Section 8.2.4 ECLIA vs ELISA samples was added: 
In line with 
 response, 
the proportion of study participants and the proportion of ADAb samples with sufficient 
volume for re-analysis with the ECLIA method out of all ADAb samples initially analyzed 
with the ELISA method will be summarized.   
First, the number and percentage of study participants with at least one ADAb sample re-
analyzed using the ECLIA method (after previous analysis using the ELISA method) will be 
presented.  For this percentage, the denominator is the number of study participants with at 
least one non-missing ADAb result from the ELISA method and the numerator is the number 
of study participants with at least one non-missing ADAb result from the ECLIA method that 
had also been analyzed with the ELISA method previously. (BLQ is considered a non-
missing result.) 
Second, the number and percentage of baseline and post-baseline ADAb samples that were 
re-analyzed using the ECLIA method (after previous analysis using the ELISA method) will 
be presented separately. For the percentage of baseline and post-baseline re-analyzed ADAb 
samples, the denominator is the number of baseline or post-baseline ADAb samples with 
non-missing ELISA results, respectively. The numerator is the number of baseline or post-
baseline ADAb samples, respectively, with non-missing ECLIA results previously where the 
same ADAb sample had previously been analyzed with the ELISA method. (Below LLOQ is 
considered a non-missing result.) 
Additionally, the proportion of study participants and the proportion of ADAb samples with 
sufficient volume for re-analysis with the ECLIA method out of all ADAb samples analyzed 
with the ECLIA method (either originally or via re-analysis) will be summarized. 
First, the number and percentage of study participants with at least one ADAb sample re-
analyzed using the ECLIA method (after previous analysis using the ELISA method) will  be 
presented.  For this percentage, the denominator is the number of study participants with at 
least one non-missing ADAb sample that was analyzed using the ECLIA method (either 
originally or via re-analyses). The numerator is the number of study participants with at least 
one non-missing ADAb result from the ECLIA method for a sample that had also been 
analyzed with the ELISA method previously.  Also, the number and percentage of study 
participants that did not have any ADAb sample re-analyzed with the ECLIA method will be 
presented.  The denominator is the same, but the numerator is the number of study 
participants for whom all non-missing ADAb results obtained using the ECLIA method were 
on samples that had never been analyzed using the ELISA method. (Below LLOQ is 
considered a non-missing result.) 
Second, the number and percentage of baseline and post-baseline ADAb samples that were 
analyzed using the ECLIA method (after previous analysis using the ELISA method) will be 
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presented.  For this percentage, the denominator is the number of non-missing baseline or 
post-baseline ADAb results, respectively, that were obtained using the ECLIA method (either 
originally or via re-analysis). The numerator is the number of those non-missing baseline or 
post-baseline ADAb results, respectively, that were obtained by re-analysis with the ECLIA 
method, after having been analyzed by the ELISA method previously. Also, the number and 
percentage of those baseline or post-baseline samples, respectively, that were not re-analyzed 
with the ECLIA method (out of those analyzed with the ECLIA method) will be presented. 
The denominator is the same for each, respectively, but the numerator is the number of those 
non-missing baseline or post-baseline ADAb results, respectively, for samples that were only 
ever analyzed using the ECLIA method. (Below LLOQ is considered a non-missing result.) 
All summaries will be provided for the Safety Set and presented for Original CZP Dose, 
Reduced CZP Dose, Complete Original CZP Dose and Complete Reduced CZP Dose by 
baseline weight. 
Change #38 
Section 8.3 CZP plasma concentrations, anti-CZP antibody titers, and PedACR response 
The plots described in this section will be generated on the FAS. Individual participants plots 
displaying CZP plasma concentrations, ADAb titers, JADAS-71 score and maximum 
PedACR response (the highest PedACR response at a given visit) will be produced by visit 
on the same plot. At each time point, the JADAS-71 score and maximum PedACR response 
at that visit will be plotted on a linear scale.  CZP plasma concentration will be plotted on a 
(natural) log scale and ADAb titer will be plotted on a log 2 scale.  CZP dosing and ADAb 
inconclusive values will be flagged in this plot. A vertical line will be plotted when dose was 
changed for the participant. For each study participant, the category of ADAb participant 
status and demographic information at baseline (body weight and age) will be displayed.  
Multi-panel spaghetti plots of individual participant (natural) log CZP plasma concentration 
by visit will be produced separately for each CZP dose (Original CZP dose, Reduced CZP 
dose) and ADAb titer classification and ADAb participant classification. Concomitant MTX 
use will be shown in different line colors and CZP concentrations for which ADAb positive 
samples were positive will be plotted with a red dot.  These individual plots will be repeated 
replacing CZP plasma concentration with maximum PedACR response (linear scale). 
Scatter plots of the plasma CZP concentration at each visit with different colors/symbols 
depending on ADAb participant classification and ADAb titer classification will be produced 
separately for the doses (Original CZP Dose, Reduced CZP Dose). 
Was changed to: 
The plots described in this section that include an efficacy endpoint will be generated on the 
FAS, otherwise on the PK-PPS. Individual participants plots displaying CZP plasma 
concentrations, ADAb titers, and maximum PedACR response (the highest PedACR response 
at a given visit) will be produced by visit on the same plot. At each time point, the maximum 
PedACR response at that visit will be plotted on a linear scale.  CZP plasma concentration 
will be plotted on a (natural) log scale and ADAb titer will be plotted on a log 2 scale.  CZP 
dosing and ADAb inconclusive values will be flagged in this plot. A vertical line will be 
plotted when dose was changed for the study participant. For each study participant, the 
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category of ADAb participant status and demographic information at baseline (body weight 
and age) will be displayed.  
Multi-panel spaghetti plots of individual participant (natural) log CZP plasma concentration 
by visit will be produced separately for each CZP dose (Original CZP dose, Reduced CZP 
dose) and ADAb titer classification and ADAb participant classification for the PK-PPS. 
Concomitant MTX use will be shown in different line colors and CZP concentrations for 
which ADAb positive samples were positive will be plotted with a red dot.  These individual 
plots will be repeated replacing CZP plasma concentration with maximum PedACR response 
(linear scale) on the FAS. 
Scatter plots of the plasma CZP concentration at each visit with different colors/symbols 
depending on ADAb participant classification and ADAb titer classification will be produced 
separately for the doses (Original CZP Dose, Reduced CZP Dose) for the PK-PPS.  
Change #39 
The section name for Section 8.4 PopPK and PK-PD analyses 
Was changed to: 
Section 8.4 PopPK analyses 
Change #40 
Section 9.1 Extent of exposure 
The extent of exposure to study drug will be evaluated by summarizing the total amount of 
CZP received in mg and the total duration of exposure in days. Total duration of exposure 
will be calculated as the date of last dose of study medication – date of first dose of study 
medication + 14 days if administration of CZP is Q2W, +28 days if administration of CZP is 
Q4W. 
Subject time at risk will also be calculated. Subject time at risk represents the time a subject 
is at risk for having an AE. Subject time (in days) at risk will generally be calculated as (date 
of the last dose of study medication – date of the first dose of study medication + 70 days) 
(70 days = 5 CZP half-lives).  However, the calculation of subject time at risk will be 
modified for study participants who change from Original CZP Dose to Reduced CZP Dose, 
or who dose escalate from Reduced CZP Dose to the Original CZP Dose. For the period of 
exposure prior to a dose change, subject time at risk ends on the date of dose change (ie, do 
not add 70 days).  For the period of exposure on the final CZP dose for a study participant, 
time at risk should include the additional 70 days.  Subject years at risk will be calculated as 
subject time at risk (in days) divided by 365.25. 
Duration of exposure and subject time at risk will be calculated as appropriate for each of the 
following CZP dose groups: 
• Reduced CZP Dose: includes period of exposure to the Reduced CZP Dose for all 
study participants enrolled on the Reduced CZP Dose; the exposure ends on the date 
of dose escalation or last dose of Reduced CZP Dose.  The exposure calculation is 
Date of Dose Escalation or Last Dose of Reduced CZP – Date of First Dose + 14 or 
28 days depending on administration of CZP. 
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• Original CZP Dose: includes period of exposure to the Original CZP Dose for all 
study participants enrolled on the Original CZP Dose; the exposure ends on the date 
of dose reduction or Last Dose of Original CZP.  The exposure calculation is Date of 
Dose Reduction or Last Dose of Original CZP – Date of First Dose of CZP +14 or 28 
days depending on administration of CZP.  
• Any CZP Dose: includes the exposure to all CZP doses for all treated study 
participants; the exposure period is calculated using the formulas above depending on 
whether the subject took a Q2W or Q4W dose. 
Study drug exposure will be summarized for the Reduced CZP Dose, Original CZP Dose, and 
Any CZP Dose groups. Exposure will be presented as follows: >0 months, ≥6 months, ≥12 
months, ≥24 months, ≥36 months, ≥48 months and ≥60 months. 
Was changed to: 
Over the course of the RA0043 study, study participants follow one of 5 dosing scenarios for 
CZP exposure: 
Table 13‒10: 
Dosing periods 
Starting the study 
taking: 
1st dosing period (of 
variable length) 
2nd dosing period (of 
variable length) 
3rd dosing period (of 
variable length) 
Reduced CZP dose 
Reduced CZP (A) 
 
 
 
Reduced CZP (B) -> 
Original CZP (E) 
 
Original CZP dose 
Original CZP (F) 
 
 
 
Original CZP (G) -> 
Reduced CZP (C) 
 
 
Original CZP (H) -> 
Reduced CZP (D) - > 
Original CZP (J) 
 
The extent of exposure to study drug will be evaluated by summarizing the total amount of 
CZP received in mg and the total duration of exposure in days. Total duration of exposure 
will be calculated using this general formula as: the Date of Last Dose of study medication – 
Date of First Dose of study medication + 14 days if administration of CZP is Q2W, +28 days 
if administration of CZP is Q4W. 
 
Duration of exposure will be calculated as appropriate for each of the following dosing 
periods: 
A: use the general formula; 
B: Date of Escalation – Date of First Dose; 
C: Date of Last Dose – Date of Dose Reduction +14 or 28 days depending on administration 
of CZP; 
D: Date of Escalation – Date of Reduction; 
E: Date of Last Dose – Date of Dose Escalation + 14 or 28 days depending on administration 
of CZP; 
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F: use the general formula; 
G: Date of Dose Reduction – Date of First Dose; 
H: Date of Dose Reduction – Date of First Dose; 
J: Date of Last Dose – Date of Dose Escalation + 14 or 28 days depending on administration 
of CZP 
Duration of exposure will be calculated as appropriate for each of the following CZP Dose 
groups: 
• Any CZP Dose: includes the exposure to all CZP doses for all treated study participants; 
the exposure period is calculated using the general formula. 
• Reduced CZP Dose: includes period of exposure to the Reduced CZP Dose for all study 
participants enrolled on the Reduced CZP dose; use the following formulas:  
− Period A - for study participants without dose escalation; and 
− Period B - for study participants with dose escalation.  
• Original CZP Dose: includes period of exposure to the Original CZP Dose for all study 
participants enrolled on the Original CZP Dose; use the following formulas:  
− Period F - for study participants without dose reduction;  
− Period G - for study participants with dose reduction and without dose escalation; and 
− Period H - for study participants with dose reduction and dose escalation. 
• Complete Reduced CZP Dose: includes all periods of exposure to Reduced CZP Dose for 
all study participants (periods A, B, C and D); use the following formulas:  
− Period A - for study participants enrolled on Reduced CZP Dose without dose 
escalation;  
− Period B - for study participants enrolled on Reduced CZP Dose with dose escalation; 
− Period C - for study participants enrolled on Original CZP Dose with dose reduction 
and without dose escalation; and 
− Period D - for study participants enrolled on Original CZP Dose with dose reduction 
and dose escalation. 
• Complete Original CZP Dose: includes all periods of exposure to Original CZP dose for 
all study participants (periods E, F, G H and J); use the following formulas:  
− Period E - for study participants enrolled on Reduced CZP Dose with dose escalation; 
− Period F - for study participants enrolled on Original CZP Dose without dose 
reduction;  
− Period G - for study participants enrolled on Original CZP Dose with dose reduction 
and without dose escalation; and 
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− Period H+J - for study participants enrolled on Original CZP Dose with dose 
reduction and dose escalation.   
13.5.1 
Subject time at risk 
Subject time at risk will also be calculated. Subject time at risk represents the time a study 
participant is at risk for having an AE. Subject time (in days) at risk will generally be 
calculated using this general formula: (date of the last dose of study medication – date of the 
first dose of study medication + 70 days) (70 days = 5 CZP half-lives).  However, the 
calculation of subject time at risk will be modified for study participants who change from 
Original CZP Dose to Reduced CZP Dose, or who dose escalate from Reduced CZP Dose to 
the Original CZP Dose. For the period of exposure prior to a dose change, subject time at risk 
ends on the date of dose change (ie, do not add 70 days).  For the period of exposure on the 
final CZP dose for a study participant, time at risk should include the additional 70 days.  
Subject years at risk will be calculated as subject time at risk (in days) divided by 365.25. 
Subject time at risk will be calculated as appropriate for each of the following CZP dosing 
periods: 
A: use the general formula; 
B: Date of Escalation – Date of First Dose; 
C: Date of Last Dose – Date of Dose Reduction +70 days; 
D: Date of Escalation – Date of Reduction; 
E: Date of Last Dose – Date of Dose Escalation + 70 days; 
F: use the general formula; 
G: Date of Dose Reduction – Date of First Dose; 
H: Date of Dose Reduction – Date of First Dose; 
J: Date of Last Dose – Date of Dose Escalation + 70 days; 
Subject time at risk will be calculated as appropriate for each of the following CZP Dose 
groups; 
• Any CZP Dose: includes the time at risk to all CZP doses for all treated study 
participants; the time at risk is calculated using the general formula. 
• Reduced CZP Dose: includes time at risk during the exposure to the Reduced CZP Dose 
for all study participants enrolled on the Reduced CZP dose up to the first dose change; 
use the following formulas:  
− Period A - for study participants without dose escalation; and 
− Period B - for study participants with dose escalation.  
• Original CZP Dose: includes time at risk during the exposure to the Original CZP Dose 
for all study participants enrolled on the Original CZP Dose up to the first dose change; 
use the following formulas:  
− Period F - for study participants without dose reduction;  
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− Period G - for study participants with dose reduction and without dose escalation; and 
− Period H - for study participants with dose reduction and dose escalation. 
• Complete Reduced CZP Dose: includes time at risk during all periods of exposure to 
Reduced CZP Dose for all study participants (periods A, B, C and D); use the following 
formulas:  
− Period A - for study participants enrolled on Reduced CZP Dose without dose 
escalation;  
− Period B - for study participants enrolled on Reduced CZP Dose with dose escalation; 
− Period C - for study participants enrolled on Original CZP Dose with dose reduction 
and without dose escalation; and 
− Period D - for study participants enrolled on Original CZP Dose with dose reduction 
and dose escalation. 
• Complete Original CZP Dose: includes all time at risk during all periods of exposure to 
Original CZP dose for all study participants (periods E, F, G H and J); use the following 
formulas:  
− Period E - for study participants enrolled on Reduced CZP Dose with dose escalation; 
− Period F - for study participants enrolled on Original CZP Dose without dose 
reduction;  
− Period G - for study participants enrolled on Original CZP Dose with dose reduction 
and without dose escalation; and 
− Period H+J - for study participants enrolled on Original CZP Dose with dose 
reduction and dose escalation.   
 
The extent of study drug exposure will be summarized for the Reduced CZP Dose, Original 
CZP Dose, and Any CZP Dose groups. Exposure over time will be presented as follows: >0 
months, ≥6 months, ≥12 months, ≥24 months, ≥36 months, ≥48 months, ≥60 months, 
≥72months, ≥84 months, and ≥96 months.  In line with 
 
 response, the extent of study drug exposure as well as 
exposure over time will be presented by Complete Original CZP Dose and Complete 
Reduced CZP Dose.  
Study medication administration will be listed. 
Change #41 
Section 9.2 Adverse events 
All AEs will be classified by SOC, HLT and PT according to the version of MedDRA® that is 
current to the sponsor at the time of data capture. A glossary for the TEAE listing will detail 
the verbatim terms that are coded to each SOC, HLT, and PT. 
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Treatment-related TEAEs are those with relationship to study medication of “Related” or 
“Possibly related” or those with a missing relationship.  Severe TEAEs are those with an 
intensity of “Severe” or those with a missing intensity. 
All TEAE summaries will be provided for the Reduced CZP Dose, Original CZP Dose, and 
Any CZP Dose groups. TEAEs occurring on the day of dose reduction or dose escalation, 
respectively, will be reviewed by the study physician in order to assign events to the most 
appropriate time period (before or after dose reduction or dose escalation, respectively). 
Was changed to: 
A glossary for the TEAE listing will detail the verbatim terms that are coded to each SOC, 
HLT, and PT. 
Treatment-related TEAEs are those with relationship to study medication of “Related” or 
“Possibly related” or those with a missing relationship.  Severe TEAEs are those with an 
intensity of “Severe” or those with a missing intensity. 
All TEAE summaries will be provided for the Reduced CZP Dose, Original CZP Dose, and 
Any CZP Dose groups. TEAEs occurring on the day of dose reduction or dose escalation, 
respectively, will be summarized in the dose groups that it appears. 
Change #42 
Section 9.2 Adverse events, the following sentence was added: 
In line with 
 response, 
incidence tables of TEAEs will be presented by primary SOC, PT, overall and Baseline 
weight group by Original CZP, Reduced CZP, Any CZP, Complete Original CZP and 
Complete Reduced CZP doses. 
Change #43 
Section 9.2.1 Adverse events 
2) Malignancies, including lymphoma. These will be presented in 2 tables using the criteria 
SMQ = “Malignant or unspecified tumours” and SMQ=”Malignant tumours”, respectively. 
Was changed to: 
2) Malignancies, including lymphoma. These will be presented in 2 tables using the criteria 
SMQ = “Malignant or unspecified tumours” and its subset, SMQ=”Malignant tumours”, 
respectively. 
Change #44 
Section 9.2.3 Covid vaccine sensitivity analysis 
The list of TEAEs to be excluded if reported with Mild or Moderate intensity are: 
Was changed to: 
The list of the PTs of these TEAEs to be excluded if reported with Mild or Moderate intensity 
are: 
Change #45 
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Section 9.3 Clinical laboratory evaluations 
All laboratory summaries described in this section will be provided  for Reduced CZP Dose, 
Original CZP Dose, and Any CZP Dose) and by Baseline weight group. 
Descriptive statistics for observed values and change from Baseline will be presented for 
each visit for the following hematology and biochemistry parameters: 
• Hematology: RBC, hemoglobin, hematocrit, platelets, WBC, neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils. 
• Biochemistry: sodium, potassium, chloride, bicarbonate, total calcium, inorganic 
phosphorus, creatinine kinase, glucose, creatinine, uric acid, urea, total protein, albumin, 
ALP, gamma glutamyl transferase (γ-GT), AST, ALT, lactate dehydrogenase, bilirubin, 
and total cholesterol. 
The following urinalysis parameters will be tested locally only: pH, protein, glucose, and 
blood. If abnormalities are found from the dipstick test, microscopy (WBC, RBC, casts, 
crystals, and bacteria) will be performed, and these results will be listed. A summary of the 
shift from Baseline to end of treatment will also be provided for hematology and 
biochemistry parameters. Results will be classified as low, normal, or high based on the 
normal ranges provided by the central laboratory. 
A summary of the incidence of markedly abnormal laboratory results by visit will be 
presented for hematology and biochemistry parameters.  Details of markedly abnormal values 
will be listed by subject and parameter for hematology and biochemistry variables for which 
there is at least 1 markedly abnormal result recorded. Definitions of markedly abnormal 
values are adopted from the UCB Central Nervous System Clinical and Laboratory Possibly 
Clinically Significant Treatment Emergent Criteria and are given below Table 9‒3 for 
markedly abnormal hematology values and Table 9‒4 for markedly abnormal biochemistry 
values). 
Was changed to: 
All laboratory summaries described in this section will be provided for Reduced CZP Dose, 
Original CZP Dose, and Any CZP Dose and by Baseline weight group. All laboratory data 
will be listed. 
Descriptive statistics for observed values and change from Baseline will be presented for 
each visit for the following hematology and biochemistry parameters: 
• Hematology: RBC, hemoglobin, hematocrit, platelets, WBC, neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils. 
• Biochemistry: sodium, potassium, chloride, bicarbonate, total calcium, inorganic 
phosphorus, creatinine kinase, glucose, creatinine, uric acid, urea, total protein, albumin, 
ALP, gamma glutamyl transferase (GGT), AST, ALT, lactate dehydrogenase, bilirubin, 
and total cholesterol. 
The following urinalysis parameters will be tested locally only: pH, protein, glucose, and 
blood. If abnormalities are found from the dipstick test, microscopic analysis (WBC, RBC, 
casts, crystals, and bacteria) will be performed, and these results will be listed. A summary of 
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the shift from Baseline to end of treatment will also be provided for hematology and 
biochemistry parameters. Results will be classified as low, normal, or high based on the 
normal ranges provided by the central laboratory. 
A summary of the incidence of markedly abnormal laboratory results by visit will be 
presented for hematology and biochemistry parameters.  Details of markedly abnormal values 
will be listed by study participant and parameter for hematology and biochemistry variables 
for which there is at least 1 markedly abnormal result recorded. Definitions of markedly 
abnormal values are adopted from the UCB Therapeutic Area: Central Nervous System : 
Clinical and Laboratory Markedly Abnormal (MA) Values and are given below Table 9‒3 for 
markedly abnormal hematology values and Table 9‒4 for markedly abnormal biochemistry 
values).  
Change #46 
Section 9.3 Clinical laboratory evaluations, the following sentence was added: 
Any data that is captured as being a suspected hepatic event will be listed. 
Change #47 
Section 9.4.1 Vital signs 
A summary of the incidence of markedly abnormal vital signs results by visit will be 
presented for temperature, blood pressure, and pulse rate parameters.  Details of markedly 
abnormal values will be listed by subject and parameter for which there is at least 1 markedly 
abnormal result recorded. Definitions of markedly abnormal values are given below in 
Table 9‒5. 
Markedly abnormal high temperature is >40.0 degrees Celsius (>104.0 degrees Fahrenheit) 
while a markedly abnormal low temperature is 32 – 35 degrees Celsius (89.6 – 95 degrees 
Fahrenheit). 
Was changed to: 
A summary of the incidence of markedly abnormal vital signs results by post-baseline 
scheduled visit will be presented for temperature, blood pressure, and pulse rate parameters.  
Details of markedly abnormal values will be listed by study participant and parameter for 
which there is at least 1 markedly abnormal result recorded. Definitions of markedly 
abnormal values are given below in Table 9‒5. 
Markedly abnormal high temperature is >40.0 degrees Celsius (>104.0 degrees Fahrenheit) 
while a markedly abnormal low temperature is 32 – 35 degrees Celsius (89.6 – 95 degrees 
Fahrenheit). Vital signs data will be listed, including the flagging of markedly abnormal 
values. 
Change #48 
Section 9.4.2.2 Tanner stages 
A summary of shift table of Tanner stages from baseline to relevant post-treatment visit(s) 
(eg., 48 week) by age and gender will be provided for the Reduced CZP Dose, Original CZP 
Dose, and Any CZP Dose. 
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Was changed to: 
A summary of shift table of Tanner stages from baseline to relevant post-treatment visit(s) 
(48 week, 96 week, etc) by age and gender will be provided for the Reduced CZP Dose, 
Original CZP Dose, and Any CZP Dose. 
Change #49 
Section 9.4.2.5 Autoantibodies 
Autoantibodies (ANA and anti-dsDNA) will be assessed at Baseline, Weeks 16 and 48, and 
Early Discontinuation/EOT. For ANA antibodies, normal corresponds to dilutions of <1:160 
and antibodies present corresponds to dilutions of 1:160 or higher. A summary of the 
cumulative shift from the Baseline through the Early Discontinuation/EOT Visit will be 
summarized for both the ANA and anti-dsDNA antibodies.   
All autoantibodies summaries will be provided for the Reduced CZP Dose, Original CZP 
Dose, and Any CZP Dose) and by Baseline weight group. 
Was changed to: 
Autoantibodies (ANA and anti-dsDNA) will be assessed at Baseline, Weeks 16 and 48, and 
Early Discontinuation/EOT. For ANA antibodies, normal corresponds to dilutions of <1:160 
and antibodies present corresponds to dilutions of 1:160 or higher. A summary of the 
maximum shift from the Baseline to anytime while on CZP treatment will be summarized for 
both the ANA and anti-dsDNA antibodies.   
All autoantibodies summaries will be provided for the Reduced CZP Dose, Original CZP 
Dose, and Any CZP Dose) and by Baseline weight group. All autoantibody assay data will be 
listed. 
Change #50 
Section 10 Efficacy analyses 
For subgroup efficacy analyses, summaries by Baseline age group, concomitant MTX use, 
and ADAb status will be presented pooling across all weight groups unless otherwise 
specified. 
Was changed to: 
For subgroup efficacy analyses, summaries by Baseline age group, concomitant MTX use, 
and ADAb titer classification will be presented pooling across all weight groups unless 
otherwise specified. 
Change #51 
Section 10.3.13.2 Final Analysis 
Descriptive statistics of the observed values and change from Baseline will be presented 
separately for the acute and standard versions for each of the specified visits. 
Was changed to: 
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Descriptive statistics of the observed values and change from Baseline will be presented 
separately for the acute and standard versions (See Protocol Amendment 9, Section 11.13) for 
each of the specified visits. 
Change #52 
Section 12.1 Comparisons with RA0138 data 
Comparisons between RA0043 and RA0138 data will focus on common timepoints (Weeks 
12 and 24).  
Separate boxplots will be performed for Week 12 and Week 24 showing plasma CZP 
concentrations for the two CZP dose groups (Original or Reduced) for RA0043 and the single 
CZP dose group for RA0138 in the same plot. The plots will be repeated separately by 
Baseline weight group, Baseline age group and concomitant MTX use. 
Was changed to: 
Comparisons between RA0043 and RA0138 data will focus on common timepoints (Weeks 
12 and 24).  The dose groups that will be compared are the Original CZP Dose and the 
Reduced CZP Dose from RA0043 (Section 3.1) and the 200 mg Q2W maintenance dose from 
RA0138. 
Separate boxplots will be performed for Week 12 and Week 24 showing plasma CZP 
concentrations for the two CZP dose groups (Original CZP Dose or Reduced CZP Dose) for 
RA0043 and the single CZP dose group for RA0138 in the same plot. Box plots of the PK 
concentrations at Weeks 12 and 24 will be presented by CZP dose group for Baseline weight 
group, Baseline age group, ADAb participant status classification, ADAb titer classification, 
and concomitant MTX use in combination with Baseline weight group. In the box plots the 
5th and 95th percentiles of the concentrations distribution will be shown. 
 
13.6 
AMENDMENT 6 
Rationale for the amendment 
The primary reasons for this SAP amendment was to: 
• pJIA was changed to pcJIA throughout the SAP, 
• Update clarifications as to which analyses were done for the Updated Week 24 Interim 
Analysis vs the Final Analysis, 
• In demographics, add a summary by country of enrollment, 
• Clarify the algorithm for calculating treatment compliance (adjusting calculation for when 
study participants are in clinical remission), 
• Clarify how data will be treated when study participants have large gaps in study 
medication dosing (eg TEAEs, time at risk), 
• Clarify the algorithm for flagging important and non-important protocol deviations when 
study participants are off study medication, 
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• Clarify that only data for n≥20 study participants for the Any CZP Dose group will be 
shown in by visit (week) summaries for all three dose groups 
• Add a new AE table, AE listings and an additional laboratory test listing, and 
• Update as to which questions from the Juvenile Arthritis School Attendance and 
Caregiver Work Productivity Survey will be summarized in tables, 
Modifications and changes 
Global changes 
pJIA was changed to pcJIA thoughout the SAP. Analyses that were completed for the 
Updated Week 24 Interim Analysis were indicated when they would not be repeated for the 
final analysis. 
Specific changes 
Change #1 
SAP/Amendment  
Date 
Final SAP 
23 Jun 2015 
SAP Amendment 1 
29 Sep 2015 
SAP Amendment 2 
24 Jun 2016 
SAP Amendment 3 
30 Jun 2021 
SAP Amendment 4 
8 Dec 2022 
SAP Amendment 5 
21 Jun 2023 
Has been changed to: 
SAP/Amendment  
Date 
Final SAP 
23 Jun 2015 
SAP Amendment 1 
29 Sep 2015 
SAP Amendment 2 
24 Jun 2016 
SAP Amendment 3 
30 Jun 2021 
SAP Amendment 4 
8 Dec 2022 
SAP Amendment 5 
21 Jun 2023 
SAP Amendment 6 
23 May 2024 
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Change #2 
CRM 
clinical remission on medication 
was changed to: 
CRM 
derived clinical remission (previously referred to as 
clinical remission on medication)  
Change #3 
Section 1 Introduction 
This document describes the planned analyses and summary tables, figures, and listings to be 
included in the final clinical study report (CSR) for RA0043 as well as for the Updated Week 
24 interim analysis and other analyses supporting marketing applications. Note that the Week 
16 interim analysis and the 2016 Week 24 interim analyses were completed as specified in 
SAP Amendment 1 and text about these analyses will be kept as is. 
If a future protocol amendment necessitates a substantial change to the statistical analysis of 
the study data, this statistical analysis plan (SAP) will be amended accordingly. If, after the 
final database lock, additional analyses are required to supplement the planned analyses 
described in this SAP, those unplanned analyses will not be described in an amended SAP, 
but they will be identified in the CSR. Any deviations from this SAP will be documented in 
the CSR. 
Was changed to: 
This document describes the planned analyses and summary tables, figures, and listings to be 
included in the final clinical study report (CSR) for RA0043 as well as for the Updated Week 
24 Interim Analysis and other analyses supporting marketing applications; specific analyses 
added just for the Updated Week 24 Interim Analysis have been updated to say that they were 
only generated for that analysis Note that the Week 16 interim analysis and the 2016 Week 
24 interim analyses were completed as specified in SAP Amendment 1 and text about these 
analyses will be kept as is. 
If, after the final database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, those unplanned analyses will not be described in an 
amended SAP, but they will be identified in the CSR. Any deviations from this SAP will be 
documented in the CSR. 
Change #4 
Section 2 Protocol Summary 
• Reduced CZP Dose – includes all data for study participants enrolled on Reduced CZP 
Dose prior to the first change in dosage 
• Complete Original CZP Dose – includes all data for study participants who took Original 
CZP Dose prior to the first change in dosage as well as the data from when study 
participants increased their dosage to Original CZP after taking Reduced CZP Dose 
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• Reduced CZP Dose – includes all data for study participants enrolled on Reduced CZP 
Dose prior to the first change in dosage 
For the Updated Week 24 Interim Analysis only, study participants were also summarized by 
the following 2 dose groups: 
• Complete Original CZP Dose – includes all data for study participants who took Original 
CZP Dose prior to the first change in dosage as well as the data from when study 
participants increased their dosage to Original CZP after taking Reduced CZP Dose 
Change #5 
Section 2, Protocol Summary 
 
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Change #6 
Section 2.2.3.4 Additional other variables 
Additional variables that were covered under other variables that will be specifically analyzed 
and intended to be used for comparison purposes to support the regulatory submission 
include: 
Was changed to: 
Additional variables that were covered under other variables that were specifically analyzed 
in the Updated Week 24 Interim Analysis only and were used for comparison purposes to 
support the regulatory submission include: 
Change #7 
Section 2.3 Study design and conduct 
The study consists of a Screening Period of up to 4 weeks; eligible study participants will 
then enter an open-label Treatment Period which will continue until the approval of the 
marketing application for the indication of pJIA in the study participant’s country or region or 
until further notice from UCB.  A Final Visit will be conducted 12 weeks after last dose of 
study medication. 
Was changed to: 
The study consists of a Screening Period of up to 4 weeks; eligible study participants will 
then enter an open-label Treatment Period which will continue until the approval of the 
marketing application for the indication of pcJIA in the study participant’s country or region 
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or closing the study by UCB.  A Final Visit will be conducted 12 weeks after last dose of 
study medication. 
Change #8 
Table 2-3: Dosing administration of CZP: the following footnote was added to the table: 
bNote that for Reduced Dose, 10 to <20kg study participants, maintenance dosing started at Week 8. 
Change #9 
Section 2.3 Study design and conduct 
A validated ECLIA method that meets the standards set in the regulatory guidance for 
analytical procedures and methods validations for drugs and biologics will be used for any 
new analyses, including re-analysis of archived samples collected before Protocol 
Amendment 9 and for the analysis of bio-samples collected from the additional 30 study 
participants after Protocol Amendment 9. 
Was changed to: 
A validated ECLIA method that meets the standards set in the regulatory guidance for 
analytical procedures and methods validations for drugs and biologics was introduced after 
Protocol Amendment 9, it has been used for all new analyses, including re-analysis of 
archived samples collected before Protocol Amendment 9 and for the analysis of bio-samples 
collected from the additional 30 study participants after Protocol Amendment 9. 
Change #10 
Section 2.3 Study design and conduct 
Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
pJIA at both the Reduced and Original CZP Doses and support the safety for the Original 
CZP Dose, as more of the safety data collected in the study to date has been on the reduced 
dose, 30 additional study participants will be enrolled on the Original CZP Dose following 
Protocol Amendment 9.  
All study participants enrolled following Protocol Amendment 9 will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using the ECLIA method. In 
addition, PK and ADAb samples (for which sufficient volume is available) collected in this 
study prior to Protocol Amendment 9 will be analyzed with the ECLIA method. The 
collective ECLIA-based PK data for this study will form the basis of any future CZP 
modeling and simulation work. 
Full interim analyses were performed in 2016 after all active study participants completed the 
Week 24 (Visit 10) assessments.  Week 24 full interim analyses were completed as described 
in SAP Amendment 1. SAP Amendment 4 comprises the analyses to be completed for an 
Updated Week 24 (Visit 10) interim analysis including the 30 new study participants enrolled 
after Protocol Amendment 9, any interim analyses to support marketing applications and the 
final analysis of the study. 
Was changed to: 
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Therefore, in order to adequately assess the exposure levels and clinical experience of CZP in 
pcJIA at both the Reduced and Original CZP Doses and support the safety for the Original 
CZP Dose, as more of the safety data collected in the study prior to Amendment 9 were on 
the reduced dose, 30 additional study participants have been enrolled on the Original CZP 
Dose following Protocol Amendment 9.  
All study participants enrolled following Protocol Amendment 9 will have plasma 
concentrations of CZP and anti-CZP antibodies analyzed using the ECLIA method. In 
addition, PK and ADAb samples (for which sufficient volume is available) collected in this 
study prior to Protocol Amendment 9 will be analyzed with the ECLIA method. The 
collective ECLIA-based PK data for this study will form the basis of any future CZP PK 
analysis, and was the basis for the modeling and simulation work that supported the interim 
PK analysis in 2023 and the 2024 submission. 
Full interim analyses were performed in 2016 after all active study participants completed the 
Week 24 (Visit 10) assessments.  Week 24 full interim analyses were completed as described 
in SAP Amendment 1. An Updated Week 24 (Visit 10) interim analysis, including the 30 
new study participants enrolled after Protocol Amendment 9, was completed as described in 
SAP Amendments 4, 5, and 6. The final analysis will be completed as described in SAP 
Amendment 6. 
Change #11 
Section 2.4 Determination of sample size 
Available ECLIA-based data from all study participants will be included in the final PopPK 
analysis as described in a separate Data Analysis Plan and reported separately, and therefore 
should allow CL/F and V/F to be determined with sufficient precision. 
Was changed to: 
Available ECLIA-based data from all study participants were included in the final PopPK 
analysis as described in a separate Data Analysis Plan and reported separately for the 
Updated Week 24 Interim Analysis only. 
Change #12 
Section 2.5 Study RA0138 
RA0138 is an open-label study in 33 adult study participants with RA who took 400mg 
loading dose (Weeks 0, 2, and 4), followed by 200mg CZP Q2W.  This study was conducted 
to generate PK and ADAb data using the same ECLIA assay as used in RA0043 to form the 
basis of “PK-matching” for CZP approval. The PK and ADAb data from RA0138 will be 
analyzed and displayed in the same manner as data from RA0043 so that comparisons and 
conclusions can be made.  Those details will be presented in the Appendix, Section 12.1. 
Was changed to: 
RA0138 is an open-label study in 33 adult study participants with RA who took 400mg 
loading dose (Weeks 0, 2, and 4), followed by 200mg CZP Q2W.  This study was conducted 
to generate PK and ADAb data using the same ECLIA assay as used in RA0043 to form the 
basis of “PK-matching” for CZP approval. For Updated Week 24 Interim Analysis, the PK 
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and ADAb data from RA0138 was analyzed and displayed in the same manner as data from 
RA0043; comparisons and conclusions were made.  Those details are presented in the 
Appendix, Section 12.1. 
Change #13 
Section 3.1 General presentation of summaries and analyses 
Generally, data will be summarized by the Original CZP Dose, Reduced CZP Dose, and Any 
CZP Dose groups.  For PK and ADAb analyses, data will be summarized by Original CZP 
Dose and Reduced CZP Dose only.  
Following recommendations received from 
 
, a few data summaries will be organized by "Complete" CZP dose groups defined 
below, which will allow assessment of exposure and safety for all time that study participants 
were receiving the specified dose regardless of dose switching: 
• Complete Original CZP Dose: includes all study participants who began treatment in 
accordance with the Original CZP Dose, as well as study participants who began 
treatment in accordance with the Reduced CZP Dose and then later dose escalated to the 
Original CZP Dose. 
 
Only data obtained while the study participant was receiving the Original CZP Dose will 
be included in summaries of the Complete Original CZP Dose. For study participants who 
began treatment with the Original CZP Dose, this includes time on the Original CZP 
Dose prior to first change in dosage, as well as time after returning to Original CZP Dose 
after a previous dose reduction. For study participants who began treatment with the 
Reduced CZP Dose, this includes only time after dose escalation to the Original CZP 
Dose. 
• Complete Reduced CZP Dose: includes all study participants who began treatment in 
accordance with the Reduced CZP Dose, as well as study participants who began 
treatment in accordance with the Original CZP Dose and later dose reduced to the 
Reduced CZP Dose. 
 
Only data obtained while the study participant was receiving the Reduced CZP Dose will 
be included in summaries of the Complete Reduced CZP Dose. For study participants 
who began treatment with the Reduced CZP Dose, this includes time on the Reduced 
CZP Dose prior to first change in dosage. For study participants who began treatment 
with the Original CZP Dose, this includes only time after dose reduction to the Reduced 
CZP Dose, and prior to any potential later dose escalation back to the Original CZP Dose. 
 
Selected exposure and TEAE summaries will be produced on Complete Original CZP Dose 
and Complete Reduced CZP Dose in order to answer specific agency questions. Similarly, 
summaries of the proportion of PK and ADAb samples and participants that have been 
reanalyzed with the ECLIA assay will also be produced with this treatment association. 
Further details regarding these displays based upon dose groups can be found in the 
respective PK, safety and efficacy analysis sections below. 
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Categorical data will be presented as summary tables. A missing category will be included as 
applicable.   
Continuous variables will be summarized with the mean, standard deviation, median, 
minimum, and maximum. For CZP plasma concentrations and CRP, the geometric mean and 
geometric coefficient of variation (CV) will be presented. 
Was changed to: 
Generally, data will be summarized by the Original CZP Dose, Reduced CZP Dose, and Any 
CZP Dose groups.  For PK and ADAb analyses, data will be summarized by Original CZP 
Dose and Reduced CZP Dose only. For the Juvenile Arthritis School Attendance and 
Caregiver Work Productivity Survey, data will be summarized by Any CZP Dose group only. 
Following recommendations received from 
 
, a few data summaries were organized for the Updated Week 24 Interim Analysis 
only, by "Complete" CZP dose groups defined below, which allowed assessment of exposure 
and safety for all time that study participants were receiving the specified dose regardless of 
dose switching: 
• Complete Original CZP Dose: included all study participants who began treatment in 
accordance with the Original CZP Dose, as well as study participants who began 
treatment in accordance with the Reduced CZP Dose and then later dose escalated to the 
Original CZP Dose. 
 
Only data obtained while the study participant was receiving the Original CZP Dose was 
included in summaries of the Complete Original CZP Dose. For study participants who 
began treatment with the Original CZP Dose, this included time on the Original CZP 
Dose prior to first change in dosage, as well as time after returning to Original CZP Dose 
after a previous dose reduction. For study participants who began treatment with the 
Reduced CZP Dose, this included only time after dose escalation to the Original CZP 
Dose. 
• Complete Reduced CZP Dose: included all study participants who began treatment in 
accordance with the Reduced CZP Dose, as well as study participants who began 
treatment in accordance with the Original CZP Dose and later dose reduced to the 
Reduced CZP Dose. 
 
Only data obtained while the study participant was receiving the Reduced CZP Dose was 
included in summaries of the Complete Reduced CZP Dose. For study participants who 
began treatment with the Reduced CZP Dose, this included time on the Reduced CZP 
Dose prior to first change in dosage. For study participants who began treatment with the 
Original CZP Dose, this included only time after dose reduction to the Reduced CZP 
Dose, and prior to any potential later dose escalation back to the Original CZP Dose. 
 
Selected exposure and TEAE summaries were produced on Complete Original CZP Dose and 
Complete Reduced CZP Dose in order to answer specific agency questions. Similarly, 
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summaries of the proportion of PK and ADAb samples and participants that have been 
reanalyzed with the ECLIA assay were also produced with this treatment association. 
Further details regarding these displays based upon dose groups can be found in the 
respective PK, safety and efficacy analysis sections below. 
Categorical data will be presented as summary tables. A missing category will be included as 
applicable.   
Continuous variables will be summarized with the mean, standard deviation, median, 
minimum, and maximum. For CZP plasma concentrations and CRP, the geometric mean and 
geometric coefficient of variation (CV) will be presented.     
Due to shifts in visit schedules per protocol amendments that were adopted at different times 
for different sites and study participants, some visits/ time points had very few study 
participants assessed. For categorical and continuous efficacy variables presented by 
visit/time point, if the visit/time point for the Any CZP Dose group contains 19 or fewer 
study participants with non-missing data, those visits/ time points will not be displayed in the 
efficacy tables or plotted in figures for Reduced CZP Dose, Original CZP Dose and Any CZP 
Dose groups.  All information will appear in the listings. 
Change #14 
Section 3.2.2 Relative day 
Relative day after last dose will have the prefix “+”, and will be calculated from the date of 
last CZP administration (date X - date of last CZP administration). Relative day will not be 
calculated when any part of a corresponding date is missing, and will not be included in 
corresponding datasets, tables and listings. 
Was changed to: 
Relative day after last dose will have the prefix “+”,and will be calculated from the date of 
last CZP administration (date X - date of last CZP administration). Relative day will not be 
calculated when any part of a corresponding date is missing,and will not be included in 
corresponding tables and listings. 
Change #15 
Section 3.4 Protocol deviations, the following was added: 
Study participants, if taking CZP Q2W, should be dosed 9 to 19 days from the previous 
dosing; if taking CZP Q4W, study participants should be dosed 23 to 33 days from the 
previous dosing. Study participants who are taking CZP Q2W, if they have instances where 
they take their study medication > 42 days from the last dosing, or for those who are taking 
CZP Q4W, if they have instances where they take their study medication > 84 days from the 
last dosing, these instances will be flagged as important protocol deviations.  For study 
participants not in derived CRM and taking CZP Q2W, gaps less than 9 days or >19 to 42 
days will be considered as protocol deviations. For study participants not in derived CRM 
and taking CZP Q4W, gaps less than 23 days or >33 to 84 days will be considered as protocol 
deviations. 
Change #16 
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Section 3.5 Exclusion of PK data points 
• Study participant being in Clinical remission (and not taking CZP), 
Was changed to: 
• Study participant being in derived CRM (and not taking CZP), 
Change #17 
Section 3.5.4 Pharmacokinetic Per-Protocol (PK-PP) Set 
The Pharmacokinetic Per-Protocol (PK-PP) Set is a subset of the SS consisting of those study 
participants who took at least 1 dose of study medication, provided measurable plasma CZP 
concentration samples (with recorded sampling date/time or for which date/time can be 
reasonably assumed and it was analyzed using the ECLIA method) on at least 1 occasion. 
The PK-PP Set will be used for the PopPK model that will be described in a separate data 
analysis plan (DAP) and for all presentations of plasma concentration. 
Was changed to: 
The Pharmacokinetic Per-Protocol (PK-PP) Set is a subset of the SS consisting of those study 
participants who took at least 1 dose of study medication, provided measurable plasma CZP 
concentration samples (with recorded sampling date/time or for which date/time can be 
reasonably assumed and it was analyzed using the ECLIA method) on at least 1 occasion. 
The PK-PP Set will be used for presentations of plasma concentration. The PK-PP Set was 
used for the PopPK model that was described in a separate data analysis plan (DAP) to 
support the marketing application in 2024. 
Change #18 
Section 3.10 Changes to protocol-defined analyses 
In line with 
 response, 
additional analyses have been added to  
• summarize exposure and treatment-emergent adverse events for when study participants 
were taking Complete Original CZP Dose and Complete Reduced CZP Dose.  
− Complete Original CZP Dose includes all data for study participants who took 
Original CZP Dose prior to the first change in dosage as well as the data from when 
study participants increased their dosage to Original CZP after taking Reduced CZP 
Dose.  
− Complete Reduced CZP Dose includes all data for study participants who took 
Reduced CZP Dose prior to the first change in dosage as well as the data from when 
study participants took Reduced CZP Dose after taking Original CZP Dose. 
• the proportion of study participants and the proportion of PK samples with sufficient 
volume for re-analysis with the ECLIA method out of all PK samples initially analyzed 
with the ELISA method will be summarized by Original CZP Dose, Reduced CZP Dose, 
Complete Original CZP Dose, and Complete Reduced CZP Dose. 
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• the proportion of study participants and the proportion of PK samples with sufficient 
volume for re-analysis with the ECLIA method out of all PK samples analyzed with the 
ECLIA method (either originally or via re-analysis) will be summarized by Original CZP 
Dose, Reduced CZP Dose, Complete Original CZP Dose, and Complete Reduced CZP 
Dose. 
• the proportion of study participants and the proportion of ADAb samples with sufficient 
volume for re-analysis with the ECLIA method out of all ADAb samples initially 
analyzed with the ELISA method will be summarized by Original CZP Dose, Reduced 
CZP Dose, Complete Original CZP Dose, and Complete Reduced CZP Dose.   
• Additionally, the proportion of study participants and the proportion of ADAb samples 
with sufficient volume for re-analysis with the ECLIA method out of all ADAb samples 
analyzed with the ECLIA method (either originally or vis re-analysis) will be summarized 
by Original CZP Dose, Reduced CZP Dose, Complete Original CZP Dose, and Complete 
Reduced CZP Dose. 
In the statistical section of the protocol, it is stated that the AEs will be summarized 
separately for the periods of exposure to Original CZP Dose and the Reduced CZP Dose, in 
addition to exposure for study participants that switched from the Reduced CZP Dose to the 
Original CZP Dose following Protocol Amendment 9.  The analysis of AEs after a study 
participant changes doses will not be separately identified and presented in the Updated 
Week 24 Interim Analysis although the AEs that occur after dose changes will be 
summarized in the Any CZP Dose group. 
In the statistical section of the protocol, it is stated that the frequency and percentage of AEs 
reported during the first 16 weeks of study medication exposure will be summarized 
separately for the 2 CZP doses (the Original CZP Dose, the Reduced CZP Dose), and that this 
analysis will be repeated, excluding any study participants who switched from the original to 
the reduced CZP dose prior to Week 16.  The protocol-specified safety Week 16 analyses 
generated for prior interim analyses will not be included in the Updated Week 24 Interim 
Analysis or any later analyses. 
Exposure-adjusted event rates (EAER) are added to selected TEAE tables. 
This analysis plan includes plots of CZP plasma concentrations, ADAb titers, and maximum 
PedACR response for individual study participants by visit. Box plots of the PK distribution 
at Weeks 12 and 24 stratified by Baseline weight group, Baseline age group, concomitant 
MTX use and participant ADAb classification will be performed as a basis of the comparison 
with the adult RA PK exposures in RA0138; this comparison of observed PK data will be 
covered in Appendix Section 12.1. Plots of PK and ADAb data were not pre-specified in the 
study protocol.   
It is not planned to perform a population PKPD modeling analysis of RA0043 data to explore 
the exposure-response relationship in JIA pediatric population for the following reasons: i) 
the purpose of the RA0043 study is to support the efficacy extrapolation to the pediatric 
population by PK matching with respect to RA adult PK, and thus the main aim of the 
analysis that will be performed by nonlinear mixed effect modeling is to characterize the PK 
in JIA pediatrics with precise parameter estimates; and ii) the W24 interim analyses 
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performed and submitted in 2016 (BLA 125160-275) included PedACR and JADAS-71 
graphical explorations by dose which concluded that a substantial improvement of the 
PedACR and JADAS-71 responses across both doses investigated in Study RA0043 was 
observed, with no differences between these, that would support a pop-PKPD analysis. Hence 
the PK-PD Set was removed as no analyses are planned for this population. 
In the protocol it was stated that continuous efficacy endpoints would be presented using both 
last observation carried forward (LOCF) and observed case (OC) analyses. Instead, only 
observed case summaries of continuous efficacy endpoints will be presented since efficacy is 
not the primary objective of this study and little difference is expected between the two 
different analyses. 
For the Updated Week 24 Interim Analysis, the efficacy data will be summarized and plotted 
up to and including Week 24; all efficacy data will be included in listings and displayed on a 
small subset of figures. 
Was changed to: 
In line with 
 response, 
for the Updated Week 24 Interim Analysis only, additional analyses were added to:  
• summarize exposure and treatment-emergent adverse events for when study participants 
were taking Complete Original CZP Dose and Complete Reduced CZP Dose.  
− Complete Original CZP Dose included all data for study participants who took 
Original CZP Dose prior to the first change in dosage as well as the data from when 
study participants increased their dosage to Original CZP after taking Reduced CZP 
Dose.  
− Complete Reduced CZP Dose included all data for study participants who took 
Reduced CZP Dose prior to the first change in dosage as well as the data from when 
study participants took Reduced CZP Dose after taking Original CZP Dose. 
• summarize the proportion of study participants and the proportion of PK samples with 
sufficient volume for re-analysis with the ECLIA method out of all PK samples initially 
analyzed with the ELISA method were summarized by Original CZP Dose, Reduced CZP 
Dose, Complete Original CZP Dose, and Complete Reduced CZP Dose. 
• summarize the proportion of study participants and the proportion of PK samples with 
sufficient volume for re-analysis with the ECLIA method out of all PK samples analyzed 
with the ECLIA method (either originally or via re-analysis) will be summarized by 
Original CZP Dose, Reduced CZP Dose, Complete Original CZP Dose, and Complete 
Reduced CZP Dose. 
• summarize the proportion of study participants and the proportion of ADAb samples with 
sufficient volume for re-analysis with the ECLIA method out of all ADAb samples 
initially analyzed with the ELISA method will be summarized by Original CZP Dose, 
Reduced CZP Dose, Complete Original CZP Dose, and Complete Reduced CZP Dose.   
• Additionally, to summarize the proportion of study participants and the proportion of 
ADAb samples with sufficient volume for re-analysis with the ECLIA method out of all 
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ADAb samples analyzed with the ECLIA method (either originally or vis re-analysis) will 
be summarized by Original CZP Dose, Reduced CZP Dose, Complete Original CZP 
Dose, and Complete Reduced CZP Dose. 
In the statistical section of the protocol, it is stated that the AEs will be summarized 
separately for the periods of exposure to Original CZP Dose and the Reduced CZP Dose, in 
addition to exposure for study participants that switched from the Reduced CZP Dose to the 
Original CZP Dose following Protocol Amendment 9.  The analysis of AEs after a study 
participant changes doses will not be separately identified and presented in the Updated 
Week 24 Interim Analysis or the final analysis although the AEs that occur after dose 
changes will be summarized in the Any CZP Dose group. 
In the statistical section of the protocol, it is stated that the frequency and percentage of AEs 
reported during the first 16 weeks of study medication exposure will be summarized 
separately for the 2 CZP doses (the Original CZP Dose, the Reduced CZP Dose), and that this 
analysis will be repeated, excluding any study participants who switched from the original to 
the reduced CZP dose prior to Week 16.  The protocol-specified safety Week 16 analyses 
generated for prior interim analyses will not be included in the Updated Week 24 Interim 
Analysis or any later analyses. 
Exposure-adjusted event rates (EAER) are added to selected TEAE tables. 
This analysis plan, for the Updated Week 24 Interim Analysis only, includes plots of CZP 
plasma concentrations, ADAb titers, and maximum PedACR response for individual study 
participants by visit. Box plots of the PK distribution at Weeks 12 and 24 stratified by 
Baseline weight group, Baseline age group, concomitant MTX use and participant ADAb 
classification will be performed as a basis of the comparison with the adult RA PK exposures 
in RA0138; this comparison of observed PK data will be covered in Appendix Section 12.1. 
Plots of PK and ADAb data were not pre-specified in the study protocol.   
It is not planned to perform a population PKPD modeling analysis of RA0043 data to explore 
the exposure-response relationship in pcJIA pediatric population for the following reasons: i) 
the purpose of the RA0043 study is to support the efficacy extrapolation to the pediatric 
population by PK matching with respect to RA adult PK, and thus the main aim of the 
analysis that will be performed by nonlinear mixed effect modeling is to characterize the PK 
in pcJIA pediatrics with precise parameter estimates; and ii) the W24 interim analyses 
performed and submitted in 2016 (BLA 125160-275) included PedACR and JADAS-71 
graphical explorations by dose which concluded that a substantial improvement of the 
PedACR and JADAS-71 responses across both doses investigated in Study RA0043 was 
observed, with no differences between these, that would support a pop-PKPD analysis. Hence 
the PK-PD Set was removed as no analyses are planned for this population. 
In the protocol it was stated that continuous efficacy endpoints would be presented using both 
last observation carried forward (LOCF) and observed case (OC) analyses. Instead, only 
observed case summaries of continuous efficacy endpoints will be presented since efficacy is 
not the primary objective of this study and little difference is expected between the two 
different analyses. 
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For the Updated Week 24 Interim Analysis, the efficacy data were summarized and plotted 
up to and including Week 24; all efficacy data were included in listings. For the Final 
Analysis, all data will be summarized and plotted, by visit (week) when there are 20 or more 
study participants with non-missing data, as applicable; all efficacy data will be included in 
listings. 
Change #19 
Section 4.2.1 Incomplete dates for adverse events and concomitant medications 
Partial adverse event (AE) and concomitant medication start dates will be imputed as follows: 
Was changed to: 
Partial adverse event (AE), medical procedures, and concomitant medication start dates will 
be imputed as follows: 
Change #20 
Section 4.3 Interim analyses and data monitoring 
At the time of Protocol Amendment 9, a new assay had been developed and would be used to 
analyze samples from the 30 new subjects enrolled on the original dose as well as any old 
samples with sufficient volume remaining. An interim analysis, including all enrolled 
participants, for all PK, immunogenicity, safety, and efficacy endpoints will be performed 
after all active study participants, including those enrolled following the implementation of 
Protocol Amendment 9, have completed the Week 24 (Visit 10) assessments; this will be 
referred to as the Updated Week 24 Interim analysis to be used in support of the re-
submission of BLA 125160-275.   
Was changed to: 
At the time of Protocol Amendment 9, a new assay had been developed and was used to 
analyze samples from the 30 new study participants enrolled on the original dose as well as 
any old samples with sufficient volume remaining. An interim analysis, including all enrolled 
study participants, for all PK, immunogenicity, safety, and efficacy endpoints was performed 
after all active study participants, including those enrolled following the implementation of 
Protocol Amendment 9, completed the Week 24 (Visit 10) assessments; this is referred to as 
the Updated Week 24 Interim analysis that was used in support of the re-submission of BLA 
125160-275.   
Change #21 
Section 5.1 Study participant disposition 
The number and percentage of study participants who were treated, who completed the study, 
and who discontinued from the study, along with the discontinuation reasons, will be 
summarized for the Safety Set by CZP Dose (Reduced, Original and Any) and Baseline 
weight group as well as by CZP Dose and ADAb titer classification.  For the Week 16, Week 
24 and other interim analyses, number of study participants completing Week 16, Week 24 
and Week 48 (respectively) will be added in addition to the number completing the study as 
appropriate. The disposition of study participants in their initial dosing phase, reduction phase 
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and escalation dosing phase of the study will also be presented. The number of study 
participants in each analysis set will be presented.  
Was changed to: 
The number and percentage of study participants who were treated, and who discontinued 
from the study, along with the discontinuation reasons, will be summarized for the Safety Set 
by CZP Dose (Reduced, Original and Any) and Baseline weight group as well as by CZP 
Dose and ADAb titer classification; because the study was closed, every ongoing study 
participant is discontinued from the study.  For the Week 16, the number of study participants 
completing Week 16 was added. For the Updated Week 24 Interim Analysis, the number of 
study participants completing Week 24 was added. For the Final Analysis, the number of 
study participants completing Week 24 and Week 48, respectively, will be added. The 
disposition of study participants in their initial dosing phase, reduction phase and escalation 
dosing phase of the study will also be presented. The number of study participants in each 
analysis set will be presented.  
Change #22 
Section 5.2 Protocol deviations, the following was removed: 
When applicable, exclusion from analysis set will also be summarized and listed. 
Change #23 
Section 6.1 Demographics 
The following categorical variables will be summarized by Baseline weight group and ADAb 
titer classification: gender (male, female), racial group (American Indian/Alaskan Native, 
Asian, Black, Native Hawaiian or Other Pacific Islander, White, Other/Mixed), ethnicity 
(Hispanic or Latino, Not Hispanic or Latino), Baseline age group (2 to 5 years, 6 to 11 years, 
and 12 to 17 years), ERA status (present, absent), Baseline MTX use group (with, without) 
and Concomitant MTX Use (with, without). Demographics information will be listed. 
Was changed to: 
The following categorical variables will be summarized by Baseline weight group and ADAb 
titer classification: gender (male, female), racial group (American Indian/Alaskan Native, 
Asian, Black, Native Hawaiian or Other Pacific Islander, White, Other/Mixed), ethnicity 
(Hispanic or Latino, Not Hispanic or Latino), Country (Argentina, Brazil, Canada, Chile, 
Mexico, Russia, and USA), Baseline age group (2 to 5 years, 6 to 11 years, and 12 to 17 
years), Baseline MTX use group (with, without) and Concomitant MTX Use (with, without). 
Demographics information will be listed. 
Change #24 
Section 7 Measurements of Treatment Compliance 
Descriptive statistics will be presented for the compliance ratio defined as total number of 
CZP administrations received/total number of CZP administrations expected for the SS. Total 
number of CZP administrations expected differs depending on the loading phase or 
maintenance phase as well as depends on the different dosing scheduling of the 3 different 
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weight groups. For example, in the Original CZP Dose, a study participant is expected to 
receive 3 loading CZP administrations and then a maintenance dose of CZP Q2W through the 
Early Discontinuation/EOT Visit, with the exception of following implementation of Protocol 
Amendment 4; study participants in the 10 to <20kg weight group change from Q2W to a 
maintenance dose of CZP Q4W.  
In addition, a study participant could change dose (or frequency of dosing if in 10-20kg 
group) if a study participant crossed into a new weight group, which is not considered in the 
above expected calculations of number of CZP administration; study participants are assigned 
dose groups (Reduced CZP Dose and Original CZP Dose) and Baseline weight group at 
baseline and do not change either for the entire analysis  regardless of weight change and 
dose adjustments. This specifically applies to the change of dose frequency from Q4W to 
Q2W if a study participant crossed into the 20 to <40kg weight group, which is not 
considered in the expected calculations. Note that the dose reduction of ongoing study 
participants following Protocol Amendment 4 is considered in the calculations. Note also the 
dose escalation of ongoing study participants following Protocol Amendment 9 is considered 
in the calculations.  
For the Original CZP Dose and Reduced CZP Dose groups, treatment compliance is 
calculated from the first dose of CZP, for the entire time the study participant is taking study 
medication up to the dose change. For the results presented for Any CZP Dose, treatment 
compliance is calculated for the entire time the study participant is taking CZP from first dose 
until the last dose. Treatment compliance will be summarized and listed for the SS for the 
Reduced CZP Dose, Original CZP Dose, and Any CZP Dose for the final analysis; for the 
Updated week 24 Interim Analysis, treatment compliance will be summarized and listed for 
the SS for the Reduced CZP Dose and Original CZP Dose. 
Was changed to: 
Compliance with study drug administration will be based upon comparing the actual number 
of injections administered Ninj.actual with the expected number of injected administered 
Ninj.expected. If a study participants is in derived CRM and is not dosed, then no doses are 
expected for the compliance calculation. Since study participants are dosed on a Q2W or 
Q4W schedule, the week number of the visit is used to identify weeks where doses are 
expected starting with Week 0 (Baseline). 
𝐶𝑅=
𝑁 𝑖𝑛𝑗. 𝑎𝑐𝑡𝑢𝑎𝑙
𝑁 𝑖𝑛𝑗. 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 
Descriptive statistics will be presented for the compliance ratio for the SS. Total number of 
CZP administrations expected differs depending on the loading phase or maintenance phase 
as well as depends on the different dosing scheduling of the 3 different weight groups. For 
example, in the Original CZP Dose, a study participant is expected to receive 3 loading CZP 
administrations and then a maintenance dose of CZP Q2W through the Early 
Discontinuation/EOT Visit, with the exception of following implementation of Protocol 
Amendment 4; study participants in the 10 to <20kg weight group change from Q2W to a 
maintenance dose of CZP Q4W.  
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In addition, a study participant could change dose (or frequency of dosing if in 10-20kg 
group) if a study participant crossed into a new weight group, which is considered in the 
above expected calculations of number of CZP administration If a study participant crossed 
into the 20 to <40kg weight group, the calculations are updated to reflect the weight change. 
Note that the dose reduction of ongoing study participants following Protocol Amendment 4 
is considered in the calculations. Note also the dose escalation of ongoing study participants 
following Protocol Amendment 9 is considered in the calculations.  
For the Original CZP Dose and Reduced CZP Dose groups, treatment compliance is 
calculated from the first dose of CZP, for the entire time the study participant is taking study 
medication up to the dose change. For the results presented for Any CZP Dose, treatment 
compliance is calculated for the entire time the study participant is taking CZP from first dose 
until the last dose.  
The ratios of compliance will be summarized as a continuous variable and categorically (eg. 
0 - <0.80, 0.8 - 1.0 and >1.0). Treatment compliance will be summarized and listed for the SS 
for the Reduced CZP Dose, Original CZP Dose, and Any CZP Dose for the final analysis; for 
the Updated week 24 Interim Analysis, treatment compliance was summarized and listed for 
the SS for the Reduced CZP Dose and Original CZP Dose. 
Change #25 
Section 8.1 CZP plasma concentrations 
Concentrations below the limit of quantification of 320.0 ng/mL (0.32μg/mL) (BLQ) will be 
replaced by the LLOQ divided by 2 for the calculation of descriptive statistics. The geometric 
mean and CV% will be derived when at least two-thirds of the concentrations at a certain 
visit are above the LLOQ. If the criteria are not met, only the maximum and minimum values 
will be shown. Similarly, the 95% CI of the geometric mean will be calculated if at least 
5 samples are available at a time point.  
All summaries will be provided for the PK-PP Set.  All plasma concentration data will be 
listed. 
Was changed to: 
Concentrations below the limit of quantification of 320.0 ng/mL (0.32μg/mL) (BLQ) will be 
replaced by the LLOQ divided by 2 for the calculation of descriptive statistics. The geometric 
mean and CV% will be derived when at least two-thirds of the concentrations at a certain 
visit are above the LLOQ and not missing. A minimum of 3 values are required to calculate 
summary statistics. If only 2 values are available then these should be presented as the 
minimum and maximum with other descriptive statistics reported as missing (“-“) When the 
mean value includes one or more replaced BLQ values then a footnote should be included to 
say “contains one or more BLQ value replaced by half the LLOQ value”. If the criteria are 
not met, only the maximum and minimum values will be shown. Similarly, the 95% CI of the 
geometric mean will be calculated if at least 5 samples are available at a time point.  
All summaries will be provided for the PK-PP Set.  All plasma concentration data will be 
listed. Concentrations should be listed to the same number of significant figures supplied by 
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the bioanalytical laboratory. For listings concentrations below the limit of quantification 
should be reported as BLQ (below the limit of quantification). 
Change #26 
Section 8.4 PopPK analyses 
Plasma concentrations will be used to build a PopPK model with the nonlinear mixed-effect 
modeling (NONMEM) software. Details of the PopPK modeling procedures will be 
described in a separate data analysis plan. 
Was changed to: 
Plasma concentrations will be used to build a PopPK model with the nonlinear mixed-effect 
modeling (NONMEM) software. Details of the PopPK modeling procedures will be 
described in a separate data analysis plan. This analysis was generated for the Updated Week 
24 Interim analysis only. 
Change #27 
Section 9.1 Extent of exposure 
The extent of exposure to study drug will be evaluated by summarizing the total amount of 
CZP received in mg and the total duration of exposure in days. Total duration of exposure 
will be calculated using this general formula as: the Date of Last Dose of study medication – 
Date of First Dose of study medication + 14 days if administration of CZP is Q2W, +28 days 
if administration of CZP is Q4W. 
Was changed to: 
The extent of exposure to study drug will be evaluated by summarizing the total amount of 
CZP received in mg and the total duration of exposure in days. Total duration of exposure 
will be calculated using this general formula as: the Date of Last Dose of study medication – 
Date of First Dose of study medication + 14 days if administration of CZP is Q2W, +28 days 
if administration of CZP is Q4W. Dosing gaps (which occur between 2 CZP doses) are not 
considered in (does not reduce) the duration of exposure calculation. 
Change #28 
Section 9.1 Extent of exposure 
Duration of exposure will be calculated as appropriate for each of the following CZP Dose 
groups: 
Was changed to: 
Duration of exposure was calculated as appropriate for each of the following CZP Dose 
groups for the Updated Week 24 Interim Analysis but will only be calculated for Any CZP 
Dose, Reduced CZP Dose and Original CZP Doze for the final analysis: 
Change #29 
Section 9.1.1 Subject time at risk 
Subject time at risk will also be calculated. Subject time at risk represents the time a study 
participant is at risk for having an AE. Subject time (in days) at risk will generally be 
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calculated using this general formula: (date of the last dose of study medication – date of the 
first dose of study medication + 70 days) (70 days = 5 CZP half-lives).  However, the 
calculation of subject time at risk will be modified for study participants who change from 
Original CZP Dose to Reduced CZP Dose, or who dose escalate from Reduced CZP Dose to 
the Original CZP Dose. For the period of exposure prior to a dose change, subject time at risk 
ends on the date of dose change (ie, do not add 70 days).  For the period of exposure on the 
final CZP dose for a study participant, time at risk should include the additional 70 days.  
Subject years at risk will be calculated as subject time at risk (in days) divided by 365.25. 
Was changed to: 
Subject time at risk will also be calculated. Subject time at risk represents the time a study 
participant is at risk for having an AE while taking CZP. Subject time (in days) at risk will 
generally be calculated using this general formula: (date of the last dose of study medication 
– date of the first dose of study medication + 70 days) (70 days = 5 CZP half-lives).  
However, the calculation of subject time at risk will be modified for study participants who 
change from Original CZP Dose to Reduced CZP Dose, or who dose escalate from Reduced 
CZP Dose to the Original CZP Dose; the subject time at risk will further be modified for 
study participants who have dosing gaps > 70 days during the study – eg. meaning if a study 
participant has 100 consecutive day dosing gap, only the first 70 days will be included in the 
subject time at risk. For the period of exposure prior to a dose change, subject time at risk 
ends on the date of dose change (ie, do not add 70 days).  For the period of exposure on the 
final CZP dose for a study participant, time at risk should include the additional 70 days.  
Subject years at risk will be calculated as subject time at risk (in days) divided by 365.25. 
Change #30 
Section 9.1.1 Subject time at risk 
Subject time at risk will be calculated as appropriate for each of the following CZP Dose 
groups; 
Was changed to: 
Subject time at risk was calculated as appropriate for each of the following CZP Dose groups 
for the Updated Week 24 Interim Analysis but will only be calculated for Any CZP Dose, 
Reduced CZP Dose and Original CZP Doze for the final analysis: 
Change #31 
Section 9.2 Adverse events 
Only treatment emergent adverse events (TEAE) will be included in the summary tables. 
Treatment emergent AEs are defined as AEs starting on or after the first administration of 
CZP and up to 70 days after the last dose of study medication. AEs that are pre-treatment or 
that start more than 70 days after the last dose of study medication will be flagged in the 
listing but excluded from summaries. 
Was changed to: 
Only treatment emergent adverse events (TEAE) will be included in the summary tables. 
Treatment emergent AEs are defined as AEs starting on or after the first administration of 
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CZP and up to 70 days after the last (most recent) dose of study medication; then only the 
adverse events occurring up to 70 days after the last (most recent) dose of study medication 
will be counted as treatment emergent; all other adverse events occurring after first dose will 
not be flagged as treatment emergent. AEs that are pre-treatment or that start more than 70 
days after the last (most recent) dose of study medication will be in the listing but excluded 
from summaries. 
Change #32 
Section 9.2 Adverse events, the following was added: 
• Injection reaction TEAEs by primary SOC, HLT, and PT, overall and by Baseline weight 
group, further subdivided into injection site reactions and systemic reactions, with 
systemic reactions further subdivided into acute vs. delayed systemic reactions 
as well as: 
For disclosure on public registries (eg, ClinicalTrials.gov), information from the incidence 
tables of TEAEs and treatment-emergent SAEs will be published. 
Change #33 
Section 9.2 Adverse events 
In line with 
 response, 
incidence tables of TEAEs will be presented by primary SOC, PT, overall and Baseline 
weight group by Original CZP, Reduced CZP, Any CZP, Complete Original CZP and 
Complete Reduced CZP doses. 
Incidence and event rate tables will include the descriptive statistics on the incidence table 
but also include the exposure-adjusted incidence rate (EAIR) with associated 95% confidence 
interval, and the exposure-adjusted event rate (EAER).  
For EAIR, the numerator will be the total number of study participants experiencing a 
particular TEAE. The denominator will be 100 subject-years, ie, the total summation of 
individual subject-years at risk up to the first occurrence of the given TEAE for study 
participants with that TEAE, plus the total subject-years at risk for those study participants 
not experiencing that TEAE, divided by 100.  Details regarding calculation of subject-years 
at risk are described in Section 9.1.  EAIR will be presented with exact 95% confidence 
intervals based on the link between the chi-square distribution and the Poisson distribution 
(Ulm, 1990). 
For EAER, the numerator will be the number of TEAEs including repeat occurrences in 
individual study participants. The denominator will be in 100 subject-years (total summation 
of individual subject-years at risk divided by 100). No confidence interval will be computed. 
Listings: 
• Individual study participant numbers experiencing a given adverse event, grouped by 
SOC, PT, intensity, and relation to study drug 
Was changed to: 
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For the Updated Week 24 Interim Analysis only, in line with 
 
 response, incidence tables of TEAEs were presented by 
primary SOC, HLT, and PT, overall and Baseline weight group by Original CZP, Reduced 
CZP, Any CZP, Complete Original CZP and Complete Reduced CZP doses. Also, incidence 
and event rate tables of TEAEs up to Week 24 were presented by primary SOC, HLT, and 
PT, overall and by Baseline weight group for Reduced CZP and Original CZP dose groups.  
For the final analysis, incidence tables of TEAEs will be presented by primary SOC, HLT, 
and PT, overall and by Baseline weight group by Original CZP, Reduced CZP and Any CZP 
doses. The incidence and event rate tables of TEAEs up to Week 24 will not be presented for 
the final analysis. 
Incidence and event rate tables will include the descriptive statistics on the incidence table 
but also include the exposure-adjusted incidence rate (EAIR) with associated 95% confidence 
interval, and the exposure-adjusted event rate (EAER).  
For EAIR, the numerator will be the total number of study participants experiencing a 
particular TEAE. The denominator will be 100 subject-years, ie, the total summation of 
individual subject-years at risk up to the first occurrence of the given TEAE for study 
participants with that TEAE, plus the total subject-years at risk for those study participants 
not experiencing that TEAE, divided by 100.  Details regarding calculation of subject-years 
at risk are described in Section 9.1.  EAIR will be presented with exact 95% confidence 
intervals based on the link between the chi-square distribution and the Poisson distribution 
(Ulm, 1990). 
For EAER, the numerator will be the number of TEAEs including repeat occurrences in 
individual study participants. The denominator will be in 100 subject-years (total summation 
of individual subject-years at risk divided by 100). No confidence interval will be computed. 
Listings: 
• Individual study participant numbers experiencing a given adverse event, grouped by 
SOC, PT, intensity, and relation to study drug 
• Individual study participant numbers experiencing a serious treatment emergent adverse 
event, grouped by SOC, PT, intensity, and relation to study drug 
• Individual study participant numbers experiencing a TEAE leading to study drug 
discontinuation, grouped by SOC, PT, intensity and relation to study drug 
Individual study participant numbers experiencing an AE leading to death, grouped by SOC, 
PT, intensity and relation to study drug 
Change #34 
Section 9.3 Clinical laboratory evaluations, the following was added: 
A listing of when blood and urine samples were taken as well as serum pregnancy tests were 
performed will also be produced. 
Change #35 
Section 10 Efficacy analyses 
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In Section 10, the analyses described will be generated for the final analysis.  For the Updated 
Week 24 Interim analysis, only efficacy data up to and including Week 24 will be presented 
in the analyses described in Section 10 for the following variables:  
• PedACR30/50/70, 90 
• Number of joints with active arthritis 
• Number of joints with limitation of range of motion 
• Physician’s Global Assessment of Disease Activity 
• Childhood Health Assessment Questionnaire 
• Parent’s Global Assessment of Overall Well-Being 
• C-Reactive protein 
• Juvenile Arthritis Disease Activity Score 71-joint 
For the Updated Week 24 Interim analysis, all reported data for other efficacy variables will 
be listed only; any calculations described for the final analysis will not be performed. These 
include the following variables: 
• Clinically Inactive Disease 
• Clinical remission on medication 
• Duration of Morning Stiffness 
Was changed to: 
In Section 10, the analyses described for all efficacy variables below will be generated for the 
final analysis.  For the Updated Week 24 Interim analysis, only efficacy data up to and 
including Week 24 was presented in the analyses described in Section 10 for the following 
variables:  
• PedACR30/50/70/90 
• Number of joints with active arthritis 
• Number of joints with limitation of range of motion 
• Physician’s Global Assessment of Disease Activity 
• Childhood Health Assessment Questionnaire 
• Parent’s Global Assessment of Overall Well-Being 
• C-Reactive protein 
• Juvenile Arthritis Disease Activity Score 71-joint 
For the Updated Week 24 Interim analysis, all reported data for other efficacy variables were 
listed only; any calculations described for the final analysis were not performed. These 
included the following variables: 
• Clinically Inactive Disease 
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• CRM 
• Duration of Morning Stiffness 
Change #36 
Section 10.3.1 PedACR30, PedACR50, PedACR70, PedACR90 
In addition to the Week 16 summary described above, the PedACR30, PedACR50, 
PedACR70, and PedACR90 response rates as compared to Baseline at every other visit 
except the Final Visit will also be summarized. Plots of PedACR30, PedACR50, PedACR70 
and PedACR90 response rates (combined on the same plot) by visit will be provided by the 
same CZP dose groups as in the summary tables above, overall and by Baseline weight 
group. 
Was changed to: 
The PedACR30, PedACR50, PedACR70, and PedACR90 response rates as compared to 
Baseline at every visit (including Week 16) except the Final Visit will be summarized. Plots 
of PedACR30, PedACR50, PedACR70 and PedACR90 response rates (combined on the 
same plot) by visit will be provided by the same CZP dose groups as in the summary tables 
above, overall and by Baseline weight group. 
Change #37 
Section 10.3.9.2 Final Analysis 
If any of the 6 criteria cannot be assessed due to missing data, the study participant will be 
assumed not to have achieved CID at the corresponding visit.   
CID will be assessed at every post-Baseline visit except the Final Visit. 
The n and percentage of study participants with CID will be summarized for each post-
Baseline visit. The exact 95% CI for the percentage will also be presented.  
Time to initial CID in days will be calculated as date of first visit where CID is achieved – 
date of first dose of study medication + 1 day. Time to initial CID in days will be presented 
using Kaplan-Meier product limit estimation.  Study participants that discontinue without 
achieving CID will be censored at the time of discontinuation; ongoing study participants that 
have not achieved CID at the time of interim analyses (Week 24 and other interim analyses) 
and the final analysis will be censored at the time of the last available assessment. The 
median and 95% CI for the time to initial CID will be presented. The 95% CI for the median 
will be based on the method of Brookmeyer and Crowley. Kaplan-Meier product limit 
survival estimates of the cumulative proportion of study participants with CID (1 minus the 
product limit estimate of the proportion of study participants without CID) will also be 
presented.  Kaplan-Meier plots of time to CID will be presented overall and by Baseline 
weight group. 
Both summaries of CID and time to CID will be provided. 
Was changed to: 
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The 6 criteria above will be used to derive CID. If any of the 6 criteria cannot be assessed due 
to missing data, the study participant will be assumed not to have achieved derived CID at the 
corresponding visit.   
Derived CID will be assessed at every post-Baseline visit except the Final Visit. 
The n and percentage of study participants with derived CID will be summarized for each 
post-Baseline visit. The exact 95% CI for the percentage will also be presented.  
Time to initial derived CID in days will be calculated as date of first visit where derived CID 
is achieved – date of first dose of study medication + 1 day. Time to initial derived CID in 
days will be presented using Kaplan-Meier product limit estimation.  Study participants that 
discontinue without achieving derived CID will be censored at the time of discontinuation; 
ongoing study participants that have not achieved derived CID at the time of interim analyses 
(Week 24 and other interim analyses) and the final analysis will be censored at the time of the 
last available assessment. The median and 95% CI for the time to initial derived CID will be 
presented. The 95% CI for the median will be based on the method of Brookmeyer and 
Crowley. Kaplan-Meier product limit survival estimates of the cumulative proportion of 
study participants with derived CID (1 minus the product limit estimate of the proportion of 
study participants without derived CID) will also be presented.  Kaplan-Meier plots of time to 
CID will be presented overall and by Baseline weight group. 
Both summaries of derived CID and time to derived CID will be provided as well as listed. 
Change #38 
Section 10.3.10.2 Final Analysis 
CRM is defined as criteria for CID achieved for at least 6 continuous months.  CRM will be 
considered achieved at a given visit if the study participant has CID at the visit and if the time 
from the first visit where CID is achieved to the given visit is ≥ 6 months (182 days) and the 
study participant had CID at all visits in between. CRM is defined as criteria for CID 
achieved for at least 6 continuous months. 
CRM will be assessed at every post-Baseline visit from Week 24 onwards, except the Final 
Visit. 
The n and percentage of study participants with CRM will be summarized for each post-
Baseline visit starting at Week 24. The exact 95% CI for the percentage will also be 
presented.  
Time to initial CRM in days will be calculated as date of first visit where CRM is achieved – 
date of first dose of study medication + 1 day. Time to CRM in days will be presented using 
Kaplan-Meier product limit estimation.  Study participants that discontinue without achieving 
CRM will be censored at the time of discontinuation; ongoing study participants that have not 
achieved CRM at the time of interim analyses (Week 24 and other interim analyses) and the 
final analysis will be censored at the time of the last available assessment. The median and 
95% CI for the time to initial CRM in days calculated using Kaplan-Meier product limit 
estimators will be presented. The 95% CI for the median will be based on the method of 
Brookmeyer and Crowley. Kaplan-Meier product limit survival estimates of the cumulative 
proportion of study participants in CRM (1 minus the product limit estimate of the proportion 
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of study participants without CRM) from 6 months onwards will also be presented.  Kaplan-
Meier plots of time to CRM will be presented overall and by Baseline weight group. 
Both summaries of CRM and time to CRM will be provided. 
Was changed to: 
CRM as indicated by the PI in the eCRF will only be listed. 
Derived CRM is defined as achieving the criteria for derived CID for at least 6 continuous 
months; study participants who reach derived CRM can either stay on CZP or stop taking 
CZP; so being in derived CRM is not an indicator of whether the study participant is taking 
CZP while in derived CRM.  Derived CRM will be considered achieved at a given visit if the 
study participant has derived CID at the visit and if the time from the first visit where derived 
CID is achieved to the given visit is ≥ 6 months (182 days) and the study participant had 
derived CID at all attended visits in between; if missed visits occur between visits where 
derived CID is achieved, then derived CID will be assumed for the missed visits. Derived 
CRM is defined as criteria for derived CID achieved for at least 6 continuous months. 
Derived CRM will be assessed at every post-Baseline visit from Week 24 onwards, except 
the Final Visit. 
The n and percentage of study participants with derived CRM will be summarized for each 
post-Baseline visit starting at Week 24. The exact 95% CI for the percentage will also be 
presented.  
Time to initial derived CRM in days will be calculated as date of first visit where derived 
CRM is achieved – date of first dose of study medication + 1 day. Time to derived CRM in 
days will be presented using Kaplan-Meier product limit estimation.  Study participants that 
discontinue without achieving derived CRM will be censored at the time of discontinuation; 
ongoing study participants that have not achieved derived CRM at the time of interim 
analyses (Week 24 and other interim analyses) and the final analysis will be censored at the 
time of the last available assessment. The median and 95% CI for the time to initial derived 
CRM in days calculated using Kaplan-Meier product limit estimators will be presented. The 
95% CI for the median will be based on the method of Brookmeyer and Crowley. Kaplan-
Meier product limit survival estimates of the cumulative proportion of study participants in 
derived CRM (1 minus the product limit estimate of the proportion of study participants 
without derived CRM) from 6 months onwards will also be presented.  Kaplan-Meier plots of 
time to derived CRM will be presented overall and by Baseline weight group. 
Both summaries of derived CRM and time to derived CRM will be provided as well as 
listings. 
Change #39 
Section 10.3.13.2 Final Analysis, the following was added: 
Study participants who are past 17 years old while still on the study will continue to be 
administered the JIA Pain VAS. 
Change #40 
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Section 10.3.15.2 Final Analysis 
The n and percentages for each of the question responses will be summarized for the 
following categorical questions: 1 – 4, 6, 10-13. Descriptive statistics for the responses to the 
remaining quantitative questions will be summarized. 
Was changed to: 
The following analysis will be presented for the Any CZP dose only. The n and percentages 
for each of the question responses will be summarized for the following categorical 
questions: 6, 10-12. Descriptive statistics for the responses to the quantitative questions (8-9, 
14-20) will be summarized. 
Change #41 
Section 12.1 Comparisons with RA0138 data 
Comparisons between RA0043 and RA0138 data will focus on common timepoints (Weeks 
12 and 24).  The dose groups that will be compared are the Original CZP Dose and the 
Reduced CZP Dose from RA0043 (Section 3.1) and the 200 mg Q2W maintenance dose from 
RA0138. 
Separate boxplots will be performed for Week 12 and Week 24 showing plasma CZP 
concentrations for the two CZP dose groups (Original CZP Dose or Reduced CZP Dose) for 
RA0043 and the single CZP dose group for RA0138 in the same plot. Box plots of the PK 
concentrations at Weeks 12 and 24 will be presented by CZP dose group for Baseline weight 
group, Baseline age group, ADAb participant status classification, ADAb titer classification, 
and concomitant MTX use in combination with Baseline weight group. In the box plots the 
5th and 95th percentiles of the concentrations distribution will be shown. 
Separate plots of individual participant (natural) log CZP plasma concentration versus log2 
ADAb titer will be produced for Week 12 and Week 24 data for both studies. In these plots, 
participants study (RA0043 or RA0138) and CZP dose group (Original or Reduced) will be 
shown as a different symbol/color to aid comparison. In addition, for RA0138 only, plots of 
individual participant area under the plasma concentration curve over the 2-week dosing 
interval (AUC0-tau) versus log2 ADAb titer at Week 12 will be produced. 
If there are signs that higher titer levels are associated with lower plasma concentrations, 
further investigations will be performed to attempt to determine at which titer levels 
differences are observed and to assess the impact on efficacy and safety. 
Further analyses may be defined in the integrated summary of immunogenicity including 
comparisons of ADAb titer levels between studies (no pooling of studies across indications 
are planned) allowing us to put the pJIA/RA data in context of the AS and PSO indications. 
Was changed to: 
The following analysis was only completed for the Updated Week 24 Interim Analysis; it will 
not be regenerated for the final analysis.   
Comparisons between RA0043 and RA0138 data focused on common timepoints (Weeks 12 
and 24).  The dose groups that were compared are the Original CZP Dose and the Reduced 
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Statistical Analysis Plan 
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CZP Dose from RA0043 (Section 3.1) and the 200 mg Q2W maintenance dose from 
RA0138. 
Separate boxplots were generated for Week 12 and Week 24 showing plasma CZP 
concentrations for the two CZP dose groups (Original CZP Dose or Reduced CZP Dose) for 
RA0043 and the single CZP dose group for RA0138 in the same plot. Box plots of the PK 
concentrations at Weeks 12 and 24 were presented by CZP dose group for Baseline weight 
group, Baseline age group, ADAb participant status classification, ADAb titer classification, 
and concomitant MTX use in combination with Baseline weight group. In the box plots the 
5th and 95th percentiles of the concentrations distribution were shown. 
Separate plots of individual participant (natural) log CZP plasma concentration versus log2 
ADAb titer were produced for Week 12 and Week 24 data for both studies. In these plots, 
participants study (RA0043 or RA0138) and CZP dose group (Original or Reduced) were 
shown as a different symbol/color to aid comparison. In addition, for RA0138 only, plots of 
individual participant area under the plasma concentration curve over the 2-week dosing 
interval (AUC0-tau) versus log2 ADAb titer at Week 12 were produced. 
If there were signs that higher titer levels were associated with lower plasma concentrations, 
further investigations were performed to attempt to determine at which titer levels differences 
are observed and to assess the impact on efficacy and safety. 
Further analyses were defined in the integrated summary of immunogenicity including 
comparisons of ADAb titer levels between studies (no pooling of studies across indications 
are planned) allowing us to put the pcJIA/RA data in context of the AS and PSO indications. 
 
 
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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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Approval Signatures
Name:
ra0043-sap-amend6
Version:
1. 0
Document Number:
CLIN-000248991
Title:
RA0043 SAP Amendment 6
Approved Date:
24 May 2024
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 23-May-2024 20:16:12 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 23-May-2024 22:39:00 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Document Author
Date of Signature: 24-May-2024 14:28:40 GMT+0000
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