Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid arthritis Phase 1 Cimzia Certolizumab pegol Electrochemiluminescent immune-assay
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 33
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the pharmacokinetics and safety of certolizumab pegol in adults with active rheumatoid arthritis.

Detailed description:

Arms:
arm 1: Subjects in this arm will receive doses of certolizumab pegol for the treatment of Rheumatoid Arthritis, in accordance with the US label.

Interventions: intervention 1: Certolizumab pegol
Intervention descriptions: intervention 1: * Pharmaceutical form: Solution for injection
* Route of administration: Subcutaneous Subjects will receive certolizumab pegol in a pre-specified sequence during the study.

Protocol document:
Prot_000.pdf: 
UCB 
 
18 Mar 2021 
Clinical Study Protocol 
Certolizumab pegol 
RA0138 
 
 
 
Confidential 
Page 1 of 66 
A MULTI-CENTER, OPEN-LABEL STUDY TO EVALUATE THE 
PHARMACOKINETICS OF CERTOLIZUMAB PEGOL IN 
ADULTS WITH ACTIVE RHEUMATOID ARTHRITIS USING AN 
ELECTROCHEMILUMINESCENT IMMUNO-ASSAY 
PROTOCOL RA0138 AMENDMENT 2 
PHASE 1B 
 
SHORT TITLE: 
A study to evaluate the PK of certolizumab pegol in adults with active rheumatoid arthritis using 
an electrochemiluminescent immune-assay (ECLIA). 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying number(s): 
IND Number: 
009869 
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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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document history 
Document 
Date 
Type of amendment 
Amendment 2 
18 Mar 2021 
Nonsubstantial 
Amendment 1 
09 Dec 2020 
Nonsubstantial 
Original Protocol 
27 Mar 2020 
Not applicable 
Amendment 2 (18 Mar 2021) 
Overall rationale for the amendment 
The primary reasons for this nonsubstantial protocol amendment were to update the Screening 
Period duration from “7 days” to “up to 28 days,” to standardize the use of “inhibitor” vs 
“antagonist,” to update text describing rescreening procedures, to change Visit 3 from a “Home 
Visit” to a “Clinic Visit,” to clarify rescreening procedures, and to clarify the prohibited 
concomitant medications and permitted rescue medications.  
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.2 Schema  
4.1 Overall design 
Changed the duration for the 
Screening Period from “7 days” to 
“up to 28 days.” 
The Screening Period was 
lengthened to 28 days to 
allow for sufficient time 
for laboratory samples to 
be processed ahead of a 
study participant’s first 
CZP dose. 
1.3 Schedule of Activities 
Visit 3 was changed from a “Home” 
visit to a “Clinic” visit. 
Due to logistical 
considerations with 
in-home nurse availability, 
this visit was changed 
from a home visit to a 
clinic visit. 
5.2 Exclusion criteria 
Modified the wording of Exclusion 
Criterion #10 to exclude the term 
“antagonist.” This change resulted 
in a global use of the term 
“inhibitor” to describe TNFα 
inhibitors. 
This change was made to 
avoid confusion in the 
understanding of 
TNFα inhibitors vs 
TNFα antagonists. 
5.2 Exclusion criteria 
Rescreening text for laboratory 
assessments was removed from 
Exclusion Criterion #13  
Updated to provide clarity 
and to be consistent with 
remainder of protocol and 
program. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.4 Screen failures 
Clarifying text was added to 
describe the window in which tests 
that result in ALT, AST, or ALP up 
to 25% above the exclusion limit 
may be repeated for confirmation. 
Updated to provide clarity 
and to be consistent with 
remainder of protocol and 
program. 
6.5.2 Prohibited 
concomitant treatments 
(medications and 
therapies) 
The specific types of prohibited 
concomitant DMARDs were 
clarified. 
Updated to provide clarity 
and avoid confusion 
regarding which 
DMARDs are prohibited. 
6.5.3 Rescue medication 
The specific types of permitted 
rescue medications were clarified. 
Updated to provide clarity 
and avoid confusion 
regarding which rescue 
medications are permitted. 
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SERIOUS ADVERSE EVENT REPORTING 
 
Serious adverse event reporting (24h) 
Fax 
US and Canada: +1 800 880 6949 or +1 866 890 3175 
Email 
Global: DS_ICT@ucb.com (for interventional clinical studies) 
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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ................................................................................................. 9 
1.1 
Synopsis ......................................................................................................................... 9 
1.2 
Schema ......................................................................................................................... 12 
1.3 
Schedule of Activities .................................................................................................. 13 
2 
INTRODUCTION ........................................................................................................... 16 
2.1 
Study rationale ............................................................................................................. 16 
2.2 
Background .................................................................................................................. 16 
2.2.1 
Rheumatoid arthritis ............................................................................................ 16 
2.2.2 
Certolizumab pegol .............................................................................................. 16 
2.3 
Benefit/Risk assessment............................................................................................... 17 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 18 
4 
STUDY DESIGN ............................................................................................................. 18 
4.1 
Overall design .............................................................................................................. 18 
4.2 
Scientific rationale for study design ............................................................................ 19 
4.3 
Justification for dose .................................................................................................... 19 
4.4 
End of study definition................................................................................................. 19 
5 
STUDY POPULATION .................................................................................................. 20 
5.1 
Inclusion criteria .......................................................................................................... 20 
5.2 
Exclusion criteria ......................................................................................................... 21 
5.3 
Lifestyle restrictions..................................................................................................... 23 
5.3.1 
Meals and dietary restrictions .............................................................................. 23 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 23 
5.3.3 
Activity ................................................................................................................ 23 
5.4 
Screen failures .............................................................................................................. 23 
6 
STUDY TREATMENTS ................................................................................................. 23 
6.1 
Treatments administered .............................................................................................. 24 
6.2 
Preparation, handling, storage, and accountability requirements ................................ 24 
6.2.1 
Drug accountability ............................................................................................. 25 
6.3 
Measures to minimize bias: randomization and blinding ............................................ 25 
6.4 
Treatment compliance .................................................................................................. 25 
6.5 
Concomitant medication(s)/treatment(s) ..................................................................... 25 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 25 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 26 
6.5.3 
Rescue medication ............................................................................................... 26 
6.6 
Dose modification ........................................................................................................ 26 
6.6.1 
Dose interruptions ................................................................................................ 26 
6.7 
Criteria for study hold or dosing stoppage ................................................................... 26 
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6.8 
Treatment after the end of the study ............................................................................ 27 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 27 
7.1 
Discontinuation of study medication ........................................................................... 27 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 27 
7.2 
Participant Discontinuation/Withdrawal from the study ............................................. 28 
7.3 
Lost to follow-up.......................................................................................................... 29 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 29 
8.1 
Efficacy assessments .................................................................................................... 30 
8.1.1 
Multi-dimensional Health Assessment Questionnaire (MDHAQ) and RAPID3 
scoring .................................................................................................................. 30 
8.2 
Safety assessments ....................................................................................................... 30 
8.2.1 
Physical examination ........................................................................................... 30 
8.2.2 
Vital signs ............................................................................................................ 30 
8.2.3 
Electrocardiograms .............................................................................................. 31 
8.2.4 
Clinical safety laboratory assessments ................................................................ 31 
8.2.5 
Tuberculosis assessment ...................................................................................... 31 
8.3 
Adverse events and serious adverse events ................................................................. 31 
8.3.1 
Time period and frequency for collecting AE and SAE information .................. 32 
8.3.2 
Method of detecting AEs and SAEs .................................................................... 32 
8.3.3 
Follow-up of AEs and SAEs ................................................................................ 32 
8.3.4 
Regulatory reporting requirements for SAEs ...................................................... 32 
8.3.5 
Pregnancy ............................................................................................................ 33 
8.3.6 
Adverse events of special interest ........................................................................ 33 
8.3.7 
Anticipated serious adverse events ...................................................................... 34 
8.4 
Safety signal detection ................................................................................................. 34 
8.5 
Treatment of overdose ................................................................................................. 34 
8.6 
Pharmacokinetics ......................................................................................................... 35 
8.7 
Genetics........................................................................................................................ 35 
8.8 
Pharmacodynamics ...................................................................................................... 35 
8.9 
Biomarkers ................................................................................................................... 35 
8.9.1 
Immunogenicity assessments ............................................................................... 35 
8.10 
Health economics or medical resource utilization and health economics ................... 35 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 35 
9.1 
Definition of analysis sets ............................................................................................ 36 
9.2 
General statistical considerations ................................................................................. 36 
9.3 
Planned safety and other analyses................................................................................ 36 
9.3.1 
Other analyses ...................................................................................................... 36 
9.3.1.1 
Pharmacokinetic analyses .......................................................................... 36 
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9.3.1.2 
Immunogenicity analyses .......................................................................... 37 
9.3.1.3 
RAPID3 analysis ....................................................................................... 37 
9.4 
Handling of protocol deviations................................................................................... 37 
9.5 
Handling of dropouts or missing data .......................................................................... 37 
9.6 
Planned interim analysis and data monitoring ............................................................. 37 
9.7 
Determination of sample size ....................................................................................... 37 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 39 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ......................... 39 
10.1.1 
Regulatory and ethical considerations ................................................................. 39 
10.1.2 
Financial disclosure ............................................................................................. 39 
10.1.3 
Informed consent process .................................................................................... 40 
10.1.4 
Data protection ..................................................................................................... 40 
10.1.5 
Committees structure ........................................................................................... 41 
10.1.6 
Data quality assurance ......................................................................................... 41 
10.1.6.1 
Case Report form completion .................................................................... 41 
10.1.7 
Source documents ................................................................................................ 41 
10.1.8 
Study and Site Closure ......................................................................................... 42 
10.1.9 
Publication Policy ................................................................................................ 42 
10.2 
Appendix 2: Clinical Laboratory Tests ........................................................................ 43 
10.3 
Appendix 3: Adverse Events – Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................ 45 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ....... 50 
10.5 
Appendix 5: Genetics ................................................................................................... 53 
10.6 
Appendix 6: Liver Safety – Suggested Actions and Follow-up Assessments ............. 54 
Liver Chemistry Stopping Criteria and Follow-up assessments .......................................... 54 
10.7 
Appendix 7: Medical Device Adverse Events (AEs), Adverse Device Effects (ADEs), 
Serious Adverse Events (SAEs) and Device Deficiencies: Definition and Procedures 
for Recording, Evaluating, Follow-up, and Reporting ................................................ 57 
10.8 
Appendix 8: Rapid Alert Procedures ........................................................................... 58 
10.9 
Appendix 9: Country-specific Requirements............................................................... 59 
10.10 Appendix 10: Abbreviations and Trademarks ............................................................. 60 
10.11 Appendix 11: Protocol Amendment History ............................................................... 62 
10.12 Appendix 12: RAPID3 Assessment ............................................................................. 63 
How to calculate RAPID3 scores ........................................................................................ 63 
11 REFERENCES ................................................................................................................ 65 
SPONSOR DECLARATION .................................................................................................. 66 
 
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Clinical Study Protocol 
Certolizumab pegol 
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LIST OF TABLES 
Table 8-1: 
Anticipated serious adverse event for RA population ..................................... 34 
 
LIST OF FIGURES 
Figure 7-1: 
Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm ....... 28 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: A multi-center, open-label study to evaluate the pharmacokinetics of 
certolizumab pegol in adults with active rheumatoid arthritis using an electrochemiluminescent 
immuno-assay 
Short Title: A study to evaluate the PK of certolizumab pegol in adults with active rheumatoid 
arthritis using an electrochemiluminescent immune-assay (ECLIA). 
Rationale: 
Certolizumab pegol (CZP) was approved in the United States (US) for adults with rheumatoid 
arthritis (RA) in May 2009. Certolizumab pegol pharmacokinetic (PK) and antidrug antibody 
(ADA) data in the adult RA population has thus far been generated with legacy bioanalytical 
methods which have more recently been superseded by new methods to comply with updated 
regulatory standards. As the safety and efficacy of CZP in adults with RA have been extensively 
studied and established, this Phase 1B study is focused on acquiring PK data in CZP-naive 
participants who receive CZP at the marketed dose within the study, and are prescribed CZP at 
the licensed dose (per US Prescribing Information) as part of the therapeutic management of 
their RA disease, using a PK or ADA electrochemiluminescent immuno-assay (ECLIA). This 
study is being undertaken in support of the polyarticular juvenile idiopathic arthritis (pJIA) 
Pediatric Research Equity Act (PREA) requirement for Cimzia. 
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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the PK of CZP (utilizing the 
ECLIA method) in adults with active RA 
• PK parameters (Cmin and AUC) following 
10 weeks of CZP dosing 
Secondary 
• To evaluate CZP exposure over a 
maximum of 24 weeks administration to 
adults with active RA 
• To evaluate the safety of CZP in adults 
with active RA 
• CZP plasma concentrations over the 
duration of study 
• Treatment-emergent SAEs and AEs 
leading to withdrawal from the time of the 
first CZP dose through the SFU Visit 
Other 
• To assess the occurrence of anti-CZP 
antibodies (utilizing the ECLIA method) 
over the duration of the study 
• ADA screening status (positive or 
negative screen), confirmatory status 
(positive or negative immunodepletion), 
and the titer for "positive 
immunodepletion" samples at each 
scheduled assessment after first CZP dose 
through SFU 
• To assess the efficacy of CZP 
• Change in Routine Assessment of Patient 
Index Data 3 (RAPID3) from Baseline to 
Week 12 
• To evaluate other safety parameters 
• TEAEs, vital signs, and laboratory 
assessments 
ADA=antidrug antibody; AE=adverse event; CZP=certolizumab pegol; ECLIA=electrochemiluminescent 
immuno-assay; PK=pharmacokinetic; RA=rheumatoid arthritis; RAPID3=Routine Assessment of Patient Index 
Data; SAE=serious adverse event; SFU=Safety Follow-up Visit; TEAE=treatment-emergent adverse event 
Overall Design 
This is a multi-center, open-label Phase 1B study to assess the PK, safety, and tolerability of 
CZP in adults with active RA. In this 24-week study, study participants (ie, male or female 
participants 18 to 69 years of age inclusive) who are naïve to CZP and are eligible to receive a 
biologic for RA will receive CZP in subcutaneous (sc) loading doses at Weeks 0, 2, and 4, 
followed by a treatment of 200mg every 2 weeks (Q2W), with the final dose taking place at 
Week 24. 
Number of Participants 
A total of 30 participants will be enrolled to receive CZP, such that a minimum of 25 evaluable 
participants are expected to complete Visit 13 (Week 12). 
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Treatment Groups and Duration 
All study participants will receive CZP treatment. Study participants may be taking concomitant 
methotrexate (MTX); however, a minimum of 8 study participants must be enrolled who are not 
on concurrent administration of MTX. 
The duration of the study is approximately 38 weeks. The study consists of a Screening Period 
(up to 28 days), Baseline Visit, a Treatment Period (24 weeks), and a Safety Follow-up (SFU) 
Visit (70 days after the last study visit). 
 
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1.2 
Schema 
 
ADA=antidrug antibody; BL=Baseline; CZP=certolizumab pegol; PK=pharmacokinetic; Q2W=every 2 weeks; W=week 
a CZP naïve at enrollment. 
 
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1.3 
Schedule of Activities 
Procedure 
Screening Baseline 
Treatment Period 
SFU/ 
EDV 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
PK profile 
V13 
V14 
V15 
V16 
V9 
V10 
V11 
V12 
D-28/ 
W-4 
D0 
D7/ 
W1 
D14/ 
W2 
D28/ 
W4 
D42/ 
W6 
D56/ 
W8 
D70/ 
W10 
D72 
W10 
D75 
W10 
D77/ 
W11 
D80/ 
W11 
D84/ 
W12 
D126/ 
W18 
D168/ 
W24 
70 
days 
after 
last 
IMP 
Visit window a 
 
 
±1 day ±1 day 
±2 days 
±2 days 
±2 day 
±1 day ±6 hrs 
±6 hrs ±6 hrs ±6 hrs ±6 hrs 
±2 days 
±2 days 
±7 day 
Location b 
Clinic 
Clinic 
Clinic 
Home 
Home 
Clinic 
Home 
Home 
Home 
Home 
Home 
Home 
Clinic 
Home 
Clinic 
Clinic 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study participant 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verification of 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General 
medical/procedure 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body 
weight/height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test c 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Laboratory 
assessments  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
12-lead ECG d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
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Procedure 
Screening Baseline 
Treatment Period 
SFU/ 
EDV 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
PK profile 
V13 
V14 
V15 
V16 
V9 
V10 
V11 
V12 
D-28/ 
W-4 
D0 
D7/ 
W1 
D14/ 
W2 
D28/ 
W4 
D42/ 
W6 
D56/ 
W8 
D70/ 
W10 
D72 
W10 
D75 
W10 
D77/ 
W11 
D80/ 
W11 
D84/ 
W12 
D126/ 
W18 
D168/ 
W24 
70 
days 
after 
last 
IMP 
Visit window a 
 
 
±1 day ±1 day 
±2 days 
±2 days 
±2 day 
±1 day ±6 hrs 
±6 hrs ±6 hrs ±6 hrs ±6 hrs 
±2 days 
±2 days 
±7 day 
Location b 
Clinic 
Clinic 
Clinic 
Home 
Home 
Clinic 
Home 
Home 
Home 
Home 
Home 
Home 
Clinic 
Home 
Clinic 
Clinic 
TB screening 
(IGRA)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and 
Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
X 
X 
IMP 
administration e  
 
X (site) 
 
X 
(nurse) 
X 
(nurse) 
X (site) 
X 
(nurse) 
X 
(nurse) 
 
 
 
 
X 
(site) 
X 
(nurse 
or self) 
X (site) 
 
IMP dispensing/ 
IXRS  
 
X 
  
 
 
X 
 
 
  
 
 
 
X 
 
 
 
IMP return 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
CZP plasma 
concentration f, g 
  
X 
X  
X  
 
X 
 
X 
X 
X  
X  
X  
X 
X 
X  
 
Anti-CZP antibody 
sampling f 
 
X 
  
  
 
X 
 
 
 
  
 
 
X 
 
X 
X  
RAPID3 testing f 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CZP=certolizumab pegol; D=day; ECG=electrocardiogram; EDV=Early Discontinuation Visit; hrs=hours; IGRA=Interferon-gamma release assay; IMP=investigational medicinal 
product; Q2W=every 2 weeks; PK=pharmacokinetic(s); RAPID3=Routine Assessment of Patient Index Data; SFU=Safety Follow-up; TB=tuberculosis; V=Visit; W=week 
a  Visit days may take place within a window relative to the Visit Day. 
b  Home Visits may occur at the clinic/site rather than at home per study participant preference. Assessments at Home Visits will be conducted by the Home Visit nurse. 
c  In WOCBP, at Screening, a serum pregnancy test will be performed; for subsequent visits, urine pregnancy tests will be performed according the to Schedule of Activities. 
d  All ECG recordings should be taken with the study participant resting in the supine position for at least 5 minutes before the recording. 
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e  Loading doses of 400mg CZP will be administered at Weeks 0, 2, and 4, followed by treatment with 200mg Q2W. Study participants will have the option to self-inject IMP at 
home on Weeks 14, 16, 20, and 22.  
f At Visits in which dosing will take place, all activities should take place prior to IMP administration (including PK collection). 
g PK profile samples to be collected at 2 (Visit 9), 5 (Visit 10), 7 (Visit 11) and 10 (Visit 12) days post-Week 10 IMP administration. 
 
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2 
INTRODUCTION 
2.1 
Study rationale 
Certolizumab pegol (CZP) was approved for adults with rheumatoid arthritis (RA) in the United 
States (US) in May 2009. Certolizumab pegol pharmacokinetic (PK) and antidrug antibody 
(ADA) data in the adult RA population has thus far been generated with legacy bioanalytical 
methods which have more recently been superseded by new methods to comply with updated 
regulatory standards. Since the change in bioanalytical methods, no PK and ADA data have been 
generated for CZP in adults with RA. Further, there is no mathematical concordance between the 
previous and current (ECLIA) bioanalytical assays for CZP to enable bridging of PK data from 
one method to the other. 
The polyarticular juvenile idiopathic arthritis (pJIA) development program for CZP, to be based 
on ECLIA-generated PK data, is reliant on comparative CZP PK data from adults with RA. This 
study is being undertaken in order to generate this latter ECLIA-based adult PK data. As the 
safety and efficacy of CZP in adults with RA have been extensively established, this Phase 1B 
study is focused solely on acquiring ECLIA-based CZP PK data in CZP-naive participants who 
are eligible to receive a biologic for management of their RA disease. 
2.2 
Background 
2.2.1 
Rheumatoid arthritis 
Rheumatoid arthritis is a chronic, systemic, autoimmune disease with peripheral synovitis as its 
primary manifestation. Untreated, RA can lead to destruction, deformation, and dysfunction of 
affected joints which, in turn, may contribute to significant morbidity and increased mortality 
(Jacobsson et al, 2007). Moderate-to-severe RA is usually, if not always, treated with disease 
modifying antirheumatic drug (DMARDs), with methotrexate (MTX) being the agent most 
commonly used. For patients with an inadequate response to conventional DMARDs, biologic 
agents which inhibit tumor necrosis factor alpha (TNFα) (known as TNFα blockers), especially 
in combination with MTX, have been employed (Smolen et al, 2009). 
2.2.2 
Certolizumab pegol 
Certolizumab pegol (CZP) is a recombinant, humanized, monoclonal, antigen-binding prime 
antibody fragment (Fab′), with specificity for human TNFα, which is conjugated to polyethylene 
glycol (PEG). Certolizumab pegol has been studied for the treatment of inflammatory diseases, 
such as Crohn’s disease (CD; including pediatric CD), rheumatoid arthritis (RA), psoriatic 
arthritis, axial spondyloarthritis (including ankylosing spondylitis and nonradiographic axial 
spondyloarthritis), pJIA, and psoriasis. 
Certolizumab pegol was first approved for adults with Crohn's disease in the US in 2008 and for 
RA in 2009; it is available commercially in the US, EU, and approximately 64 other countries 
worldwide for the treatment of moderately to severely active RA in adults. Its safety and 
tolerability have been extensively studied and are detailed within the US Prescribing Information 
for health care professionals. 
Additional information on the nonclinical and clinical data for CZP is also available in the 
current version of the CZP Investigator’s Brochure. 
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2.3 
Benefit/Risk assessment 
Adult study participants, naive to CZP, will receive loading doses of 400mg CZP at Weeks 0, 2, 
and 4, followed by treatment with 200mg every 2 weeks (Q2W), with the final dose taking place 
at Week 24. This CZP dosing regimen has been approved for use in the US in adults with 
moderately to severely active RA. 
The risks of the present study are essentially those of experiencing an adverse event (AE) 
following administration of CZP and for progressive disability if the study participant does not 
respond to CZP. As a therapeutic class, currently available TNFα-inhibitors are known to be 
associated with serious infections, particularly reactivation of tuberculosis (TB) and 
opportunistic fungal infections. An association has also been reported with TNFα-inhibitor 
therapy and the development of malignancies including lymphoma and leukemia, Merkel Cell 
carcinoma, T-cell lymphoma, and melanoma, 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). Other serious adverse events 
(SAEs) that have been reported in participants treated with currently available TNFα-inhibitors, 
including CZP, include moderate-to-severe congestive heart failure, hypersensitivity reactions 
including anaphylaxis, new-onset psoriasis, demyelinating disorders, blood dyscrasias including 
aplastic anemia, immunogenicity including sarcoidosis, lupus, lupus-like illness, and 
hepatobiliary events. The additional risks to participants due to participation in the study will be 
nominal (eg, possible complications associated with collection of blood samples and collection 
of participant data). 
For a full list of potential AEs please refer to the Cimzia US Prescribing Information. 
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3 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To evaluate the PK of CZP (utilizing the 
ECLIA method) in adults with active RA 
• PK parameters (Cmin and AUC) following 
10 weeks of CZP dosing 
Secondary 
• To evaluate CZP exposure over a 
maximum of 24 weeks administration to 
adults with active RA 
• To evaluate the safety of CZP in adults 
with active RA 
• CZP plasma concentrations over the 
duration of study 
• Treatment-emergent SAEs and AEs 
leading to withdrawal from the time of the 
first CZP dose through the SFU Visit 
Other 
• To assess the occurrence of anti-CZP 
antibodies (utilizing the ECLIA method) 
over the duration of the study 
• ADA screening status (positive or 
negative screen), confirmatory status 
(positive or negative immunodepletion), 
and the titer for "positive 
immunodepletion" samples at each 
scheduled assessment after first CZP dose 
through SFU 
• To assess the efficacy of CZP 
• Change in Routine Assessment of Patient 
Index Data 3 (RAPID3) from Baseline to 
Week 12 
• To evaluate other safety parameters 
• TEAEs, vital signs, and laboratory 
assessments 
ADA=antidrug antibody; AE=adverse event; CZP=certolizumab pegol; ECLIA=electrochemiluminescent 
immuno-assay; PK=pharmacokinetic; RA=rheumatoid arthritis; RAPID3=Routine Assessment of Patient Index 
Data; SAE=serious adverse event; SFU=Safety Follow-up Visit; TEAE=treatment-emergent adverse event 
4 
STUDY DESIGN 
4.1 
Overall design 
This is a multi-center, open-label Phase 1B study to assess the PK, safety, and tolerability of 
CZP in adults with active RA. In this 24-week study, study participants who are naïve to CZP 
and have not previously failed to respond to treatment with ≥1 TNFα inhibitor will receive CZP 
in subcutaneous loading doses of 400 mg at Weeks 0, 2, and 4, followed by a treatment of 
200mg Q2W, with the final dose taking place at Week 24. 
A total of 30 study participants will be enrolled and will receive CZP. Study participants may be 
taking concomitant MTX; however, a minimum of 8 study participants must be enrolled who are 
not on concurrent administration of MTX. 
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The study consists of a Screening Period (up to 28 days), Baseline Visit, a Treatment Period 
(24 weeks), and a Safety Follow-Up (SFU) Visit (70 days after the last study visit). 
A schematic of the study design is presented in Section 1.2 and the Schedule of Activities for the 
study is presented in Section 1.3. 
4.2 
Scientific rationale for study design 
This study is being undertaken in support of the pJIA Pediatric Research Equity Act (PREA) 
requirement for Cimzia in pJIA. 
Through extensive interactions between the Food and Drug Administration 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 has been derived for TNF-α inhibitors based on the relationship 
between RA and pJIA and the extensive knowledge of TNF-α inhibitors as therapeutic agents. 
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. 
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. Although 
CZP has been approved in the US for RA in adults since May 2009, CZP PK and ADA data in 
the adult RA population have thus far been generated with legacy bioanalytical methods, which 
have more recently been superseded by new methods (namely, ECLIA) to comply with updated 
regulatory standards. Since the change in bioanalytical methods, no PK and ADA data have been 
generated for CZP in adults with RA. Further, there is no mathematical concordance between the 
previous and current (ECLIA) bioanalytical assays for CZP to enable bridging of PK data from 
one method to the other. 
The pJIA development program for CZP, to be based on ECLIA-generated PK data, is reliant on 
comparative CZP PK data from adults with RA. Thus, 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. At present, such ECLIA-based PK data for CZP in the adult RA population are 
not available. Accordingly, this study is being undertaken in order to generate ECLIA-based 
CZP PK data for CZP in adults with RA. As the safety and efficacy of CZP in adults with RA 
have been extensively established, this Phase 1B study is focused solely on acquiring 
ECLIA-based CZP PK data in CZP-naive participants who are eligible to receive a biologic for 
management of their RA disease. 
4.3 
Justification for dose 
The commercially approved dosing regimen for adult patients with RA (loading doses of 400mg 
at Weeks 0, 2, and 4 then 200 mg Q2W) will be used for the duration of the study. This CZP 
dosing regimen has been approved for use in the US in adults with moderately to severely active 
RA. 
4.4 
End of study definition 
A participant is considered to have completed the study if he/she has completed all portions 
(Screening, Baseline Visit, Treatment Period [through Week 24], and SFU) of the study. 
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Following investigational medicinal product (IMP) administration at Week 24, participants may 
transition to treatment with commercial CZP in consultation with their health care professional. 
The SFU Visit will be conducted 70 days post last administration of IMP. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 18 to 69 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
2. Participant must have a diagnosis of moderately-to-severely active RA. 
3. Participant must have had an inadequate response to, or intolerance to, at least 1 DMARD 
(nonbiologic or biologic). For example, the study participant had prior inadequate response to 
MTX (based on the Investigator’s clinical judgment). 
4. Participant has a negative interferon-gamma release assay (IGRA) at Screening. 
Weight 
5. Participant has a body mass index within the range 18.0kg/m2 to 35.0kg/m2 (inclusive). 
Sex 
6. Male or female 
− A female participant is eligible to participate if: 
◦ 
 she is not pregnant (see Appendix 4 [Section 10.4]), 
◦ 
not breastfeeding, 
◦ 
at least one of the following conditions applies: 
(1) Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
OR 
(2) A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during 
the Treatment Period and until the SFU Visit. 
Informed consent 
7. The participant is capable of giving signed informed consent as described in Appendix 1 
(Section 10.1) which includes compliance with the requirements and restrictions listed in the 
Informed Consent Form (ICF) and in this protocol. 
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5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Participant has any medical or psychiatric condition (including clinically significant 
laboratory abnormalities) that, in the opinion of the Investigator, could jeopardize or would 
compromise the study participant’s ability to participate in this study. 
2. Participant has a known hypersensitivity to any components of the study medication 
(including PEG) or comparative drugs (and/or an investigational device) as stated in this 
protocol. 
3. Participant with known concurrent viral hepatitis or known positivity for hepatitis B surface 
antigen or hepatitis C virus (HCV) antibody or known human immunodeficiency virus (HIV) 
infection. At Screening, a hepatitis panel result that indicates immunity due to hepatitis B 
vaccination is not considered an exclusion criterion. At Screening, a participant may not have 
any of the following: 
− Hepatitis B surface antigen, hepatitis B core antibody, hepatitis B virus deoxyribonucleic 
acid (DNA) assay: Positive to any of these. 
− HCV antibody: Positive. 
− HIV antigen or antibody: Positive to either test. 
4. Participant with a history of chronic or recurrent infections, or recent serious or 
life-threatening infection within the 6 months prior to the Baseline Visit (including 
hospitalization for any infection in the last 6 months or any current sign or symptom that may 
indicate an infection). 
5. Participant has known TB infection, is at high risk of acquiring TB infection, has latent TB 
infection, or has current or history of nontuberculous mycobacterial (NTMB) infection. 
− Known active TB disease 
− History of active TB involving any organ system unless adequately treated according to 
World Health Organization/Centers for Disease Control therapeutic guidance and proven 
to be fully recovered upon consult with a TB specialist 
− Latent tuberculosis infection (unless appropriate prophylaxis is initiated at least 4 weeks 
prior to IMP dosing and will be continued to completion of prophylaxis). Prophylaxis 
should be in accordance with applicable clinical guidelines and TB specialist judgment 
based on the origin of the infection. 
− High risk of acquiring TB infection. 
− Current NTMB infection or history of NTMB infection unless proven to be fully 
recovered 
Nontuberculous mycobacterial infection is defined as a group of lung infections caused by 
mycobacteria different from mycobacterium TB infections. 
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For further information relating to definitions of known active TB, past history of TB, latent 
TB infection, high risk of acquiring TB infection, and NTMB infection, refer to 
Section 8.2.5. 
6. Participant has active neoplastic disease or a history of neoplastic disease within 5 years of 
enrollment (except for basal or squamous cell carcinoma of the skin or carcinoma in situ 
which has been definitively treated with standard of care approaches). 
7. Participant has concomitant diagnosis of any other inflammatory condition (eg, psoriatic 
arthritis, sarcoidosis, or systemic lupus erythematosus). 
8. Participant has clinically significant electrocardiogram (ECG) abnormalities at Screening. 
Prior/Concomitant therapy 
9. Participant has previously been exposed to CZP. 
10. Participant is a primary failure to at least 1 TNFα inhibitor (a primary failure 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. 
11. Participant has received a live vaccination within 6 weeks prior to Screening or intends to 
have a live vaccination during the course of the study or within 3 months following CZP 
treatment in the study. 
Prior/Concurrent clinical study experience 
12. Participant has received any investigational drug or experimental procedure within 90 days 
prior to the first dose of IMP. 
Diagnostic assessments 
13. Participant has a laboratory abnormality at Screening, including any of the following: 
− >3.0x upper limit of normal (ULN) of any of the following: alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP); or >ULN total 
bilirubin (>1.5xULN total bilirubin if the participant has a documented pre-study 
diagnosis of Gilbert’s syndrome). 
− white blood cell count <3.00x103/μL. 
− absolute neutrophil count (ANC) <1.5x103/μL. 
− lymphocyte count <500 cells/μL. 
− hemoglobin <8.5g/dL. 
− Any other laboratory abnormality, which, in the opinion of the Investigator, will prevent 
the study participant from completing the study or will interfere with the interpretation of 
the study results. 
 
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5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
No meal or dietary restrictions are required during this study. 
5.3.2 
Caffeine, alcohol, and tobacco 
No caffeine, alcohol, and tobacco restrictions are required during this study; any restrictions (for 
the purposes of routine clinical management) are left to the judgment of the Investigator. 
5.3.3 
Activity 
No activity restrictions are required during this study. 
5.4 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated only 
once for confirmation. This one-time repeat testing may be within the initial screening window 
or as part of a rescreening following a screen failure. Upon retesting, study participants whose 
results remain outside the exclusion limit are not to be enrolled. 
6 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
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6.1 
Treatments administered 
Certolizumab pegol is an engineered, humanized, monoclonal antibody Fab’ fragment with 
specificity for human TNFα, produced in an Escherichia coli expression system. The antibody 
fragment is subsequently purified and conjugated with high molecular weight PEG (40kDa). 
Intervention name 
CZP 
Type 
Biologic 
Dose formulation 
Pre-filled syringe (1mL) 
Unit dose strength(s) 
200mg/mL 
Dosage levels 
400mg loading dose for first 3 doses (at Weeks 0, 2, and 4), followed by 
200mg Q2W maintenance dose thereafter 
Route of 
administration 
sc injection 
Use 
Experimental 
Sourcing 
Provided by UCB Clinical Trial Supply or designee 
Packaging and labeling 
The study medication is packaged according to GMP guidelines and 
applicable laws or regulations; study medication is labeled in accordance with 
current ICH, GCP, and GMP and includes any locally required statements. 
Current/Former names 
CDP870, Cimzia, CZP 
CZP=certolizumab pegol; GCP=Good Clinical Practice; GMP=Good Manufacturing Practice; ICH=International 
Council for Harmonisation; Q2W=every 2 weeks; sc=subcutaneous 
6.2 
Preparation, handling, storage, and accountability requirements 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment and only authorized site staff 
and home health nurses may supply and administer study treatment prior to Week 12. After 
Week 12, study participants will have the choice to self-administer CZP or receive treatment at 
the clinic/study site. All study treatments must be stored in a secure, environmentally-controlled, 
and monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
The Investigator (or designee) will instruct the participant to store the study medication 
following the instructions on the label. 
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Further guidance and information for the final disposition of unused study treatment are provided 
in the Study Reference Manual. 
6.2.1 
Drug accountability 
The Case Report Form (CRF) will be used to record study medication dispensing and return 
information on a by-participant basis and will serve as source documentation during the course 
of the study. Details of any study medication lost, damaged (due to breakage or wastage), not 
used, partially 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. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of study medication 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 study medication is used only in accordance with this 
protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired study medication must be reconciled 
and either destroyed at the site according to local laws, regulations, and UCB Standard Operating 
Procedures or returned to UCB (or designee). Investigational medicinal product intended for the 
study cannot be used for any other purpose than that described in this protocol. 
6.3 
Measures to minimize bias: randomization and blinding 
This is an open-label study. 
6.4 
Treatment compliance 
At each visit after study medication is dispensed, participants must return all unused study 
medication and empty study medication containers. Drug accountability must be done in the 
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. 
6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
The following concomitant medications are permitted during the study: 
• Methotrexate, under the following conditions: 
− Participant must have been stable for at least 1 month before Screening. 
− The participant’s route of MTX administration and dose of MTX should not change until 
after Week 12 of the study. 
− The (minimum of) 8 participants who are not taking MTX upon study entry cannot begin 
MTX until after Week 12 of the Treatment Period. 
− Dose reductions are permitted at any point during the study for safety reasons. 
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Other medications not explicitly prohibited per Section 6.5.2 are also included as permitted 
concomitant treatments. 
6.5.2 
Prohibited concomitant treatments (medications and therapies) 
The following concomitant medications are prohibited during the study: 
• Conventional synthetic DMARDs (csDMARDs) other than MTX (see Section 6.5.1 for MTX 
parameters). 
• Targeted synthetic DMARDs (tsDMARDs), eg, the Janus kinase inhibitor, tofacitinib. 
• Biologic DMARDs (CZP study medication excepted). 
• Any experimental (biological or nonbiological) 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, 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. 
6.5.3 
Rescue medication 
The Sponsor will not supply rescue medications. Such medicines should be sourced/prescribed 
locally by the treating physician. The following rescue medications may be used: 
• Any RA rescue medications available, excluding biologic DMARDs (CZP study medication 
excepted), csDMARDs other than MTX (see Section 6.5.1), and tsDMARDs. Any 
participants who use a biologic DMARD (other than study medication), csDMARD other 
than MTX (as per Section 6.5.1), or tsDMARD should be immediately withdrawn from the 
study. 
The date and time of rescue medication administration as well as the name and dosage regimen 
of the rescue medication must be recorded. 
If the study participant requires administration of a biologic DMARD, csDMARD other than 
MTX (as per Section 6.5.1), or tsDMARD, they must be removed from the study (Section 7.2). 
6.6 
Dose modification 
No dose modifications of the IMP will be allowed in this study, outside the transition from the 
loading doses to the maintenance dose (Section 6.1). 
6.6.1 
Dose interruptions 
Dose interruptions may only take place due to safety concerns. Participants who have a dose 
interruption will be followed according to the Schedule of Activities (Section 1.3). 
6.7 
Criteria for study hold or dosing stoppage 
As this is a study of an approved therapeutic for an approved indication, there are no anticipated 
study hold or dosing stoppage criteria planned. 
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6.8 
Treatment after the end of the study 
Study participants may transition to treatment with commercially-available CZP in consultation 
with their health care professional following completion of the last administration of IMP. 
7 
DISCONTINUATION OF STUDY MEDICATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
7.1.1 
Liver chemistry stopping criteria 
Discontinuation of study treatment for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in Figure 7-1 or if the 
Investigator believes that it is in best interest of the participant. 
Study medication will be discontinued immediately and permanently for a participant if liver 
chemistry stopping criteria are met. 
 
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Figure 7-1: Liver Chemistry Stopping Criteria and Increased Monitoring 
Algorithm 
 
 
Abbreviations: ALT=alanine transaminase; AST=aspartate aminotransferase; INR=international normalized ratio; 
SAE=serious adverse event; ULN=upper limit of normal 
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix 6 
(Section 10.6). 
7.2 
Participant Discontinuation/Withdrawal from the study 
Participants are free to withdraw from the study at any time, without prejudice to their continued 
care. 
A 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 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 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 (Section 1.3) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
ALT 
≥3xULN 
but 
<8xULN
Yes
Refer to the Liver Safety Required Actions and Follow-up Assessments section in 
Appendix 6. 
Report as an SAE if possible Hy’s Law case: AST/ALT ≥3xULN and Bilirubin 
≥2xULN (>35% direct) or INR >1.5, if measured* 
(Note: INR value not applicable to patients on anticoagulants) 
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Participants should be withdrawn from the study if any of the following events occur: 
1. Participant develops an illness that would interfere with his/her continued participation. 
2. Participant is noncompliant with the study procedures or medications in the opinion of the 
Investigator. 
3. Participant takes prohibited concomitant medications as defined in this protocol. 
4. Participant may withdrawal at any time due to lack of efficacy. At study discontinuation, the 
participant may be offered other treatment options, at the Investigator’s discretion. 
5. Participant withdraws his/her consent. 
6. Participant has confirmation of a pregnancy during the study, as evidenced by a positive 
pregnancy test. 
7. The Sponsor or a regulatory agency requests withdrawal of the participant. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a participant in advance. 
7.3 
Lost to follow-up 
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. 
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 CRF 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 CRF. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Section 1.3). 
Protocol waivers or exemptions are not allowed. Immediate safety concerns should be discussed 
with the Sponsor immediately upon occurrence or awareness to determine if the participant 
should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3), is essential and required for study conduct. All Screening evaluations 
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must be completed and reviewed to confirm that potential participants meet all eligibility criteria. 
The Investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for Screening or Baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the Schedule of Activities (Section 1.3). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 100mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
8.1 
Efficacy assessments 
8.1.1 
Multi-dimensional Health Assessment Questionnaire (MDHAQ) and 
RAPID3 scoring 
The MDHAQ items that make up the Routine Assessment of Patient Index Data 3 RAPID3 
(Appendix 12 [Section 10.12]) will be assessed at Baseline and Week 12 as indicated in the 
Schedule of Activities (Section 1.3). The MDHAQ is derived from the HAQ, and the sections 
that will be utilized are the following: 
• MDHAQ-FN : Physical function listed in 10 activities; converted to a scale from 0 to 10 for 
the RAPID3 score 
• MDHAQ-PN : Pain assessed as 0.5 increments from 0 to 10 
• MDHAQ-PTGL : Patient's global status assessed as 0.5 increments from 0 to 10 
RAPID3 is calculated as the sum (0 to 30) of FN, PN, and PTGL. 
8.2 
Safety assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3). 
8.2.1 
Physical examination 
A complete physical examination will include, at a minimum, vital signs; general appearance; 
ear, nose, and throat; eyes, hair, and skin; and assessments of the Cardiovascular, Respiratory, 
Gastrointestinal Neurological, Musculoskeletal, and Hepatic systems. Height and weight will 
also be measured and recorded. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Clinically relevant findings or worsening of previous findings will be recorded as AEs. 
8.2.2 
Vital signs 
Oral temperature, pulse rate, respiratory rate, and blood pressure will be measured as described 
in the Schedule of Activities (Section 1.3). 
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8.2.3 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the Schedule of Activities (see Section 1.3) 
using an ECG machine that automatically calculates heart rate and measures PR, QRS, QT, and 
QTc intervals. 
All ECG recordings should be taken with the study participant resting in the supine position for 
at least 5 minutes before the recording. 
8.2.4 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered to be clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or Baseline or are 
no longer considered clinically significant by the Investigator or Medical Monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the Schedule of Activities (Section 1.3). 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the CRF. 
8.2.5 
Tuberculosis assessment 
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. 
8.3 
Adverse events and serious adverse events 
The definitions of AEs and SAEs are provided in Appendix 3 (Section 10.3). 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
participant to discontinue the CZP (Section 7). 
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8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the signing of the ICF until the SFU visit as specified 
in the Schedule of Activities (Section 1.3). 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the CRF even if no study medication was taken but specific study 
procedures were conducted. This includes all AEs not present prior to the initial visit and all AEs 
that recurred or worsened after the initial visit. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
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 study 
medication), up to 70 days from the end of the study for each participant, and to also inform 
participants of the need to inform the Investigator of any SAE within this period. Serious AEs 
that the Investigator thinks may be associated with the study medication must be reported to 
UCB regardless of the time between the event and the end of the study. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as 
defined in Section 8.3.6), will be followed until resolution, stabilization, the Investigator 
determines that it is no longer clinically significant, the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). Further information on follow-up 
procedures is given in Appendix 3 (Section 10.3). 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
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Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study treatment and until SFU Visit. 
If a pregnancy is reported, the Investigator must inform the Sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 4 (Section 10.4). 
The participant should be withdrawn from the study as soon as pregnancy is known (by positive 
pregnancy test), and the following should be completed: 
• The participant should immediately stop the intake of the study medication. 
• The participant should return for an Early Discontinuation Visit. 
• An SFU Visit should be scheduled 70 days after the participant has discontinued her study 
medication. 
• The participant should complete a Pregnancy Outcome Form per UCB Standard Operating 
Procedures. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. For CZP, the following events require immediate 
reporting (within 24 hours regardless of seriousness) to UCB: 
• 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. 
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• 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). 
8.3.7 
Anticipated serious adverse events 
The anticipated SAE in Table 8-1 is anticipated to occur in the population studied in this protocol 
at some frequency that is independent of drug exposure. 
• This list does not change the Investigator’s obligation to report all SAEs (including 
anticipated SAEs) as detailed in Section 8.3.4 and Appendix 3 (Section 10.3). 
Table 8-1: 
Anticipated serious adverse event for RA population 
Preferred term: 
Rheumatoid arthritis 
8.4 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the study medication so that Investigators, clinical study participants, 
regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the Patient Safety 
representative. 
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, laboratory or ECG results) for which data will be periodically reviewed 
during the course of the study. 
8.5 
Treatment of overdose 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the Drug Accountability module of the CRF. Any SAE or nonserious AE associated 
with excessive dosing must be followed as any other SAE or nonserious AE. These events are 
only considered AEs or SAEs if there are associated clinical signs and symptoms or if the act of 
taking the excess medicine itself is an AE or SAE (eg, suicide attempt). 
UCB does not recommend specific treatment for an overdose. In the event of an overdose, the 
Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until CZP can 
no longer be detected systemically (at least 70 days). 
3. Obtain a plasma sample for PK analysis within 70 days from the date of the last dose of study 
treatment if requested by the Medical Monitor (determined on a case-by-case basis). 
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4. Document the quantity of the excess dose as well as the duration of the overdose in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.6 
Pharmacokinetics 
Pharmacokinetic samples will be tested using the ECLIA method. All PK assessments will be 
evaluated as described in the Schedule of Activities (Section 1.3). 
Whole blood samples of approximately 5 mL will be collected for measurement of plasma 
concentrations of CZP as specified in the Schedule of Activities (Section 1.3). A maximum of 
3 samples may be collected at additional time points during the study if warranted and agreed 
upon between the Investigator and the Sponsor. Instructions for the collection and handling of 
biological samples will be provided by the Sponsor. The actual date and time (24-hour clock 
time) of each sample will be recorded. 
Samples will be used to evaluate the PK of CZP. Samples collected for analyses of CZP 
(plasma/serum/whole blood) concentration may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study. 
Genetic analyses will not be performed on the plasma or whole blood samples. 
8.7 
Genetics 
Genetics will not be evaluated in this study. 
8.8 
Pharmacodynamics 
Pharmacodynamic parameters will not be evaluated in this study. 
8.9 
Biomarkers 
Biomarkers will not be evaluated in this study. 
8.9.1 
Immunogenicity assessments 
Immunogenicity samples will be tested using the ECLIA method. Antibodies to CZP will be 
evaluated in plasma samples collected from all participants according to the Schedule of 
Activities (Section 1.3). These samples will be tested by the Sponsor or Sponsor's designee. 
Plasma samples will be screened for antibodies binding to CZP and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to further characterize the 
immunogenicity of CZP. 
8.10 
Health economics or medical resource utilization and health 
economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan. 
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9.1 
Definition of analysis sets 
The following analysis sets will be used in the study: 
• All Study Participants (ASP) will include those study participants who are confirmed as 
having signed the ICF form to participate in the study. 
• The Safety Set (SS) will include all study participants enrolled who receive ≥1 injection of 
study medication. Safety variables will be summarized using the SS. 
• The Pharmacokinetic Set (PKS) is a subset of the SS, consisting of study participants who 
have provided plasma samples with measurable concentrations (with recorded sampling 
time) on at least 1 visit, and who have no important protocol deviations affecting the PK 
parameters. 
9.2 
General statistical considerations 
Statistical analysis and generation of tables, figures, and study participant data listings will be 
performed using statistical analysis system (SAS®, SAS Institute, Cary, NC, US) version 9.3 or 
higher using validated program code according to relevant standard operating procedures. 
For categorical parameters, the number and percentage of study participants in each category will 
be presented. The denominator for percentages will be based on the number of study participants 
appropriate for the purpose of the analysis. For continuous parameters, descriptive statistics will 
include number of study participants, arithmetic mean, standard deviation, median, minimum, 
and maximum (with 25th and 75th percentiles as optional). 
For CZP plasma concentration, the geometric mean and corresponding coefficient of variation 
will be presented. The geometric coefficient of variation (CV) is calculated as 
sqrt (exp(std ln^2)-1)*100, where std ln is the standard deviation of the log-transformed data. 
Baseline is defined as the last nonmissing measurement collected before the first injection. 
9.3 
Planned safety and other analyses 
Safety will be assessed using the SS. Pharmacokinetics and immunogenicity will be assessed 
using the PKS. 
All safety endpoints will be analyzed using descriptive statistics. Safety summaries will include 
presentations of AEs, laboratory values, and vital signs. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities. 
Treatment-emergent AEs will be defined as events that have a start date on or following the first 
administration of study treatment in RA0138 through the final administration of study treatment 
+70 days. 
9.3.1 
Other analyses 
9.3.1.1 
Pharmacokinetic analyses 
Pharmacokinetic analysis will be performed on the PKS population. 
Concentration-time profiles will be summarized by visit, and descriptive statistics performed, 
including: n, geometric mean, CV%, maximum, minimum, arithmetic mean, and standard 
deviation. 
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A PK analysis will be performed to derive noncompartmental CZP PK parameters (Cmin and 
AUC) after their Week 10 dose. If needed, additional PK parameters may be derived based on 
the data. Further details of the analysis will be specified in the Statistical Analysis Plan. 
9.3.1.2 
Immunogenicity analyses 
The incidence of immunogenicity will be summarized by body weight group and visit, as 
specified. Individual plots of the CZP concentrations, clinical response, and safety will be 
expressed by ADA titer category. 
9.3.1.3 
RAPID3 analysis 
As this is a PK study, the RAPID3 assessment (utilizing the MDHAQ) is included to assist in 
clinical decision-making, and RAPID3 data will be listed (including change from Baseline) 
based on the SS population (Appendix 12 [Section 10.12]). 
9.4 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary efficacy, key safety, or PK outcomes for 
an individual study participant. The criteria for identifying important protocol deviations and the 
classification of important protocol deviations will be defined within the Important Protocol 
Deviations Template. To the extent feasible, rules for identifying protocol deviations will be 
defined without review of the data and without consideration of the frequency of occurrence of 
such deviations. Whenever possible, criteria for identifying important protocol deviations will be 
implemented algorithmically to ensure consistency in the classification of important protocol 
deviations across all study participants. 
All important protocol deviations will be listed by study participant. 
9.5 
Handling of dropouts or missing data 
Missing or partial dates for safety evaluations will be imputed and full details of these algorithms 
will be presented in the Statistical Analysis Plan. 
As discussed in Section 9.2, Baseline is defined as the last nonmissing pretreatment 
measurement. Therefore, data from the Screening Visit (if available) will be used as Baseline 
values, if data are missing at Week 0. 
No further imputations of any other missing data are planned. 
9.6 
Planned interim analysis and data monitoring 
No interim analysis or data monitoring is planned. 
9.7 
Determination of sample size 
With no formal hypothesis testing, a sample size of 30 enrolled participants with 25 participants 
who completed Visit 13 is deemed to provide sufficient plasma CZP concentration data with the 
ECLIA analytical method to serve as a reference PK dataset for PK matching in the pJIA 
program. Further, a simulation and re-estimation method applied using a non-RA CZP 
population PK model indicated that a sample size of 25 participants who completed Visit 13 in a 
study with the PK sampling scheme as that presently planned can estimate absorption rate 
constant, clearance, and distribution volume with acceptable precision (relative standard 
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deviation of <16%). Participants who withdraw from the study may be replaced at the discretion 
of the Investigator and Sponsor, depending on the circumstances. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
International Council for Harmonisation (ICH)-Good Clinical Practice (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, ICF, 
Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), advertisement (if 
applicable), and all other 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 participants or others, and any protocol deviations, to 
eliminate immediate hazards to 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 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 IRB/IEC 
requirements), at intervals appropriate to the degree of 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. 
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
Finance and insurance are addressed in the Investigator and/or contract research organization 
agreements, as applicable. 
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10.1.3 
Informed consent process 
A participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant, in both oral and written form, by the Investigator 
(or designee). Each participant will have the opportunity to discuss the study and its alternatives 
with the Investigator. 
Prior to participation in the study, the ICF should be signed and personally dated by the 
participant, or his/her legal representative, and by the person who conducted the informed 
consent discussion (Investigator or designee). The participant or his/her legal representative must 
receive a copy of the signed and dated ICF. As part of the consent process, each participant must 
consent to direct access to his/her medical records for study-related monitoring, auditing, 
IRB/IEC review, and regulatory inspection. 
If the ICF 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 ICF by 
the IRB/IEC and use of the amended form. 
All studies conducted at centers in the US must include the use of a Health Insurance Portability 
and Accountability Act Authorization form. 
The participant may withdraw his/her consent to participate in the study at any time. A 
participant is considered as enrolled in the study when he/she has signed the ICF. A CRF must 
not be started, nor may any study-specific procedure be performed for a given participant, 
without having obtained his/her written consent to participate in the study. 
10.1.4 
Data protection 
UCB staff (or designee) will affirm and uphold the participant’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the 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 
participant’s primary medical records that directly concerns this study (including, but not limited 
to, laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a participant’s study participation, and autopsy reports for deaths 
occurring during the study). 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
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10.1.5 
Committees structure 
Not applicable. 
10.1.6 
Data quality assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, legible, contemporaneous, original, and 
attributable from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
All essential documents must be retained by the Investigator for the minimum retention period 
mandatory under the applicable local laws and regulations. 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 trial master 
file. 
10.1.6.1 
Case Report form completion 
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) will 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. 
10.1.7 
Source documents 
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). 
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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, quality of life 
questionnaires, or video, for example. Source documents should be kept in a secure, limited 
access area. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the participant’s source documents. The 
Investigator will facilitate the process for enabling 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). 
10.1.8 
Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, requirements of the IRB/IEC or local 
health authorities, Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study medication development 
10.1.9 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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10.2 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in the table below will be performed by the central laboratory (PK and 
ADA samples) or by the local laboratory (safety samples). 
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study treatment administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
treatment decision or response evaluation, the results must be entered into the CRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistrya 
Blood Urea 
Nitrogen 
Potassium 
AST/ Serum glutamic-
oxaloacetic transaminase 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
ALT/ Serum glutamic-pyruvic 
transaminase 
Total protein 
 
Glucose 
(nonfasting) 
Calcium 
ALP 
 
Routine 
Urinalysis 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
Other Screening 
Tests 
• 
Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines) 
• 
Serum or urine hCG pregnancy test (as needed for women of childbearing 
potential)b 
All study-required laboratory assessments will be performed by a central laboratory, 
with the exception of the urine pregnancy test. 
 
The results of each test must be entered into the CRF. 
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Laboratory 
Assessments 
Parameters 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; eCRF=electronic 
Case Report form; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; 
IEC=Independent Ethics Committee; INR=international normalized ratio; IRB=Institutional Review Board; 
LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin 
concentration; MCV=mean corpuscular volume; RBC=red blood cell; ULN=upper limit of normal; 
WBC=white blood cell 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring events are given in Section 7.1.1 and Appendix 6 (Section 10.6). All events of ALT 3 ×upper 
limit of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international 
normalized ratio (INR) >1.5, if INR measured, may indicate severe liver injury (possible Hy’s Law) and must 
be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
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10.3 
Appendix 3: Adverse Events – Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study medication, whether or not considered related to the study 
medication. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study medication. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study medication administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study medication or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as an AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE. 
 
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Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the study participant’s 
condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
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f. Important medical events: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
• 
Examples of such events include, but are not limited to, potential Hy’s law, invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related 
to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records 
to UCB in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
UCB. In this case, all participant identifiers, with the exception of the participant number, will 
be redacted on the copies of the medical records before submission to UCB. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to 1 of the following categories: 
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with a SAE. Severe is a category utilized for rating the intensity of an 
event; and both AEs and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe (eg, a severe AE may be 
either serious or not serious, depending on whether these criteria are also met). 
The National Cancer Institute Common Terminology Criteria for Adverse Events should be used as a 
supportive standardization instrument to evaluate AEs and SAEs, but the final intensity grading by the 
Investigator must be mild, moderate, or severe. 
 
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Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study medication and each 
occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study medication administration will be 
considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to UCB. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to UCB. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by UCB to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
• 
An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the participant is lost to follow-up. This 
follow-up requirement applies to AEs, SAEs, and AEs of special interest. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide UCB with a copy of any post-mortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to UCB within 24 hours of receipt of the 
information. 
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Reporting of SAEs 
SAE Reporting to UCB via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to UCB will be the electronic data collection 
tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use the paper 
SAE data collection tool (see next section). 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then 
the site can report this information on a paper SAE form (see next section) or to the Medical 
Monitor or SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in the section on SERIOUS ADVERSE EVENT 
REPORTING. 
 
SAE Reporting to UCB via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Medical Monitor or SAE coordinator. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in the section on SERIOUS ADVERSE EVENT 
REPORTING. 
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10.4 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
− A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
− Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
Contraception Guidance 
Female participants 
Sexually active female participants of childbearing potential are eligible to participate if they 
agree to use an effective method of contraception consistently and correctly as described below: 
− hormonal contraceptives  (stable at least 2 months prior to Screening [Visit 1] if initiated 
prior to entering the study) 
− a combination of barrier and spermicide 
Study participants must agree to use an effective contraception during the study and for at least 
10 weeks after their final dose of IMP (or longer based on local approved label). 
In addition, 
− A vasectomized partner is an effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional effective method of contraception should be used. 
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− Sexual abstinence is considered an effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
medication. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 
Pregnancy testing 
• WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. For women who become WOCBP during the study, her first 
pregnancy test should be a serum pregnancy test. 
• Additional pregnancy testing should be performed during the Treatment Period and at the 
SFU (10 weeks after the last dose of study medication) and as required locally. 
• Pregnancy testing will be performed as outlined in the Schedule of Activities, to the 
sensitivity specified by the central laboratory. 
• Pregnancy testing will also be performed whenever pregnancy is suspected. 
Collection of pregnancy information 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive study medication. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be within 30 days after the delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study medication and be withdrawn from the study. 
The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a participant's pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate and the information will 
be forwarded to the Sponsor. Generally, the follow-up will be within 30 days after the 
delivery date. Any terminations of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
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pregnancy related SAE considered reasonably related to the study medication by the 
Investigator will be reported to the Sponsor as described in Section 8.3.5. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
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10.5 
Appendix 5: Genetics 
Not applicable. 
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10.6 
Appendix 6: Liver Safety – Suggested Actions and Follow-up 
Assessments 
Participants with potential drug-induced liver injury must be assessed to determine if study 
medication must be discontinued (Section 7.1.1). In addition, all concomitant medications and 
herbal supplements that are not medically necessary should be discontinued. 
Investigators should attempt to obtain information on study participants in the case of study 
medication discontinuation to complete the final evaluation. 
Study participants with potential drug-induced liver injury 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 study medication discontinuation and/or participant 
withdrawal (if applicable), must be recorded in the source documents. The CRF must document 
the primary reason for discontinuation of study medication. 
A specific monitoring plan must be agreed between the UCB Study Physician and the 
Investigator for study participants who have ALT >5xULN. The monitoring plan should include 
any necessary follow-up assessments (until resolution of the abnormal lab values). 
Liver chemistry stopping criteria are designed to assure participant safety and to evaluate liver 
event etiology. 
Liver Chemistry Stopping Criteria and Follow-up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute 
ALT 8xULN 
ALT Increase 
ALT 5xULN but <8xULN persists for 2 weeks 
ALT 3xULN but <5xULN persists for 4 weeks 
Bilirubina,b 
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)  
INRb 
ALT 3xULN and international normalized ratio (INR) >1.5, if INR measured 
Cannot 
Monitor 
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks 
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks 
Symptomaticc 
ALT 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity 
Suggested Actions and Follow-up Assessments 
Actions 
Follow-up Assessments 
• 
Immediately discontinue study medication. 
• 
Report the event to UCB within 24 hours. 
• 
Complete the liver event case report form 
(CRF), and complete a serious adverse event 
(SAE) data collection tool if the event also met 
the criteria for an SAE.b 
• 
Perform liver chemistry follow-up assessments. 
• 
Viral hepatitis serology.d 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the transaminase 
values show downward trend. 
• 
Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen), 
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Liver Chemistry Stopping Criteria 
• 
Monitor the participant until liver chemistry 
test abnormalities resolve, stabilize, or return to 
baseline (see MONITORING). 
• 
Do not restart/rechallenge participant with 
study medication unless allowed per protocol 
and UCB approval is granted. 
• 
If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
medication and continue participant in the 
study for any protocol-specified follow-up 
assessments.Consider the need for a toxicology 
screening. 
 
MONITORING: 
For bilirubin or INR criteria 
• 
Repeat liver chemistry tests (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin) and perform liver event 
follow-up assessments within 24 hours. 
• 
Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, 
or return to baseline. 
• 
A specialist or hepatology consultation is 
recommended. 
For all other criteria 
• 
Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver chemistry follow-up assessments 
within 24 to 72 hours. 
• 
Monitor participants weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to baseline. 
quantitative hepatitis B deoxyribonucleic 
acid (DNA), and hepatitis delta antibody.e 
• 
Obtain blood sample for pharmacokinetic 
(PK) analysis as soon as possible.f 
• 
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total bilirubin 
2xULN. 
• 
Obtain complete blood count with 
differential to assess eosinophilia. 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury (eg, 
fatigue, nausea, vomiting, right upper 
quadrant pain), or hypersensitivity, on the 
adverse event (AE) report form. 
• 
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) on 
the concomitant medications CRF. 
• 
Record alcohol use on the liver event 
alcohol intake CRF. 
• 
Exclude pregnancy. 
For bilirubin or INR criteria: 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• 
Serum acetaminophen adduct high 
performance liquid chromatography (HPLC) 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week; James, 2009). 
NOTE: Not required in China. 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete Liver Imaging and/or Liver 
Biopsy CRFs. 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study medication if ALT ≥3xULN and bilirubin ≥2xULN. Additionally, if 
serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin 
on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. 
b All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3xULN and INR >1.5 may 
indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of 
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hepatic impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not 
apply to participants receiving anticoagulants. 
c New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia). 
d Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E IgM antibody. 
e If hepatitis delta antibody assay cannot be performed, it can be replaced with a polymerase chain reaction (PCR) of 
hepatitis D RNA virus (where needed; Le Gal, 2005). 
f Record the date/time of the PK blood sample draw and the date/time of the last dose of study medication prior to 
the PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the 
Study Reference Manual. 
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10.7 
Appendix 7: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Not applicable. 
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10.8 
Appendix 8: Rapid Alert Procedures 
Not applicable. 
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10.9 
Appendix 9: Country-specific Requirements 
Not applicable. 
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RA0138 
 
 
 
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10.10 
Appendix 10: Abbreviations and Trademarks 
ADA 
antidrug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report form 
csDMARD 
conventional synthetic disease modifying antirheumatic drug  
CV 
coefficient of variation 
CZP 
certolizumab pegol 
DMARD 
disease modifying antirheumatic drug 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECLIA 
electrochemiluminescent immuno-assay 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGRA 
Interferon-gamma release assay 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
MDHAQ 
Multi-dimensional Health Assessment Questionnaire 
MTX 
methotrexate 
NTMB 
nontuberculous mycobacterial 
PDILI 
potential drug-induced liver injury 
PEG 
polyethylene glycol 
pJIA 
polyarticular juvenile idiopathic arthritis 
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PK 
pharmacokinetic 
PKS 
Pharmacokinetic Set 
PREA 
Pediatric Research Equity Act 
Q2W 
every 2 weeks 
RA 
rheumatoid arthritis 
RAPID3 
Routine Assessment of Patient Index Data 3 
SAE 
serious adverse event 
SFU 
Safety Follow-up 
SS 
Safety Set 
TB 
tuberculosis 
TNF 
tumor necrosis factor 
tsDMARD 
targeted synthetic disease modifying antirheumatic drug  
ULN 
upper limit of normal 
US 
United States 
WOCBP 
woman of childbearing potential 
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10.11 
Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
Amendment 1 (09 Dec 2020) 
Overall rationale for the amendment 
The primary reason for this nonsubstantial protocol amendment was to update the Schedule of 
Activities (Section 1.3) to include a safety laboratory assessment at Week 12 (Visit 13) that was 
omitted in error and to correct the study day associated with Visit 14. 
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Minor administrative, formatting, 
and typographical changes have 
been made. 
Updated to provide clarity 
and to be consistent with 
remainder of protocol and 
program. 
1.3 Schedule of Activities 
Included a safety laboratory 
assessment at Week 12 (Visit 13). 
This was planned but 
omitted in the original 
protocol. 
1.3 Schedule of Activities 
Corrected the study day for Visit 14 
from Day 140 to Day 126. 
Updated to correct an 
error.  
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10.12 
Appendix 12: RAPID3 Assessment 
The RAPID3 includes a subset of core variables found in the Multi-dimensional HAQ 
(MDHAQ). The MDHAQ, shown here, includes an assessment of physical function (Section 1 of 
the RAPID3 assessment [below]), a patient global assessment for pain (Section 2 of the RAPID3 
assessment [below]), and a patient global assessment for global health (Section 3 of the RAPID3 
assessment [below]). RAPID3 scores are quickly tallied by adding subsets of the MDHAQ as 
follows: 
How to calculate RAPID3 scores 
1. Ask the patient to complete questions 1, 2, and 3 while in the waiting room prior to his/her 
visit. 
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2. For question 1, add up the scores in questions a to j only (questions k to m have been found 
to be informative, but are not scored formally). Use the formula in the box on the right to 
calculate the formal score (0 to 10). For example, a patient whose answers total 19 would 
score a 6.3. Enter this score as an evaluation of the patient’s functional status. 
3. For question 2, enter the raw score (0 to 10) in the box on the right as an evaluation of the 
patient’s pain tolerance. 
4. For question 3, enter the raw score (0 to 10) in the box on the right as an evaluation of the 
patient’s global estimate. 
5. Add the total score (0 to 30) from questions 1, 2, and 3 and enter them as the patient’s 
RAPID3 cumulative score. Use the final conversion table to simplify the patient’s weighed 
RAPID3 score. For example, a patient who scores 11 on the cumulative RAPID3 scale would 
score a weighed 3.7. A patient who scores between 0 and 1.0 is defined as near remission; 
1.3 and 2.0 as low severity; 2.3 and 4.0 as moderate severity; and 4.3 and 10.0 as high 
severity. 
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11 
REFERENCES 
Jacobsson LT, Turesson C, Nilsson JA, et al. Treatment with TNF blockers and mortality risk in 
patients with rheumatoid arthritis. Ann Rheum Dis. 2007;66(5):670-5. 
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of Acetaminophen-Adduct in Adults 
with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos. 2009;37:1779-84. 
Smolen J, Landewé RB, Mease P, et al. Efficacy and safety of certolizumab pegol plus 
methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. 
Ann Rheum Dis. 2009;68(6):797-804. 
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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:
RA0138-protocol-amend-2
Version:
1. 0
Document Number:
CLIN-000171341
Title:
RA0138-protocol-amend-2
Approved Date:
19 Mar 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 18-Mar-2021 19:36:56 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 18-Mar-2021 21:47:55 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Medical
Date of Signature: 19-Mar-2021 09:32:11 GMT+0000
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SAP_001.pdf: 
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Statistical Analysis Plan 
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RA0138 
 
 
 
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STATISTICAL ANALYSIS PLAN 
Study: RA0138 
Product: Certolizumab Pegol 
A MULTI-CENTER, OPEN-LABEL STUDY TO EVALUATE THE 
PHARMACOKINETICS OF CERTOLIZUMAB PEGOL IN 
ADULTS WITH ACTIVE RHEUMATOID ARTHRITIS USING AN 
ELECTROCHEMILUMINESCENT IMMUNO-ASSAY 
SHORT TITLE: 
A study to evaluate the PK of certolizumab pegol in adults with active rheumatoid arthritis using 
an electrochemiluminescent immune-assay (ECLIA). 
 
Sponsor Name: UCB Biopharma SRL 
Legal Registered Address: Allée de la Recherche 60 1070 Brussels BELGIUM 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND Number: 
009869 
 
 
 
 
 Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 6 
1 
INTRODUCTION ............................................................................................................. 7 
1.1 
Objectives and Estimands/Endpoints ............................................................................. 9 
1.2 
Study design ................................................................................................................... 9 
1.2.1 
Overall Design ....................................................................................................... 9 
1.2.2 
Number of Participants ........................................................................................ 10 
1.2.3 
Treatment Groups and Duration .......................................................................... 10 
1.2.4 
Schema- Schedule of Activities ........................................................................... 11 
2 
STATISTICAL HYPOTHESES ...................................................................................... 12 
3 
SAMPLE SIZE DETERMINATION .............................................................................. 12 
4 
POPULATIONS FOR ANALYSIS ................................................................................. 12 
5 
STATISTICAL ANALYSES .......................................................................................... 12 
5.1 
General Considerations ................................................................................................ 12 
5.1.1 
General study level definitions ............................................................................ 13 
5.1.1.1 
Analysis Time Points ................................................................................. 13 
5.1.1.2 
Protocol Deviations ................................................................................... 15 
5.1.1.3 
Treatment assignment and treatment groups ............................................. 15 
5.1.1.4 
Center pooling strategy ............................................................................. 15 
5.1.1.5 
Coding dictionaries .................................................................................... 15 
5.1.1.6 
Multicenter studies .................................................................................... 16 
5.2 
Participant Dispositions ............................................................................................... 16 
5.3 
Primary Endpoint(s) Analysis ...................................................................................... 17 
5.3.1 
Definition of endpoint(s) ..................................................................................... 17 
5.3.2 
Main analytical approach ..................................................................................... 17 
5.3.2.1 
Handling of dropouts or missing data ....................................................... 18 
5.3.3 
Sensitivity analysis .............................................................................................. 18 
5.3.4 
Supplementary analyses ....................................................................................... 18 
5.4 
Secondary Endpoint(s) Analysis .................................................................................. 18 
5.4.1 
Key secondary endpoint(s) .................................................................................. 18 
5.4.1.1 
Definition of endpoint(s) ........................................................................... 18 
5.4.1.2 
Main analytical approach .......................................................................... 18 
5.4.1.3 
Sensitivity analysis .................................................................................... 20 
5.4.1.4 
Supplementary analyses ............................................................................ 20 
5.4.2 
Supportive secondary endpoint(s) ....................................................................... 20 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis.................................................................. 20 
5.5.1.1 
Immunological Analyses ........................................................................... 21 
5.5.1.2 
RAPID3 analysis ....................................................................................... 25 
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5.5.1.3 
Adverse Events .......................................................................................... 25 
5.5.1.4 
Vital Signs ................................................................................................. 26 
5.5.1.5 
Clinical laboratory evaluations .................................................................. 27 
5.6 
(Other) Safety Analyses ............................................................................................... 29 
5.6.1 
Extent of Exposure .............................................................................................. 29 
5.6.1.1 
Electrocardiograms .................................................................................... 29 
5.6.1.2 
Electrocardiogram Values Over Time ....................................................... 29 
5.6.2 
Additional Safety Assessments ............................................................................ 30 
5.6.2.1 
Other safety endpoint(s) ............................................................................ 30 
5.7 
Other Analyses ............................................................................................................. 30 
5.7.1 
Other endpoints and/or parameters ...................................................................... 30 
5.7.1.1 
Pharmacokinetics ....................................................................................... 30 
5.7.1.2 
Pharmacodynamics .................................................................................... 30 
5.7.1.3 
Genomics ................................................................................................... 30 
5.7.1.4 
Tuberculosis screening (IGRA) and Tuberculosis Questionnaire ............. 30 
5.7.1.5 
COVID-19 Impact ..................................................................................... 30 
5.8 
Subgroup analyses ....................................................................................................... 31 
5.9 
Interim Analyses .......................................................................................................... 31 
5.10 
Data Monitoring Committee (DMC) or Other Review Board ..................................... 31 
6 
SUPPORTING DOCUMENTATION ............................................................................. 31 
6.1 
Appendix 1 Non-key analysis specifications ............................................................... 31 
6.1.1 
Baseline characteristics and demographics ......................................................... 31 
6.1.2 
Protocol deviations .............................................................................................. 32 
6.1.3 
Medical history .................................................................................................... 33 
6.1.4 
History of Rheumatoid Arthritis .......................................................................... 33 
6.1.5 
Prior/concomitant medications ............................................................................ 34 
6.1.5.1 
Prior medication definition ........................................................................ 34 
6.1.5.2 
Concomitant medication definition ........................................................... 34 
6.1.6 
Data derivation rules ............................................................................................ 34 
6.1.6.1 
Handling of repeated and unscheduled measurements .............................. 34 
6.1.6.2 
Handling of Dates and times ..................................................................... 35 
6.1.7 
AEs of Special Interest (AESIs) .......................................................................... 37 
6.1.8 
Potentially Clinically Significant Criteria for Safety Endpoints ......................... 40 
6.1.9 
Compliance .......................................................................................................... 40 
6.2 
Appendix 2: Changes to Protocol-Planned Analyses .................................................. 40 
7 
REFERENCES ................................................................................................................ 40 
8 
APPENDICES ................................................................................................................. 42 
8.1 
RAPID3 Assessment .................................................................................................... 42 
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8.2 
SAP Amendment 1 ...................................................................................................... 43 
 
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VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study RA0138  is based on the protocol amendment 2 
dated 18 Mar 2021.   
SAP Version 
Approval Date 
Change 
Rationale 
1.0 
23-APR-2021 
Not Applicable 
Original version 
2.0 
30-Aug-2022 
Section 5.1.1.2 Anti-
drug antibodies 
analysis has been 
added new analysis  
To be consistent with  
CZP ISAP  
 
 
 
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LIST OF ABBREVIATIONS 
 
ADAb 
Antidrug Antibody 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ALQ 
Above The Limit Of Quantification 
AST 
Aspartate Aminotransferase 
ASP 
All Subject Population 
AUC0-tau 
Area Under The Plasma Concentration-Time Curve From Time Zero To 
Infinity. 
BLQ 
Below The Limit Of Quantification 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CI 
Confidence Interval 
Cmin 
Minimum Observed Plasma Drug Concentration 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CV 
Coefficient Of Variation 
CZP 
Certolizumab Pegol 
DCP 
Data Cleaning Plan 
DEM 
Data Evaluation Meeting 
DILI 
Drug Induce Liver Injury 
ECG 
Electrocardiogram 
ECLIA 
Electrochemiluminescent Immuno-Assay 
EMA 
European Medicines Agency 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
geoCV 
Geometric Coefficient Of Variation 
geoMean 
Geometric Mean 
ICF 
Informed Consent Form 
ICH 
International Council For Harmonisation 
IGRA 
Interferon-Gamma Release Assay 
IMP 
Investigational Medicinal Product 
IPD 
Important Protocol Deviation 
LLOQ 
Lower Limit Of Quantification 
MDHAQ 
Multi-dimensional Health Assessment Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTX 
Methotrexate 
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NI 
Negative Immunodepletion 
NS 
Negative Screen 
pJIA 
Polyarticular Juvenile Idiopathic Arthritis 
PI 
Positive Immunodepletion 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic Set 
PS 
Positive Screen 
PT 
Preferred Term 
Q2W 
Every 2 Weeks 
RA 
Rheumatoid Arthritis 
RAPID3 
Routine Assessment of Patient Index Data 3 
RCTC 
rheumatology common toxicity criteria 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sc 
Subcutaneous 
SD 
Standard Deviation 
SOC 
System Organ Class 
SFU 
Safety Follow-up 
SS 
Safety Set 
TB 
Tuberculosis 
TFL 
tables, figures and listings 
TEAE 
treatment-emergent adverse event 
ULN 
Upper Limit Of Normal 
US 
United States 
WHODD 
World Health Organization Drug Dictionary 
1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the required statistical analysis of RA0138. It also defines the summary tables, figures 
and listings (TFLs) to be included in the final Clinical Study Report (CSR) according to the 
protocol. 
This SAP is based upon, and assumes familiarity, with the following study documents: 
1. Final Protocol Amendment 2: 18 Mar 2021 
If a future protocol amendment necessitates a substantial change to the statistical analysis of the 
study data, this SAP will be amended accordingly. If, after 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 described in a separate statistical 
analysis plan. However, if analysis definitions have to be modified or updated, a SAP 
amendment will be required. The content of this SAP is compatible with: 
• 
The International Council for Harmonisation (ICH) and E9 guidance documents2  
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• Food and Drug Administration (FDA) guidance3 
• European Medicines Agency (EMA) guidelines4,5 
• Canada Health ministry guidances6,7. 
UCB is the sponsor and PAREXEL International is the Contract Research Organization (CRO) 
for this study. 
 
 
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1.1 
Objectives and Estimands/Endpoints 
Table 1‒1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To evaluate the PK of CZP (utilizing the 
ECLIA method) in adults with active RA 
• PK parameters (Cmin and AUC0-tau) 
following 10 weeks of CZP dosing 
Secondary 
 
• 
• 
To evaluate CZP exposure over a 
maximum of 24 weeks administration to 
adults with active RA 
To evaluate the safety of CZP in adults 
with active RA 
• 
• 
CZP plasma concentrations over the 
duration of study 
Treatment-emergent SAEs and TEAEs 
leading to withdrawal from the time of the 
first CZP dose through the SFU Visit 
Other 
 
• 
• 
• 
To assess the occurrence of anti-CZP 
antibodies (utilizing the ECLIA method) 
over the duration of the study 
To assess the efficacy of CZP 
To evaluate other safety parameters 
• 
• 
• 
ADAb screening status (positive or negative 
screen), confirmatory status (positive or 
negative immunodepletion), and the titer for 
"positive immunodepletion" samples at each 
scheduled assessment after first CZP dose 
through SFU 
Change in Routine Assessment of Patient 
Index Data 3 (RAPID3) from Baseline to 
Week 12 
TEAEs, vital signs, and laboratory 
assessments 
ADAb=antidrug antibody; AE=adverse event; CZP=certolizumab pegol; ECLIA=electrochemiluminescent 
immuno-assay; PK=pharmacokinetic; RA=rheumatoid arthritis; RAPID3=Routine Assessment of Patient 
Index Data; SAE=serious adverse event; SFU=Safety Follow-up Visit; TEAE=treatment-emergent adverse 
event 
 
1.2 
Study design 
1.2.1 
Overall Design 
This is a multi-center, open-label Phase 1B study to assess the PK, safety, and tolerability 
of CZP in adults with active RA. In this 24-week study, study participants (ie, male or 
female participants 18 to 69 years of age inclusive) who are naïve to CZP and are eligible to 
receive a biologic for RA will receive CZP in subcutaneous (sc) loading doses at Weeks 0, 
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2, and 4, followed by a treatment of 200mg every 2 weeks (Q2W), with the final dose 
taking place at Week 24. 
1.2.2 
Number of Participants 
A total of 30 participants will be enrolled to receive CZP, such that a minimum of 25 
evaluable participants are expected to complete Visit 13 (Week 12). 
1.2.3 
Treatment Groups and Duration 
All study participants will receive CZP treatment. Study participants may be taking 
concomitant methotrexate (MTX); however, a minimum of 8 study participants must be 
enrolled who are not on concurrent administration of MTX. 
The duration of the study is approximately 38 weeks. The study consists of a Screening 
Period (28 days), Baseline Visit, a Treatment Period (24 weeks), and a Safety Follow-up 
(SFU) Visit (70 days after the last study visit). 
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1.2.4 
Schema- Schedule of Activities 
 
 
ADAb=antidrug antibody; BL=Baseline; CZP=certolizumab pegol; PK=pharmacokinetic; Q2W=every 2 weeks; W=week  
a CZP naïve at enrollment. 
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2 
STATISTICAL HYPOTHESES 
No formal statistical hypothesis testing is planned in this study. 
3 
SAMPLE SIZE DETERMINATION 
With no formal hypothesis testing, a sample size of 30 enrolled participants with 25 participants 
who completed Visit 13 is deemed to provide sufficient plasma CZP concentration data with the 
ECLIA analytical method to serve as a reference PK dataset for PK matching in the pJIA program. 
Further, a simulation and re-estimation method applied using a non-RA CZP population PK model 
indicated that a sample size of 25 participants who completed Visit 13 in a study with the PK 
sampling scheme as that presently planned can estimate absorption rate constant, clearance, and 
distribution volume with acceptable precision (relative standard deviation of <16%). Participants 
who withdraw from the study may be replaced at the discretion of the Investigator and Sponsor, 
depending on the circumstances. 
4 
POPULATIONS FOR ANALYSIS 
The following analysis sets will be used in the study: 
• All Study Participants (ASP) will include those study participants who are confirmed as having 
signed the ICF form to participate in the study. 
• The Safety Set (SS) will include all study participants enrolled who receive ≥1 injection of 
study medication. Safety variables will be summarized using the SS. 
• The Pharmacokinetic Set (PKS) is a subset of the SS, consisting of study participants who have 
provided plasma samples with measurable concentrations (with recorded sampling time) on at 
least 1 visit, and who have no important protocol deviations affecting the PK parameters. 
5 
STATISTICAL ANALYSES 
5.1 
General Considerations 
Statistical analysis and generation of tables, figures, and study participant data listings will be 
performed using statistical analysis system (SAS®, SAS Institute, Cary, NC, US) version 9.3 or 
higher using validated program code according to relevant standard operating procedures. PK 
parameters will be calculated by Non-Compartmental Analysis (NCA) methods from the 
concentration-time data with actual time using Phoenix® WinNonlin® Version 8.3 or higher 
following UCB guideline: Guideline on performing NCA analysis , Nov 2017. 
In general, there will be no imputation of missing data unless otherwise stated.  
For categorical parameters, the number and percentage of study participants in each category will 
be presented. The denominator for percentages will be based on the number of study participants 
appropriate for the purpose of the analysis. For continuous parameters, descriptive statistics will 
include number of study participants, arithmetic mean, standard deviation, median, minimum, and 
maximum (with 25th and 75th percentiles as optional). 
Baseline is defined as the last nonmissing measurement collected before the first injection. 
When reporting relative frequencies or other percentage values, the following rules apply: 
• For values where all study participants fulfill certain criteria, the percentage value will be 
displayed as 100 
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• For values where the absolute frequency is zero, there will be no percentage displayed at all 
• All other percentage displays will use 1 decimal place 
Percentages displayed based on continuous data (eg, percentage changes from baseline) will be 
displayed to 1 decimal place. 
When reporting descriptive statistics, the following rules will apply in general: 
• n will be an integer 
• Mean (arithmetic and geometric), SD and median will use 1 decimal place more than the 
original data 
• geoCV will be reported as a percentage to 1 decimal place 
• Minimum and maximum will be reported using the same number of decimal places as the 
original value 
• If no study participants have data at a given time point, for example, then only n=0 will be 
presented. If n<3, then only n, minimum and maximum will be presented. If n=3, then only n, 
mean, median, minimum and maximum will be presented. The other descriptive statistics will 
be left blank. 
For CZP plasma concentration, the geometric mean and corresponding coefficient of variation will 
be presented. The geometric coefficient of variation (CV) is calculated as sqrt (exp(std ln^2)-
1)*100, where std ln is the standard deviation of the log-transformed data.  
All tabulations will be performed for PKS, visit and timepoint (where applicable). Data listings 
containing all documented data and all derived data will be generated. 
 
5.1.1 
General study level definitions 
5.1.1.1 
Analysis Time Points 
5.1.1.1.1 
Relative day 
Relative day for an event will be derived with the date of the first sc injection of study drug as 
reference. 
Relative days for an event or measurement occurring before the date of the sc injection of study 
drug are calculated as follows: 
Relative Day = [(Event Date – Date of First Injection)] 
The relative day for an event or measurement occurring on or after the reference date to the date of 
the sc injection is calculated as follows: 
 
Relative Day = [(Event Date - Date of First Injection) + 1] 
In the listing, Relative Day will be presented as below:  numbers with no prefix are days after first 
dose at visit 2 +1, ‘-’ prefixed numbers are days before first dose at visit 2 and ‘+’ prefixed 
numbers will be days after last dose at visit 15. 
For PK , the relative time (hour) is calculated as the date time of each sample minus the date time 
of dose at the PK sample date. 
 
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5.1.1.1.2 
End date of the Treatment Period 
The end date of the Treatment Period will be either the date of Visit 15(Week 24) for study 
participants completing the Treatment Period, or the date of the Early Discontinuation Visit (EDV) 
for study participants who discontinued during the Treatment Period. If a participant does not have 
a Visit 15(Week 24)/EDV, then either the date of the last scheduled or unscheduled visit during the 
Treatment Period or the date of last known dose of study drug during the Treatment Period, 
whichever is later, will define the end date of the Treatment Period. 
 
5.1.1.1.3 
Study periods 
The duration of the study for each study participant is approximately 38 weeks.; consisting of the 
following 3 periods: 
• Screening Period (up to 28 days): Visit 1, Day -28 to Day -1 
• Treatment Period (24 weeks) including Baseline visit:  based on the first planned treatment 
starting from Visit 2 at Day 0 to the last planned treatment on Visit 15 at Day 168 (Week 24) 
− 400mg loading dose phase for doses at Week 0, Weeks 2 and 4 followed by 200mg Q2W 
maintenance dose phase thereafter (at Week 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24) 
− PK profile treatment Period: Day 72±6 hours to Day 80±6 hours. These visits may be 
conducted at home visit. 
• Safety Follow-Up: The end of study visit will be performed on 70 days after last IMP through 
SFU visit.  
The end of the study is defined as the date of the last visit of the last study participant in the study. 
Study participants are considered to have completed the study if they complete the last scheduled 
study visit (Screening, Baseline Visit, Treatment Period [through Week 24], and SFU).  The safety 
follow-up visit is 70 days post last dose.  If study participants are continuing onto commercial 
Cimzia, the safety follow-up is 30 days post last dose.    
 
5.1.1.1.4 
Mapping of assessments performed at Early Discontinuation Visit 
For time course displays it may be necessary to assign premature withdrawal visits to a specific 
study time point.  In general, premature withdrawal visits should be assigned to what would have 
been the next scheduled visit for the particular assessment that is being summarized. This re-
assignment should be based upon the study day (relative to the baseline visit date). For example, a 
study assesses anti-CZP antibody sampling at Baseline (Day 0), Weeks 6, 12, 24 and SFU. If a 
participant discontinues on day 150 of the study, and the previous assessment was done at Week 6, 
the next scheduled assessment would normally be Week 12. However, study Day 150 is closer to 
the Week 24 visit (Study Day 168). Therefore, the termination assessment should be re-assigned to 
the Week 24 visit. If the premature withdrawal visit of study day is tied in the middle of two visits, 
then earlier visit will be chosen, (assuming earlier visit also without valid datapoint also, to avoid 
data overwritten). For example, suppose the patient also discontinues at Day 126 ( in the midpoint 
of Week 24, Day 168 and Week 12, Day 84), then the Week 12, Day 84 will be assigned and firstly 
considered. However, if there was recently assessed at Week 12,  the assessments obtained at 
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premature termination visit should be re-mapped and analyzed at the Week 24 visit, as there is 
already valid data available at the Week 12 visit.  
Generally speaking, assessments at an Early Discontinuation Visit (EDV) that correspond to a 
scheduled visit will be summarized at the scheduled visit corresponding to the EDV if the 
assessment was scheduled to occur at that visit. Such assessments will also be considered for Last 
Value. 
Different domains from the same EDV may be assigned to different visit weeks.  For example, the 
TB questionnaire is scheduled to be collected at screening, Weeks 12,and 24; RAPID3 testing at 
baseline, and Week 12.  If a participant has screening, baseline, and an EDV, both the TB 
questionnaire and RAPID3 testing withdrawal assessments should map to Week 12.   
5.1.1.1.5 
Definition of Baseline values 
Baseline is defined as the last nonmissing pretreatment measurement. Therefore, data from the 
Screening Visit (if available) will be used as Baseline values if data are missing at Week 0. No 
other data will be considered for Baseline.    
 
5.1.1.2 
Protocol Deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary PK outcome for an individual study 
participant. PK samples outside the protocol windows, missing doses or delayed doses potentially 
impacting PK, will be reviewed. PK sampling protocol deviations will not automatically cause their 
exclusion from the PKS set. The table of summary PK statistics and geometric mean PK 
concentration-time figure will be presented with and without those PK samples determined to be 
protocol deviations.  
The criteria for identifying important protocol deviations will be defined within the appropriate 
protocol-specific document at study start. Important protocol deviations will be reviewed as part of 
the ongoing data cleaning process.  
Furthermore, overall trends in protocol deviations will be discussed at the Data Evaluation 
Meeting. Through this data cleaning and evaluation process, all decisions regarding important 
protocol deviations and exclusions from analysis populations will be made. Important protocol 
deviations including those that lead to exclusion from the analysis sets will be identified and 
documented prior to database lock. 
All tabulations and listing of protocol deviations will be performed for all study participants. 
5.1.1.3 
Treatment assignment and treatment groups 
This is open label and one arm study; the case of treatment misallocation will be not applicable.  
 
5.1.1.4 
Center pooling strategy 
The data from all centers will be pooled together for analyses. 
5.1.1.5 
Coding dictionaries 
All AEs and medical history will be coded for analysis according to the Medical Dictionary for 
Regulatory Activities (MedDRA)® coding dictionary, using the MedDRA version 23.1. Prior and 
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concomitant medications will be coded for analysis using the version Sep/2020 B3 update of the 
World Health Organization Drug dictionary (WHO-DD). Medical procedures will not be coded. 
 
5.1.1.6 
Multicenter studies 
The data from all centers will be pooled together for analyses. Individual center results will not be 
displayed. 
5.2 
Participant Dispositions 
The following summary outputs will be presented. 
− Reasons for screen failures will be summarized using the All Study Participants (ASP), 
including rescreened study participants. 
− Disposition of study participants screened will be summarized using the ASP for overall 
and by site. In this summary, the site number, principal investigator name, first participant 
in date, last participant out date, number of study participants screened will be captured by 
each analysis set (SS). 
− Disposition and Discontinuation Reasons using the SS will contain the number and 
percentage of study participants by loading dose phase and maintenance phase. 
− Discontinuation due to AEs will be summarized for following type of AEs using the SS: 
o AE, serious fatal, 
o AE, non-fatal, 
o Other (AE, non-serious fatal). 
- 
Impact of COVID-19 using the ASP will summarize number and percentage of 
participants in each impact category by visit. 
The number of study participants who started into the study and study participants who completed 
or prematurely discontinued the study, as well as the reason for discontinuation, will be presented 
by CZP loading dose(400 mg) and CZP maintenance dose (200 mg) for SS. A participant who 
completed the whole study is defined as a participant who completed the last scheduled Safety-
Follow-Up Visit, ie, the participant will be regarded as a completer if the safety-follow-up (Visit 
16, 70 days after last IMP through SFU visit) visit was completed. The number and percentage of 
study participants who discontinued due to AEs will be separately summarized based on the SS. 
Screen failure reasons will be summarized based on All Study Participants (ASP). A listing of 
study participants who did not meet study eligibility criteria (including glossary) will also be 
presented based on All Study Participants (ASP). 
In addition, the following listings will be presented for all study participants : 
• 
Study participant disposition (ASP) 
• 
Study discontinuation (ASP) 
• 
Visit dates (ASP) 
• 
Subject analysis sets (ASP ) 
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Study participant disposition will be listed for all study participants based on the All Study 
Participants (ASP), and will include the date of informed consent, date and time of dosing, date of 
premature termination and primary reason (if applicable), and date of final contact. 
 
5.3 
Primary Endpoint(s) Analysis 
The primary endpoint analysis is to evaluate the PK of CZP (utilizing the ECLIA method) in 
adults with active RA. 
Pharmacokinetics will be assessed using the PKS. 
5.3.1 
Definition of endpoint(s) 
The primary PK variables will include the following PK parameters (Cmin and AUC0-tau ) following 
10 weeks of CZP dosing. 
• AUC0-tau : area under the curve over a dosing interval 
• Cmin: Minimum plasma drug concentration during a dosage interval.  
5.3.2 
Main analytical approach 
The primary PK parameters in plasma are: Cmin and AUC0-tau.  
The primary PK parameters of CZP will be summarized by MTX use at screening using descriptive 
statistics (number of available observations (n), arithmetic mean, median, SD, minimum, 
maximum, geometric mean, geometric CV and 95% CI for the geometric mean (assuming 
lognormally distributed data)).  Values below the LLOQ will be reported with a clear sign 
indicating that they were below the LLOQ. 
For calculation of the PK data (including parameter), the actual blood sampling times will be used. 
All PK data will be listed and summarized for all study participants for the PKS including n, 
arithmetic mean, median, SD, minimum, maximum, geometric mean, geoCV and 95% CI for the 
geometric mean. 
The following rules will apply for the PK data summaries: 
• PK parameters are reported with 3 significant digits and Descriptive statistics reported to 4 
significant figures for the mean, median and standard deviation (SD) and to 3 significant 
figures for all others. 
• Values below the LLOQ will be reported as BLQ for individual data and will be substituted 
with LLOQ/2 for the descriptive statistics 
• Descriptive statistics of PK concentrations will be calculated only if at least ⅔ of the 
individual data at a specific sampling timepoint are measured and are quantifiable (ie, above 
LLOQ) and if n≥4. If n<3, then only n, minimum and maximum will be presented and if 
n=3, then only n, median, minimum and maximum will be presented and the other 
descriptive statistics will be left blank. 
• Descriptive statistics of PK parameters will be calculated only if at least ⅔ of the individual 
data are calculable and if n≥4. If n<3, then only n, minimum and maximum will be 
presented and if n=3, then only n, median, minimum and maximum will be presented and 
the other descriptive statistics will be left blank.  
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• If no study participants have data, only n=0 will be presented. 
• The 95% lower and upper CI should be left blank if the SD (or equivalently the geoCV) is 
equal to 0 
• The geoCV will be calculated using the following formula where SD is the standard 
deviation of the log-transformed values: geoCV (%) = sqrt[(exp(SD^2) – 1)] x 100 
5.3.2.1 
Handling of dropouts or missing data 
Measurements that are BLQ will be imputed with half of the LLOQ for the purpose of calculating 
the geoMean and its 95% CI, the geoCV, the arithmetic mean, and SD for summaries and figures. 
If any summary value (geoMean, arithmetic mean, lower CI level or minimum) is lower than 
LLOQ, then ‘BLQ’ will be displayed.  
For the individual figures, any concentrations that are BLQ will be regarded as missing, with the 
exception of predose measurements BLQ on Day 0, which will be imputed with zero for linear 
scale plots. 
5.3.3 
Sensitivity analysis 
Not applicable. 
5.3.4 
Supplementary analyses 
Not applicable. 
5.4 
Secondary Endpoint(s) Analysis 
The secondary objective is to evaluate CZP exposure over a maximum of 24 weeks 
administration to adults with active RA and evaluate the safety of CZP in adults with active 
RA. 
5.4.1 
Key secondary endpoint(s) 
The secondary variables will include the following endpoints. 
• CZP plasma concentrations over duration of the study including Visit 2 till Visit 16 (70 Days 
through SFU visit). 
• Treatment-emergent SAEs from first dose through the SFU Visit.  
• Treatment-emergent AEs leading to withdrawal from first dose through the SFU Visit 
 
5.4.1.1 
Definition of endpoint(s) 
Key secondary endpoints will be to evaluate CZP plasma concentrations over the duration 
of study and treatment emergent SAEs and AEs leading to withdrawal from the time of the 
first CZP dose through the SFU Visit. 
 
5.4.1.2 
Main analytical approach 
5.4.1.2.1 
CZP plasma concentrations over the duration of study 
Individual plasma concentrations of CZP (from conventional venous sampling) will be listed for 
PKS and will include the actual and nominal sampling times. Any samples that are obtained outside 
the tolerance window permitted at the specified time point will be discussed at the DEM and any 
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possible exclusion from any specific analyses (i.e. summary statistics table and geomean figure) 
will be documented accordingly. If deemed appropriate, the analyses of the summary stats table and 
geomean figure may be repeated with and without the specific samples affected.  
The PK plasma concentrations of CZP will be summarized nominal sampling times by MTX use at 
screening (same definition in Section 6.1.1)  using descriptive statistics (number of available 
observations (n), arithmetic mean, median, SD, minimum, maximum, geometric mean, geometric 
CV and 95% CI for the geometric mean (assuming lognormally distributed data)).  Values below 
the LLOQ will be reported with a clear sign indicating that they were below the LLOQ.  
Geometric mean profiles of plasma concentrations for CZP over time will be presented in both 
linear and semi-logarithmic scale. For the linear scale plot only, the lower and upper 95% 
confidence interval (CI) for the geometric mean will be displayed.  
All plasma concentration figures will include the LLOQ on the semi-logarithmic scale plots and 
will be based on scheduled times and grouped by MTX use at screening. 
Further PK data handling rules are described in Section 5.3.2 . 
 
5.4.1.2.2 
Treatment-emergent SAEs  
A treatment-emergent adverse event (TEAE) is defined as events that have a start date on or 
following the first administration of study treatment in RA0138 through the final administration of 
study treatment+70 days through SFU visit. The treatment-emergent serious adverse event 
(TESAE) will follow the same definition and also mark serious adverse event as “Yes” in the 
adverse events CRF form. 
The analysis for secondary endpoint for treatment-emergent SAEs  will be included as follows: 
• 
Incidence of treatment-emergent SAEs  
• 
Incidence of treatment-emergent SAEs by Maximum Intensity  
• 
Incidence of treatment-emergent SAEs by Maximum Relationship 
Serious AEs summaries will be ordered by alphabetical SOC , HLT and decreasing frequency of 
PT within SOC in the CZP column for tables including event counts.  
A listing will be presented for SS for treatment-emergent SAEs . This will include the SOC, HLT 
and PT, onset date/time and outcome date/time of the event (including relative days), the AE 
duration, pattern of event, serious/intensity, relationship, action taken and outcome. In addition, the 
listing will flag hospitalization, SAEs, and AE of special interest. 
 
5.4.1.2.3 
Treatment-emergent AEs leading to withdrawal 
Similarly, the analysis for treatment emergent AEs leading to withdrawal from the time of the first 
CZP dose through the SFU Visit will be included as follows: 
• 
Incidence of treatment emergent AEs leading to withdrawal 
• 
Incidence of treatment emergent AEs leading to withdrawal by Maximum Intensity  
• 
Incidence of treatment emergent AEs leading to withdrawal by Maximum Relationship 
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Treatment emergent AE summaries will be ordered by alphabetical SOC and decreasing frequency 
of PT within SOC in the CZP column for tables including event counts.  
A listing will be presented for SS for treatment emergent AE leading to withdrawal and follow the 
same display of output as described in Section 5.4.1.2.2 . The other similar AE data handling rule 
will be also followed in Section 5.5.1.2. 
 
 
5.4.1.3 
Sensitivity analysis 
Not applicable. 
 
5.4.1.4 
Supplementary analyses 
Not applicable. 
 
5.4.2 
Supportive secondary endpoint(s) 
Not applicable. 
 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis 
Tertiary/Exploratory Endpoint(s) analysis or Other Objects and Endpoints will be performed  
and consist of following objectives: 
• To assess the occurrence of anti-CZP antibodies (utilizing the ECLIA method) over the 
duration of the study 
• To assess the efficacy of CZP 
• To evaluate other safety parameters 
 
The endpoints will be as follows: 
• ADAb screening status (positive or negative screen), confirmatory status (positive or negative 
immunodepletion), and the titer for "positive immunodepletion" samples at each scheduled 
assessment after first CZP dose through SFU 
• Change in Routine Assessment of Patient Index Data 3 (RAPID3) from Baseline to Week 12  
• TEAEs, vital signs, and laboratory assessments 
 
The following section will present the endpoints except ECG which are described in 
Section 5.6.1.1.  
. 
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5.5.1.1 
Immunological Analyses  
Immunogenicity samples will be tested using the ECLIA method. Antibodies to CZP will be 
evaluated in plasma samples collected from all participants according to the Schedule of Activities.  
Plasma samples will be screened for antibodies binding to CZP and the titer of confirmed positive 
samples will be reported. Other analyses may be performed to further characterize the 
immunogenicity of CZP. 
The incidence of immunogenicity will be summarized by visit, as specified and based on SS.  
 
5.5.1.1.1 
Handling of dropouts or missing data 
Levels of ADAb that are negative or no titer provided will be regarded as zero (negative) for all 
individual ADAb figures. 
5.5.1.1.2 
Anti-drug antibodies 
ADAb antibodies will be measured using a tiered assay approach: screening assay, confirmatory 
assay and titration assay. The ADA status at sample level will be defined in Table 5‒1 . 
A screening cut point will be determined by the bioanalytical laboratory that will be used to 
determine the status of ADAb as Positive Screen (PS) or Negative Screen (NS).  Samples 
presenting ADAb levels PS are considered “potentially ADAb positive” and will be further 
evaluated in the confirmatory assay, the result of which will be reported as either “Positive 
Immunodepletion” (PI) or “Negative Immunodepletion” (NI). Confirmed positive samples 
(reported as PI) will be titrated, and the titer (reciprocal dilution factor including minimum required 
dilution) will be reported.  
ADAb status at  sample level: 
Table 5‒1 : 
ADA status at Sample level 
ADA positive 
(ADAb+) 
  Sample values that are ‘positive screen’ and ‘positive immuno-
depletion’ 
ADA 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 ADA or limit dictated by the ADA assay and project needs 
(e.g. 250 ng/ml). 
ADA 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 ADA or limit dictated by the ADA assay and project needs (e.g. 
250 ng/ml)  
Missing  
Samples that were not collected per schedule or that could not be tested 
for ADA status due to inadequate sample volume, mishandling, or 
errors in sample collection, processing, storage, etc. 
 
Participant  Classification: 
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• A participant will be classified as overall positive if at least one post Baseline measurement is 
ADAb+ (see definition above) (this includes participant who have negative and positive results 
at baseline) 
• A participant will be classified as overall negative if at all post Baseline visits the ADAb status 
is negative (this includes study participants who have positive and negative results at Baseline) 
• A participant will be classified as having classification of ADA status as stated in below 
Table 5‒2 . 
Table 5‒2 
: 
Classification of ADA status 
1. 
Pre ADA negative and treatment-
emergent ADA negative  
Study participant who were negative at Baseline and 
negative at all sampling points post treatment at all 
timepoints 
2. 
Pre ADA negative and treatment-
(emergent)  induced ADA positive 
Study participant who were negative at Baseline and 
positive at any sampling point post treatment. This group 
also included study participants who had a missing pre-
treatment sample (either missing or insufficient volume) 
with 1 or more positive post-treatment samples. 
3. 
Pre ADA positive and treatment-
emergent reduced ADA  
Study participants who were positive at Baseline, and 
negative at all sampling points post treatment  all 
timepoints. 
4. 
Pre ADA positive and treatment-
emergent unaffected ADA 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 a 
predefined fold difference from the Baseline value of 4.11). 
5. 
Pre ADA positive and treatment-
emergent ADA boosted positive 
 Study participant 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 4.11 from Baseline value which 
is defined within the validation of the assay). 
6. 
ADA inconclusive 
 Study participants who were positive at Baseline and 
some post-treatment samples were missing, while 
other post-treatment samples were negative. 
7. 
Treatment emergent ADA positive 
Combination of 2 and 5 
8. 
Pre-treatment ADA positive  
Combination of 3, 4 and 5 
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 
post-treatment scheduled assessment.  
 
 
Analysis: 
Immunogenicity will be assessed through summary tables and figures and listing of individual 
results by study participant. All analyses will be run on the SS, unless specified otherwise. For all 
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tabulations, percentages will be calculated based on the number of study participants with non-
missing data. 
• Individual participant concentration-time profiles of CZP will be displayed graphically in linear 
and semi-logarithmic scale and grouped by MTX use at screening.  
• 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). 
• Summary table displaying the number and percentage of study participants with a positive 
ADA, negative ADA, inconclusive or missing ADA sample status at the time of each visit by 
treatment group. [Note that in case of presence of pre-ADA, no differentiation can be made 
between pre-ADA and treatment emergent ADA (either newly induced or boosted ADA). Note 
this table is not be used for incidence interpretation]. 
• Based on the overall ADA study participant classification above from Table 5-2, the following 
will be determined and presented: summary tables displaying the number and percentage of 
study participants in each of ADA participant status categories (1–9), with the denominator 
being the total number of study participants having an individual ADA participant category 
defined during the corresponding analysis period and treatment group. (All study participants 
will be assigned to a category in this table and should not be confused with ADA incidence that 
is defined below). 
Incidence and prevalence: 
• Total prevalence of pre-Ab overall and by treatment group.  Total prevalence of pre-Ab: n/NN 
% number of participants that have a pre-ADA positive ADA sample status, with NN being the 
denominator defined as all participants having an evaluable baseline ADA sample.  
• Overall ADA incidence and by treatment group, Treatment-Emergent Anti-CZP Antibody 
Positivity Activity for combined results of treatment-boosted ADA-positive participants and 
treatment induced ADA-positive participants. n/N % of participants that are treatment 
emergent, with N being the denominator defined as all participants except the participants 
categorized as inconclusive. 
• Summary tables of the time point of the first occurrence of treatment emergent (TE) ADA 
positivity (i.e first ADA sampling time point with ADA positive status if participant is pre-
ADA negative or first ADA sampling time point with fold difference increase from Baseline > 
the MSR if participant is pre-ADA positive) for study participants in category 2 and 5. The 
table will summarize the number and percentage of TE ADA positive participants who present 
first occurrence of TE ADA positivity at the specified time point and will include the 
cumulative number and cumulative percentage of participants at each time point. In case of 
ADA samples with missing or inconclusive status before the first ADA sampling time point 
considered TE ADA positive, the time point of the first occurrence of TE ADA positivity will 
be reported as ≤ than the respective ADA time point. In case of pre-ADA present in more than 
10% of the study participants, the table is split out between ADA participant category 2 and 5. 
The denominator for % calculations will be the total number of TE ADA positive participants. 
• Number and percentage of study participant Baseline Anti-CZP status and Treatment-Emergent 
Anti-CZP Antibody Status will be summarized during the entire study. The change in category 
from Baseline ADAb status including ADAb-, ADAb+, Missing and total will be presented in 
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shift tables at each post-Baseline treatment treatment-emergent anti-CZP antibody status. 
Treatment Treatment-Emergent Anti-CZP Antibody Status will be categorized as below: 
− Negative : Treatment Treatment-Emergent Anti-CZP Antibody Status is ADAb- 
− Positive <512 : Treatment Treatment-Emergent Anti-CZP Antibody Status is ADAb+ and 
ADAb titer is less than 512. 
− Positive 512-<=1024: Treatment Treatment-Emergent Anti-CZP Antibody Status is ADAb+ 
and ADAb titer is greater than 512 and less than or equal to 1024. 
− Positive>1024: Treatment Treatment-Emergent Anti-CZP Antibody Status is ADAb+ and 
ADAb titer is greater than 1024. 
− Any positive : Study participants having treatment-emergent ADAb+. 
− Total : total Treatment Treatment-Emergent Anti-CZP Antibody Status 
• Number and percentage of study participant Anti-CZP titer by visit will be summarized during 
the entire study. ADAb titer will be categorized as below: 
− Negative : The ADAb status is ADAb- 
− <=32 : The ADAb titer result is less than or equal to 32. 
− >32-128: The ADAb titer result is greater than 32 and less than or equal to 128. 
− >128-512: The ADAb titer result is greater than 128 and less than or equal to 512. 
− >512-1024: The ADAb titer result is greater than 512 and less than or equal to 1024. 
− >1024-4096: The ADAb titer result is greater than 1024 and less than or equal to 4096. 
− >4096: The ADAb titer result is greater than 4096. 
A listing will be presented showing the CZP concentrations and ADAb measurements in the same 
output in adjacent columns, based on the SS. The listing will include the CZP concentration and 
ADAb status (positive or negative) and screening assay results (PS or NS) and confirmatory assay 
results if applicable (NI or PI), together with the titer if applicable. In addition, the time since the 
administration of study medication will be reported (in days). ADAb samples that are negative but 
have drug concentration above the drug tolerance characteristics of the assay will be flagged. 
Time course plots of all individual CZP plasma concentrations profiles (each participant 
corresponding to a line) (spaghetti plot) with identification of the individual ADA participant 
category  using different colors ( categories 1, 3,4 and 7. If not sufficient participants in category 3 
and 4, these could be combined for this plot). These plots will be produced on a linear and 
semilogarithmic scale and multi-panel per treatment group. Individual samples with positive ADA 
sample status will be visualized using a symbol or a red dot. Dosing nominal time points should be 
indicated below the x-axis. A similar plot may be considered for PD endpoints.  The plot may be 
stratified based on MTX use at baseline/screening.  
Finally, individual participant plots will be presented displaying the ADAb titer and CZP 
concentrations overlaid on the same figure. The figure will also show the timing and dose of each 
administration of CZP received during the study. The ADAb data will be plotted using a semi-
logarithmic scale. ADAb samples that are negative but have drug concentration above the drug 
tolerance characteristics of the assay will be flagged on the plot. 
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The rules for handling values that are BLQ in the CZP concentration data are described in 
Section 5.5.1.1.1.  For the ADAb data, any negative results for which there are no titers (as 
applicable) available at a specific visit will be substituted with 0.001 for the purpose of the figure. 
 
5.5.1.2 
RAPID3 analysis 
The MDHAQ items that make up the RAPID3 (Routine Assessment of Patient Index Data 3) 
will be assessed at Baseline and Week 12. The MDHAQ is derived from the HAQ, and the 
sections that will be utilized are the following: 
• 
MDHAQ-FN : Physical function listed in 10 activities; converted to a scale from 0 to 10 
for the RAPID3 score 
• 
MDHAQ-PN : Pain assessed as 0.5 increments from 0 to 10 
• 
MDHAQ-PTGL : Patient's global status assessed as 0.5 increments from 0 to 10  
• 
RAPID3 cumulative score is calculated as the sum (0 to 30) of FN, PN, and 
PTGL. 
RAPID3 analysis will be based on the SS population. By participant list of the MDHAQ-FN 
(converted scale), MDHAQ-PN, MDHAQ-PTGL  and RAPID3 cumulative score with  actual 
values and change from Baseline will be provided at Baseline and Week 12. 
 
5.5.1.3 
Adverse Events 
Adverse events will be recorded from the time of informed consent until study completion. All AEs 
will be coded and categorized by relationship to CZP. The definitions of TEAE can be found in 
Section 5.4.1.2.2. 
The number and percentage of study participants who experience TEAEs will be for all study 
participants, SOC, and PT, based on the SS (unless otherwise stated). 
Summaries of TEAEs will include the following: 
• 
Summaries of TEAEs will include the following: 
o Incidence of TEAEs (overview including number and percentage of study 
participants with any TEAEs, serious TEAEs, discontinuations due to TEAEs, drug 
related TEAEs, severe TEAEs and deaths; event counts will also be included) 
• 
Incidence of TEAEs 
• 
Incidence of TEAEs by maximum relationship 
• 
Incidence of TEAEs by maximum intensity 
• 
Incidence of non-serious TEAEs above threshold of 5% of study participants 
• 
Incidence of non-serious TEAEs above threshold of 5% of study participants by 
Relationship 
 
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Where dates are missing or partially missing, AEs will be assumed to be treatment-emergent, 
unless there is clear evidence (through comparison of partial dates, see Section 6.1.6.2) to suggest 
that the AE started prior to dosing. 
Summary tables will contain counts of study participants, percentages of study participants in 
parentheses and the number of events. A participant who has multiple events in the same SOC and 
PT will be counted only once in the participant counts, but all events will be included. For the 
summary of injection site reactions, the specific PTs to be included will be reviewed and 
documented at the DEM. 
In summaries including intensity, the following intensity categories will be summarized: ‘Mild’, 
‘Moderate’, ‘Severe’. Study participants who experience the same event multiple times will be 
included in the most severe category for tabulations by maximum intensity. Events with missing 
intensity will be considered as ‘Severe’ events for summary purposes but recorded as missing in the 
listings. 
In summaries including relationship to CZP, the following relationships will be summarized: ‘Not 
related’, ‘Related’. Study participants who experience the same event multiple times will be 
included in the most related category for tabulations by maximum relationship. Events with missing 
relationship (for CZP) will be considered as ‘Related’ for the tabulations but recorded as missing in 
the listings. 
A listing will be presented for SS for AEs including TEAE and non-TEAE. This listing will follow 
the same structure as described in Section 5.4.1.2.2. 
 
5.5.1.4 
Vital Signs 
5.5.1.4.1 
Vital Sign Values Over Time 
The following vital signs measurements will be collected at Screening visit and End of Study visit 
(SFU/EDV): 
• Pulse rate (bpm) 
• Systolic and diastolic blood pressure (mmHg) 
• Oral Temperature (°F or °C) 
• Respiratory rate (breaths per minute) 
Descriptive statistics will be reported for all vital sign for SS. Measured values and changes from 
Baseline will be summarized by vital signs variables and time point(screening and SFU). 
Summarization will be as treated, and study participants who missed treatments will not be 
summarized. 
 
5.5.1.4.2 
Individual Participant Changes of Vital Sign Values 
A by- participant listing of all vital sign measurements and change from Baseline will be presented 
for all study participants and time point. Body weight will be included in the listing.  
 
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5.5.1.5 
Clinical laboratory evaluations 
5.5.1.5.1 
Handling of dropouts or missing data 
Measurements below the limit of quantification (BLQ) will be imputed with half of the lower limit 
of quantification (LLOQ) for the lab purpose of calculating change and percentage change from 
Baseline for summaries and figures. Measurements above the limit of quantification (ALQ), if 
applicable, will be imputed to the upper limit of quantification. 
Descriptive statistics will be calculated if at most 33% of the individual data points at a time point  
(Visit 13, Week 12 and SFU) are missing or are either not quantifiable (<LLOQ) or ALQ.  The 
denominator for percentages will be based on the number of study participants at corresponding 
analysis visit for the purpose of the safety analysis. Unscheduled and additional laboratory results 
will not be summarized but only listed. 
5.5.1.5.2 
Laboratory values over time 
Laboratory data (clinical chemistry, hematology, urinalysis and other screening test) and changes 
from Baseline (if applicable) for numeric variables will be listed for SS and time point. Any 
laboratory measurements that are BLQ or ALQ will be handled as described in Section 5.5.1.5.1 . 
Values outside the reference range for the numeric variables will be flagged in the listings. The 
reference ranges will also be reported in the listings.  
Chemistry and hematology parameters will be summarized on the SS at each time point, for both 
absolute values and changes from Baseline.  
Laboratory variables will be grouped according to the laboratory function panel and categorized as 
normal, high or low, if applicable, based on the reference range supplied by the analytical 
laboratory.  
Liver function test elevations should be listed. Potential Hy’s Law is defined as a participant with 
(AST or ALT > 3 x ULN) and TBL > 2 x ULN and ALP < 2 x ULN on the same visit.  
In order to meet the above criteria, a participant must experience the elevation in bilirubin and ALT 
or AST at the same visit. For example, a participant who experiences a >=2 x ULN elevation of 
bilirubin at one visit and a 3 x ULN elevation in ALT (or AST) at a subsequent visit has not 
fulfilled the Hy’s law criteria.  
Markedly abnormal laboratory values will generally be defined as those categorized as Grade 3 or 
higher based on the Rheumatology Common Toxicity Criteria (RCTC) v2.1 (Woodworth et al, 
2007). Definitions of markedly abnormal values using the Grade 3 cutpoints are given in the tables 
below (Table 5‒3 for markedly abnormal hematology values and Table 5‒4  for markedly abnormal 
biochemistry values). Any ambiguity about the RCTC criteria was resolved by correspondence 
with the senior author. In particular, the published Grade 3 cutpoint for lymphocytes (<1.0) was 
found to be too high, corresponding with the lower limit of normal, and thus was changed to <0.5. 
Markedly abnormal laboratory (hematology and biochemistry) values with abnormality flag and 
Hy’s Law will be flagged in laboratory listing together for SS and each time point. 
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Table 5‒3 
Definitions of Markedly Abnormal Hematology Values 
Parameter (SI units) 
Markedly Abnormal Definition 
Low 
High 
Hemoglobin (g/L) 
< LLN  
AND decrease from Baseline>20 
N/A 
Hemoglobin (g/L) 
<80 
N/A 
Leukocytes (total x 1000) 
<2.0 
N/A 
Lymphocytes (x 1000) 
<0.5 
N/A 
Neutrophils (x 1000) 
<1.0 
N/A 
Platelets (x 1000) 
<50 
N/A 
N/A = Not Applicable 
 
 
Table 5‒4 
Definitions of Markedly Abnormal Biochemistry Values 
Parameter (SI units) 
Markedly Abnormal Definition 
Low  
High 
Alkaline Phosphatase 
N/A 
>3 x ULN 
ALT 
N/A 
>3 x ULN 
AST 
N/A 
>3 x ULN 
Calcium (mmol/L) 
<1.75 
>3.125 
CPK 
N/A 
>4 x ULN 
Creatinine 
N/A 
>1.8 x ULN 
Glucose (mmol/L) 
<2.22 
>13.89 
Potassium (mmol/L) 
<3.0 
>6.4 
Sodium (mmol/L) 
<125 
N/A 
Total bilirubin 
N/A 
≥2 x ULN 
Uric acid 
N/A 
≥3 x ULN 
N/A = Not Applicable 
Unscheduled visit and duplicate measurement will be handled in Section 6.1.6.1 and 
baseline definition will be described in Section  5.1.1.1.5. 
 
5.5.1.5.3 
Individual Participant Changes of Laboratory Values 
For selected laboratory variables that are identified in Section 5.5.1.5.2  , the change in category 
from Baseline will be presented in shift tables at each post-Baseline assessment. 
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5.6 
 (Other) Safety Analyses 
Other safety will be assessed using the SS. All safety endpoints will be analyzed using 
descriptive statistics. Safety summaries will include presentations of extent of exposure, and 
additional safety assessments including ECG and physical examination. For safety analysis, 
unscheduled visit and duplicate measurement will be handled in Section 6.1.6.1 and baseline 
definition will be described in Section  5.1.1.1.5. 
 
5.6.1 
Extent of Exposure 
The number of injections, total doses received, and total duration of exposure will be summarized 
for SS with continuous statistics (eg, mean, std, median).  
Duration of exposure to study medication will be calculated as: 
• Date of last administration of study medication – date of first administration + 14 days 
Time at risk (days) will be calculated as:  
• Date of last administration of study medication – date of first administration + 70 days.   
 
In addition, all IMP administration details (including date/time of administration, dose), where to  
perform injection (home or study site), who to perform the injection (study participant or site 
personnel), injection site (arm , abdomen or thigh), side of body (left or right),volume, injection 
speed (fastest-8 seconds, fast-11 seconds, slow-14 seconds and slowest-17 seconds ) will be listed 
using the SS. All dosing records including self-injection at Week 14, 16, 20 and 22 with no specific 
visit label will also be listed and considered into exposure summary. 
 
5.6.1.1 
Electrocardiograms 
Standard 12-lead ECG recordings will be taken with the participant resting in the supine position 
for at least 5 minutes and will be presented in SS.  
 
5.6.1.2 
Electrocardiogram Values Over Time 
As ECG is only collected at Screening visit based on schedule of activities.  
The following variables will be reported: 
• Heart rate 
• RR interval 
• PR interval 
• QRS duration 
• QT interval 
• QT interval corrected for heart rate (Bazett’s formula) 
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Measured values will be summarized for each variable for all study participants at screening visit.  
Electrocardiogram findings will be listed separately. 
 
5.6.1.2.1 
Individual Participant of Electrocardiograms Values 
The results of all ECG variables will be reported in the by-participant listings. The listing will be 
presented for ASP at screening visit. All participants who may have clinically significant 
electrocardiogram (ECT) abnormalities at screening will be presented. 
 
5.6.2 
Additional Safety Assessments  
 
5.6.2.1 
Other safety endpoint(s) 
5.6.2.1.1 
Physical examination 
Study participants with abnormalities in the physical examination will be listed including details of 
the abnormality and based on SS. 
5.6.2.1.2 
Additional Laboratory Tests  
In this study, details of all pregnancies in female participants will be collected after the start of 
study treatment and until SFU Visit and listed in additional laboratory test. In addition, other 
screening tests results also include serum or urine alcohol and drug screen and will be listed for SS.  
5.7 
Other Analyses 
 
5.7.1 
Other endpoints and/or parameters 
5.7.1.1 
Pharmacokinetics 
Pharmacokinetic samples will be tested using the ECLIA method. All PK assessments will be 
evaluated as described in the Section 5.3. 
5.7.1.2 
Pharmacodynamics 
Pharmacodynamic parameters will not be evaluated in this study. 
 
5.7.1.3 
Genomics 
Genomics will not be evaluated in this study. 
5.7.1.4 
Tuberculosis screening (IGRA) and Tuberculosis Questionnaire  
TB test data at Screening period and TB questionnaire at Week 12 and Week 24 be listed on the SS. 
5.7.1.5 
COVID-19 Impact 
For study participants impacted by the COVID-19 global pandemic, data was collected on a 
separate eCRF. This form was collected for study visits that were affected by COVID-19, and it 
collected how the visits were impacted by the pandemic (e.g., performed out of window, done by 
telephone instead of on-site, not done, etc).     
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Based on how the visit was affected by the global pandemic, all visits will have following impact 
categories indicating how the visit was performed:  
• Visit not done  
• Visit performed out of window 
• Home visit 
• Missed study drug 
• Administration/dispensation 
• Temporary discontinuation of study drug 
• Termination of study participation 
• Other (if other ,specify the details) 
Additionally, for visits that are affected by COVID-19, all assessments that are missing will be 
flagged as missing due to COVID-19. Further, the specific reason of missing data will be captured 
as the following flags: 
• Confirmed COVID-19 infection  
• Suspected COVID-19 infection  
• General circumstances around COVID-19 without infection 
• Other 
A summary of number and percentage of study participants with COVID-19 impact for all study 
participants and visit will be provided for the ASP.  
A by-site, participant and visit listing of COVID-19 related protocol deviations will be provided 
including impacted visit and date of impacted visit. 
5.8 
Subgroup analyses 
Not applicable. 
 
5.9 
Interim Analyses 
No interim analysis is planned. 
 
5.10 
Data Monitoring Committee (DMC) or Other Review Board 
No data monitoring is planned. 
 
6 
SUPPORTING DOCUMENTATION 
6.1 
Appendix 1 Non-key analysis specifications 
6.1.1 
Baseline characteristics and demographics 
A by- participant listing of Baseline demographics will be presented for ASP. This will include the 
participant number, year of birth (if available), age (in years), country, sex, race, ethnicity, height 
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(in cm), weight (in kg at screening and at pre-dose) and body mass index (BMI). The age will be 
directly entered into the study database and will not be re-calculated for the statistical analysis. 
Concomitant MTX use will also be presented and include: 
• 
With MTX use at screening  
• 
Without MTX use at screening 
As study participants may take concomitant methotrexate (MTX) during the study, a minimum of 8 
study participants must be enrolled who are not on concurrent administration of MTX, so at least 8 
study participants will be expected for subgroup of “without MTX use at screening”. In addition, 
the non-MTX study participant may start to take MTX after Week 12, Day 84 where a study 
participant not on MTX at screening. The MTX user subgroup above will be only based on MTX 
status at screening status, even if a study participant enrolled to study as non -MTX user but then 
used an MTX after Week 12, this study participant will be still classified into “without MTX use at 
screening”.  
All demographic characteristics obtained at the Screening visit and at pre-dose visit for weight will 
be summarized for the SS and the ASP (apart from the date of birth). 
Body mass index in kg/m2 is calculated based on the height (in m) and the weight (in kg) using the 
following formula: 
BMI (kg/m2) = weight (kg)/[height (m)]2 
The BMI will be reported to 1 decimal place. 
For the EudraCT reporting, the age categories will include 
• 
18 to <65 years 
• 
65 to <85 years 
• 
≥85 years 
For the clinicaltrials.gov reporting, the age categories will include: 
• 
≤18 years 
• 
19 to <65 years 
• 
≥65 years 
Childbearing potential will be listed by all study participants screened. 
6.1.2 
Protocol deviations 
Important protocol deviations (IPDs) will be identified and classified by the deviation types 
identified in the IPD document.  
Important protocol deviations will be summarized for all study participants (ASP) to include 
number and percentage of participants with  
1) No important protocol deviations 
2) At least one protocol deviation and the  
− Inclusion criteria deviation  
− Exclusion criteria deviation 
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− Withdrawal criteria deviation  
− Prohibited concomitant medication use  
− Incorrect treatment or dose 
− Treatment non-compliance  
3) Exclusion from the PKS (and all categories in item 2 above). 
A by-participant listing of important protocol deviations will be provided using the SS.  
A by-site participant listing of COVID-19 related important protocol deviations will be provided 
using the SS.  
6.1.3 
Medical history 
Medical history will be listed and summarized for the SS and will include the MedDRA version 
23.1 system organ class (SOC) and preferred term (PT). Procedure history will be listed separately 
from the medical history including date of procedure and relationship with RA  based on the SS. 
Similarly, concomitant medical procedure will be also listed separately including  date of procedure 
and procedure primarily relationship based on the SS. For study participants with DILI events, 
hepatic events supplemental medical history and relevant data (potentially hepato-toxic medication, 
symptoms of hepatitis and symptoms of hypersensitivity) for study participants with suspected 
DILI event will be listed with liver function laboratory results. 
6.1.4 
History of Rheumatoid Arthritis 
The study participants’ history of RA will be summarized on the SS and listed. The following RA 
history variables will be included: 
• Presence of extra-articular features (ever had and present at Screening) 
• 
 Duration of RA (first persistent symptoms). Duration of RA should be calculated as the 
difference between screening date and first persistent symptoms. If the date of diagnosis 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). Sometimes 
Baseline date is used instead of Screening date. 
• Duration of RA (since date of diagnosis). Duration of RA should be calculated as the 
difference between screening date and date of diagnosis. If the date of diagnosis 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). Sometimes Baseline date 
is used instead of Screening date. 
• Duration category of RA since first diagnosis (typically < 2 years and ≥ 2 years, but 
other cutpoints may be used depending on the study). 
• Duration of RA (years) will be calculated as: 
− Duration of RA (first persistent symptoms)= (screening date - first persistent 
symptoms)/365.25 
 
− Duration of RA (since date of diagnosis)=(screening date - date of 
diagnosis)/365.25. 
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History of rheumatoid arthritis will be listed for the SS for all study participants including date of 
first persistent symptoms of RA, date of first diagnosis, history or current of extra-articular features 
(keratoconjunctivitis sicca (yes/no), rheumatoid nodules(yes/no), scleritis(yes/no), 
neuropathy(yes/no), vasculitis(yes/no), pulmonary fibrosis(yes/no), other ). 
 
6.1.5 
Prior/concomitant medications 
 
6.1.5.1 
Prior medication definition 
Prior medications include any medications that started prior to the start date of study medication. If 
a participant takes a medication before the date of administration of IMP, this medication will be 
classified as ‘prior medication’. With this definition, any medication recorded that has been taken 
for at least 1 day before the date of administration of IMP will be considered as prior. This includes 
medications that started prior to dosing and continued after.  
6.1.5.2 
Concomitant medication definition 
Concomitant medications are medications taken at least one day in common with the study 
medication dosing period. For Cimzia, the dosing period is typically 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.  
From the definitions above, any medication that started prior to dosing and continued after dosing 
will be classified as both prior and concomitant.  
Any medications with missing dates and/or times will be handled as described in Section 6.1.6.2  in 
order to classify them as prior or concomitant. 
Prior and concomitant medications will be listed and summarized, separately, for the SS for all 
study participants by WHODD version Sep/2020 B3 update Anatomical Main Group [Level 1], 
Pharmacological Subgroup [Level 3], preferred term (PT) and reported term (listing only).  
Separate tabulations will be presented for the following: 
• 
Prior medications 
• 
Concomitant medications 
All medications will be listed including glossary and will include coding information, reported 
term, dose per intake and unit, frequency, formulation, route of administration, indication, category 
(prior/concomitant) and start and end date (or ongoing, if applicable). 
6.1.6 
Data derivation rules 
6.1.6.1 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the listings. Repeated and 
unscheduled measurements will not be used for statistical analysis or summary tables, unless the 
repeated measurement was performed due to unreliable values/technical reasons, or the repeated 
measurement occurred prior to Investigational Medicinal Product (IMP) administration and is 
defined as the 'baseline'. The following general rules will apply to all repeated and unscheduled 
measurements: 
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• For repeated measurements obtained prior to the first dose of IMP the latest reliable value 
(which may be scheduled or unscheduled) will be used in the calculation of descriptive statistics  
• For repeated measurements obtained at the designated Baseline visit, the latest reliable value 
(which may be scheduled or unscheduled) will be defined as the Baseline. Repeated 
measurements designated Baseline will be used in descriptive statistics rather than the planned 
measurement they replace 
• For repeated measurements obtained at any time point after the first dose of IMP, the first 
reliable value of any repeated measurements will be used in the calculation of changes from 
Baseline and for the descriptive statistics.  
6.1.6.2 
Handling of Dates and times 
Partial dates may be imputed for the following reasons: 
• Classification of adverse events (AEs) as treatment-emergent AEs 
• Classification of medications as prior or concomitant 
• Durations of AEs. 
Imputed dates will not be shown in the listings; all dates will be displayed as reported in the 
database. 
The following rules will be applied for partial start dates/times:  
If time is not collected for a certain domain, time will not be imputed for that domain. 
• If only start month and year are specified and not the same as month and year of dosing then 
use the 1st of the month, or the date of screening if this is later (if the latter imputation results in 
an end date that is earlier than the start date, then use the 1st of the month). If time is missing 
this will be imputed as 00:00 h; 
• If only the month and year are specified and the month and year of dosing is the same as the 
month and year of the start date, then use the date of dosing. If this results in an imputed start 
date that is after the specified end date, then use the 1st of the start month, or the date of 
screening if this is later (if the latter imputation results in an end date that is earlier than the start 
date, then use the 1st of the month). If the imputed date is the date of dosing then time will be 
imputed as the start time of the sc injection (ie, event will be regarded as treatment-emergent); 
• If only the year is specified, and the year of dosing is not the same as the year of the start date 
then use January 01 of the year of the start date. If time is missing this will be imputed as 00:00 
h; 
• If only the year is specified, and the year of dosing is the same as the year of the start date, then 
use the date of dosing. If this results in an imputed start date that is after the specified end date, 
then use January 01 of the year of the start date, or the date of screening if this is later (if the 
latter imputation results in an end date that is earlier than the start date, then use January 01). If 
the imputed date is the date of dosing then time will be imputed as the start time of the sc 
injection (ie, event will be regarded as treatment-emergent); 
• If the start date is completely unknown, then use the date of dosing. If this results in an imputed 
start date that is after the specified end date, then use January 01 of the year of the end date, or 
the date of screening if this is later (if the latter imputation results in an end date that is earlier 
than the start date, then use January 01). If the imputed date is the date of dosing then time will 
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be imputed as the start time of the sc injection (ie, event will be regarded as treatment-
emergent). 
Any medication with a start date on the dosing date and time unknown, will be assumed to be 
concomitant. 
The following rules will be applied for partial stop dates: 
• If only the month and year are specified, then use the last day of the month; 
• If only the year is specified, then use December 31 of the known year; 
• If the stop date is completely unknown, do not impute the stop date 
Missing or partially missing date and/or times will be imputed as described in Table 6‒1 for the 
calculation of duration of each AE. Adverse event duration is computed in and reported in day and 
time format: xx d hh:mm. 
Table 6‒1: 
Calculation rules for duration  
Data 
availability 
Onset 
date/time 
Outcome 
date/time 
Calculation rules 
Complete data 
D1/T1 
D2/T2 
Duration = [(D2 – D1)*24 + (T2 – T1)]/24 d 
End time 
missing 
D1/T1 
D2/-- 
End time is substituted by time 23:59h (=23.98 in 
decimal format) 
Duration = <[(D2 – D1)*24 + (23.98 – T1)]/24 d 
Start time 
missing 
D1/-- 
D2/T2 
Onset time is substituted by time 00:00h. 
Note: if onset date is on the same date of first study 
administration, then the time point of first study 
administration will be used for missing onset time. 
Duration ≤ [(D2 – D1)*24 + T2] / 24 d 
Start and end 
time missing 
D1/-- 
D2/-- 
Duration = <D2 – D1 + 1 
Start day and 
time missing 
--/-- 
D2/T2 
Duration = <[(D2 – D0)*24 + (T2 – T0)]/24 d 
For a participant in the SS, D0 and T0 are the date and 
time of dosing and for screen failures, D0 is the date of 
the screening visit and T0 = 00:00h 
End day and 
time missing 
D1/T1 
--/-- 
For ongoing AE: 
Duration = >Discharge day – D1 d OR 
For resolved AE: 
Duration = <Discharge day – D1 d OR 
Where discharge refers to the date of the end of study 
visit for completed study participants or the date of 
discontinuation for study participants that were 
withdrawn. 
For any AEs with known start date/time after the date of 
discontinuation, the date of last contact will be used as 
the discharge day. 
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Table 6‒1: 
Calculation rules for duration  
Data 
availability 
Onset 
date/time 
Outcome 
date/time 
Calculation rules 
Start and end 
date missing 
--/-- 
--/-- 
For ongoing AE: 
Duration = >Discharge day – D0 d OR 
For resolved AE: 
Duration = <Discharge day – D0 d OR 
For a participant in the SS, D0 and T0 are the date and 
time of dosing and for screen failures, D0 is the date of 
the screening visit and T0 = 00:00h. 
Discharge refers to the date of the end of study visit or 
the date of discontinuation for study participants that 
were withdrawn. 
For any AEs with known start date/time after the date of 
discontinuation, the date of last contact will be used as 
the discharge day. 
SS=Safety Set; IMP=investigational medicinal product. 
6.1.7 
AEs of Special Interest (AESIs) 
An AE of special interest is defined as following events: 
• Hy’s Law (as described in Section 5.5.1.5.2) 
• Serious infections, including opportunistic infections. 
• Malignancies, including lymphoma. 
• Serious cardiovascular events - also called Major Adverse Cardiac Events (MACE) 
• 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). 
Subsets on Adverse Events of Special Interest (AESIs) will either be extracted via Structured 
MedDRA Query (SMQ), via other automated queries based on search criteria specified by UCB or 
via manual medical review from the set of TEAEs or serious TEAEs.  
Some types of AESIs are identified manually. For those, textual reporting in the CSR is deemed 
sufficient and no additional summary tables need to be generated. For others, especially those with 
automated search criteria additional TEAE summary tables are planned. 
All manual searches and reviews have to be occurred prior to data cleaning meeting(DCM) and 
data evaluation meeting (DEM). A final review after database lock will be also executed in the 
framework of the data cleaning and data evaluation meeting. 
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The MedDRA SMQ terms are based on MedDRA version 23.1. In case that later MedDRA 
versions will be used, the appropriateness and spelling of the terms need to be reviewed and 
adapted accordingly.  
The following summary tables will be produced for AESIs:  
• TEAEs by SOC, HLT and PT for AESIs  along with number and percentage summary 
• Serious TEAEs by SOC, HLT and PT for AESI along with number and percentage summary 
All AESIs the term(s) for extraction are specified in Table 6‒1: 
 
 
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Table 6‒1:Adverse Events of Special Interest (AESIs) 
AESIs term and other  
AE subsets 
Extraction way 
Term of SMQ (for SMQ extraction only) or 
other search strategy 
AESIs: Infections, 
including serious 
opportunistic infections 
and tuberculosis 
1) Serious infections 
 
 
2) Opportunistic 
infections including 
tuberculosis, manual 
 
2) UCB defined search criteria for opportunistic 
infections including Tuberculosis 
 
 
AESIs: Malignancies, 
including lymphoma 
1) SMQ 
2) SMQ 
1) SMQ=”Malignant or unspecified tumours” 
2) SMQ=”Malignant tumours” 
Note: Non melanomic skin cancer will also be 
summarized  by using HLT= “Skin neoplasms 
malignant and unspecified (excluding  
melanoma)” 
AESIs: Congestive heart 
failure 
1) Congestive heart 
failure, manual 
 
2) Major adverse 
cardiovascular events 
(MACE) 
2) UCB defined search criteria1) 
AESIs: Demyelinating-
like disorders 
SMQ 
SMQ = “Demyelination (SMQ)” 
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AESIs term and other  
AE subsets 
Extraction way 
Term of SMQ (for SMQ extraction only) or 
other search strategy 
AESIs: Aplastic anemia, 
pancytopenia, 
thrombocytopenia, 
neutropenia, and 
leucopenia 
SMQ 
SMQ=”Haematopoietic cytopenias” on subset of 
serious TEAEs 
AESIs: Serious bleeding 
events 
SMQ 
SMQ=”Haemorrhages” on subset of serious TEAEs 
AESIs: Lupus and lupus-
like syndrome 
Manual 
Medical review of TEAE table 
AESIs: Serious skin 
reactions (eg, Stevens-
Johnson Syndrome, toxic 
epidermal necrosis, and 
erythema multiforme) 
Manual 
Medical review of serious TEAE table 
1) 
Will include fatal and serious non-fatal myocardial infarctions, cerebrovascular events and congestive heart failures based on MedDRA 
terms and medical reviews. 
6.1.8 
Potentially Clinically Significant Criteria for Safety Endpoints 
Not applicable. 
6.1.9 
Compliance 
At each visit after study medication is dispensed, participants must return all unused study 
medication and empty study medication containers. Drug accountability must be done in the 
participant’s presence in order to obtain explanations regarding discrepancies in compliance with 
the dosing regimen.  
The compliance will be provided via drug accountability CRF form. No summary table will be 
provided for drug accountability, However,  a by-participant listing of drug accountability 
including visit dispensed, kit number, and counter for RTSM integration (misallocation of drug kit) 
will be provided using the SS.  
 
6.2 
Appendix 2: Changes to Protocol-Planned Analyses 
Not applicable. 
7 
REFERENCES 
1. UCB Guideline: Guideline on performing NCA analysis, Nov 2017 
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2. Phillips, A. and Haudiquet, V. (2003), ICH E9 guideline ‘Statistical principles for clinical 
trials’: a case study. Statist. Med., 22: 1-11. doi:10.1002/sim.1328 
3. Food and Drug Administration. Guidance for Industry. Bioavailability and Bioequivalence 
Studies Submitted in NDAs or INDs —General Considerations. US Dept of Health and Human 
Services, Center for Drug Evaluation and Research. Biopharmaceutics. March 2017. 
4. EMEA/CHMP/BMWP/42832/2005 Rev. 1 Guideline on similar biological medicinal products 
containing biotechnology-derived proteins as active substance: non -clinical and clinical issues 
, 18 Dec 2014. 
5. CPMP/EWP/QWP/1401/98 Rev. 1/Corr Guideline on the investigation of bioequivalence 
(EMEA), 20 January 2010. 
6. Health Canada Guidance, Conduct and Analysis of Comparative Bioavailability Studies, 8 Jun 
2018. 
7. Health Canada Guidance, Comparative Bioavailability Standards: Formulations use for 
Systemic Effects, 8 Jun 2018. 
 
 
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8.  
8 
APPENDICES 
8.1 
RAPID3 Assessment 
 
The RAPID3 includes a subset of core variables found in the Multi-dimensional HAQ 
(MDHAQ). The MDHAQ, shown here, includes an assessment of physical function (Section 1 of 
the RAPID3 assessment [below]), a patient global assessment for pain (Section 2 of the RAPID3 
assessment [below]), and a patient global assessment for global health (Section 3 of the RAPID3 
assessment [below]). RAPID3 scores are quickly tallied by adding subsets of the MDHAQ as 
follows:
 
 
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How to calculate RAPID3 scores 
1. Ask the patient to complete questions 1, 2, and 3 while in the waiting room prior to 
his/her visit. 
2. For question 1, add up the scores in questions a to j only (questions k to m have been 
found to be informative, but are not scored formally). Use the formula in the box on the 
right to calculate the formal score (0 to 10). For example, a patient whose answers total 
19 would score a 6.3. Enter this score as an evaluation of the patient’s functional status. 
3. For question 2, enter the raw score (0 to 10) in the box on the right as an evaluation of 
the patient’s pain tolerance. 
4. For question 3, enter the raw score (0 to 10) in the box on the right as an evaluation of 
the patient’s global estimate. 
5. Add the total score (0 to 30) from questions 1, 2, and 3 and enter them as the patient’s 
RAPID3 cumulative score. Use the final conversion table to simplify the patient’s 
weighed RAPID3 score. For example, a patient who scores 11 on the cumulative 
RAPID3 scale would score a weighed 3.7. A patient who scores between 0 and 1.0 is 
defined as near remission; 1.3 and 2.0 as low severity; 2.3 and 4.0 as moderate 
severity; and 4.3 and 10.0 as high severity. 
 
8.2 
SAP Amendment 1 
Rationale for the amendment 
The main purposes of this amendment were:  
• General update to analyses following Data Evaluation Meetings. 
• To implement anti-drug antibody additional analyses. 
Modifications and changes 
Specific changes 
Change #1 
Section 5.1 General Considerations 
Statistical analysis and generation of tables, figures, and study participant data listings will be 
performed using statistical analysis system (SAS®, SAS Institute, Cary, NC, US) version 9.3 or 
higher using validated program code according to relevant standard operating procedures. 
Has been changed to: 
Statistical analysis and generation of tables, figures, and study participant data listings will be 
performed using statistical analysis system (SAS®, SAS Institute, Cary, NC, US) version 9.3 or 
higher using validated program code according to relevant standard operating procedures. PK 
parameters will be calculated by Non-Compartmental Analysis (NCA) methods from the 
concentration-time data with actual time using Phoenix® WinNonlin® Version 8.3 or 
higher following UCB guideline: Guideline on performing NCA analysis , Nov 2017. 
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Change #2 
Section  5.1.1.1.3 Study periods 
The duration of the study for each study participant is approximately 38 weeks.; consisting of the 
following 3 periods: 
Screening Period ( up to 28 days): Visit 1, Day -28 to Day -1 
Treatment Period (24 weeks) including Baseline visit:  based on the first planned treatment 
starting from Visit 2 at Day 0 to the last planned treatment on Visit 15 at Day 168 (Week 24) 
− 400mg loading dose phase for doses at Week 0, Weeks 2 and 4 followed by 200mg Q2W 
maintenance dose phase thereafter (at Week 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24) 
− PK profile treatment Period: Day 72±6 hours to Day 80±6 hours. These visits may be 
conducted at home vist. 
Safety Follow-Up: The end of study visit will be performed on 70 days after last IMP through 
SFU visit.  
The end of the study is defined as the date of the last visit of the last study participant in the 
study. Study participants are considered to have completed the study if they complete the last 
scheduled study visit, not including safety follow-up visits.  The safety follow-up visit is 70 days 
post last dose.  If study participants are continuing onto commercial Cimzia, the safety follow-up 
is 30 days post last dose.    
Has been changed to: 
The duration of the study for each study participant is approximately 38 weeks.; consisting of the 
following 3 periods: 
Screening Period ( up to 28 days): Visit 1, Day -28 to Day -1 
Treatment Period (24 weeks) including Baseline visit:  based on the first planned treatment 
starting from Visit 2 at Day 0 to the last planned treatment on Visit 15 at Day 168 (Week 24) 
− 400mg loading dose phase for doses at Week 0, Weeks 2 and 4 followed by 200mg Q2W 
maintenance dose phase thereafter (at Week 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24) 
− PK profile treatment Period: Day 72±6 hours to Day 80±6 hours. These visits may be 
conducted at home visit. 
Safety Follow-Up: The end of study visit will be performed on 70 days after last IMP through 
SFU visit.  
The end of the study is defined as the date of the last visit of the last study participant in the 
study. Study participants are considered to have completed the study if they complete the last 
scheduled study visit(Screening, Baseline Visit, Treatment Period [through Week 24], and 
SFU).  The safety follow-up visit is 70 days post last dose.  If study participants are continuing 
onto commercial Cimzia, the safety follow-up is 30 days post last dose.    
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Change #3 
Section  5.1.1.1.4 Mapping of assessments performed at Early Discontinuation Visit 
For example, suppose the patient also discontinues at Day 176 ( in the midpoint of Week 24, Day 
168 and Week 12, Day 84), then the Week 12, Day 84 will be assigned and firstly considered. 
However, if there was recently assessed at Week 12,  the assessments obtained at premature 
termination visit should be re-mapped and analyzed at the Week 24 visit, as there is already valid 
data available at the Week 12 visit. 
Has been changed to: 
For example, suppose the patient also discontinues at Day 126 ( in the midpoint of Week 24, Day 
168 and Week 12, Day 84), then the Week 12, Day 84 will be assigned and firstly considered. 
However, if there was recently assessed at Week 12,  the assessments obtained at premature 
termination visit should be re-mapped and analyzed at the Week 24 visit, as there is already valid 
data available at the Week 12 visit. 
Change #4 
Section  5.1.1.2 
Protocol Deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary PK outcome for an individual study 
participant. 
Has been changed to: 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary PK outcome for an individual study 
participant. PK samples outside the protocol windows, missing doses or delayed doses 
potentially impacting PK, will be reviewed. PK sampling protocol deviations will not 
automatically cause their exclusion from the PKS set. The table of summary PK statistics 
and geometric mean PK concentration-time figure will be presented with and without those 
PK samples determined to be protocol deviations. 
 
Change #5 
Section  5.3.2 Main analytical approach 
The following rules will apply for the PK data summaries: 
• Values below the LLOQ will be reported as BLQ for individual data and will be 
substituted with LLOQ/2 for the descriptive statistics 
Has been changed to: 
The following rules will apply for the PK data summaries: 
• PK parameters are reported with 3 significant digits and Descriptive statistics 
reported to 4 significant figures for the mean, median and standard deviation (SD) 
and to 3 significant figures for all others. 
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• Values below the LLOQ will be reported as BLQ for individual data and will be 
substituted with LLOQ/2 for the descriptive statistics 
 
Change #6 
Section  5.4.1.2.1 CZP plasma concentrations over the duration of study 
Individual plasma concentrations of CZP (from conventional venous sampling) will be listed for 
PKS and will include the actual and nominal sampling times. Any samples that are obtained 
outside the tolerance window permitted at the specified time point will be discussed at the DEM 
and any possible exclusion from analysis will be documented accordingly. 
Has been changed to: 
Individual plasma concentrations of CZP (from conventional venous sampling) will be listed for 
PKS and will include the actual and nominal sampling times. Any samples that are obtained 
outside the tolerance window permitted at the specified time point will be discussed at the DEM 
and any possible exclusion from any specific analyses (i.e. summary statistics table and 
geomean figure) will be documented accordingly. If deemed appropriate, the analyses of 
the summary stats table and geomean figure may be repeated with and without the specific 
samples affected.  
 
Change #7 
Section  5.4.1.2.1 CZP plasma concentrations over the duration of study 
The other similar PK data handling rule will be also followed in Section 5.3.2 . 
Has been changed to: 
All plasma concentration figures will include the LLOQ on the semi-logarithmic scale plots and 
will be based on scheduled times and grouped by MTX use at screening. 
Further PK data handling rules are described in Section 5.3.2 . 
Change #8 
Section  5.5.1.1.2 Anti-drug antibodies 
ADAb antibodies will be measured using a tiered assay approach: screening assay, confirmatory 
assay and titration assay. 
A screening cut point will be determined by the bioanalytical laboratory that will be used to 
determine the status of ADAb as Positive Screen (PS) or Negative Screen (NS).  Samples 
presenting ADAb levels PS are considered “potentially ADAb positive” and will be further 
evaluated in the confirmatory assay, the result of which will be reported as either “Positive 
Immunodepletion” (PI) or “Negative Immunodepletion” (NI). Confirmed positive samples 
(reported as PI) will be titrated, and the titer (reciprocal dilution factor including minimum 
required dilution) will be reported.  
ADAb status at  sample level: 
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An ADAb status of positive (ADAb+) will be concluded for any sample with an ADAb level that 
is Positive Screen (PS) and Positive Immunodepletion (PI); 
An ADAb status of negative (ADAb-) will be concluded for any sample with an ADAb level that 
is either Negative Screen (NS) or Positive Screen (PS) and Negative Immunodepletion (NI);  
Participant  Classification: 
A participant will be classified as having ADAb positivity at Baseline if the Day 0, predose 
result is ADAb+ 
A participant will be classified as overall positive if at least one post-Baseline measurement is 
ADAb+ (see definition above) (this includes participant who have negative and positive results 
at baseline) 
A participant will be classified as overall negative if at all post-Baseline visits the ADAb status is 
negative (this includes study participants who have positive and negative results at Baseline) 
A participant will be classified as having treatment-emergent ADAb positivity when meeting one 
of the following criteria: 
− The Baseline result is ADAb-, and at least one postBaseline time point is ADAb+ 
− The Baseline result is ADAb+, and at least one postBaseline measurement shows a 
predefined fold increase in titer from the Baseline value (the fold increase from Baseline 
required to meet these criteria will be defined with the development of the assay and will 
be included in the TFLs) 
Analysis: 
Immunogenicity will be assessed through summary tables and figures and listing of individual 
results by study participant. All analyses will be run on the SS, unless specified otherwise. For 
all tabulations, percentages will be calculated based on the number of study participants with 
non-missing data. 
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). 
Number and percentage of study participants with a positive and negative ADAb status will be 
summarized at the time of each visit and overall.  
In addition, the first occurrence of treatment-emergent ADAb positivity (based on the definitions 
above) will be summarized (number and percentage of study participants) at each postBaseline 
visit, based on the PK. This tabulation will present the number and percentage of study 
participants at each postBaseline visit who fulfill at least one of the above defined criteria for 
treatment-emergent positivity; study participants will be counted in the numerator based on the 
earliest visit at which one of these criteria is fulfilled. At other visits, study participants will be 
counted in the denominator (assuming a measurement is available). For all tabulations, 
percentages will be based on the number of observations at each visit. This summary will 
exclude any samples with CZP concentrations confirmed to be above the drug tolerance. 
A listing will be presented showing the CZP concentrations and ADAb measurements in the 
same output in adjacent columns, based on the PK. The listing will include the CZP 
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concentration and ADAb status (positive or negative) and screening assay results (PS or NS) and 
confirmatory assay results if applicable (NI or PI), together with the titer if applicable. In 
addition, the time since the administration of study medication will be reported (in days). ADAb 
samples that are negative but have drug concentration above the drug tolerance characteristics of 
the assay will be flagged. 
Finally, individual participant plots will be presented displaying the ADAb titer and CZP 
concentrations overlaid on the same figure. The figure will also show the timing and dose of 
each administration of CZP received during the study. The ADAb data will be plotted using a 
semi-logarithmic scale. ADAb samples that are negative but have drug concentration above the 
drug tolerance characteristics of the assay will be flagged on the plot. 
The rules for handling values that are BLQ in the CZP concentration data are described in 
Section 5.5.1.1.1.  For the ADAb data, any negative results for which there are no titers (as 
applicable) available at a specific visit will be substituted with 0.001 for the purpose of the 
figure. 
 
Has been changed to: 
ADAb antibodies will be measured using a tiered assay approach: screening assay, confirmatory 
assay and titration assay. The ADA status at sample level will be defined in Table 5‒1 . 
A screening cut point will be determined by the bioanalytical laboratory that will be used to 
determine the status of ADAb as Positive Screen (PS) or Negative Screen (NS).  Samples 
presenting ADAb levels PS are considered “potentially ADAb positive” and will be further 
evaluated in the confirmatory assay, the result of which will be reported as either “Positive 
Immunodepletion” (PI) or “Negative Immunodepletion” (NI). Confirmed positive samples 
(reported as PI) will be titrated, and the titer (reciprocal dilution factor including minimum 
required dilution) will be reported.  
ADAb status at  sample level: 
Table 8‒1 : 
ADA status at Sample level 
ADA positive 
(ADAb+) 
  Sample values that are ‘positive screen’ and ‘positive immuno-
depletion’ 
ADA 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 ADA or limit dictated by the ADA 
assay and project needs (e.g. 250 ng/ml). 
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ADA 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 ADA or limit dictated by the ADA assay and 
project needs (e.g. 250 ng/ml)  
Missing  
Samples that were not collected per schedule or that could not be 
tested for ADA status due to inadequate sample volume, 
mishandling, or errors in sample collection, processing, storage, etc. 
 
Participant  Classification: 
A participant will be classified as overall positive if at least one post Baseline measurement is 
ADAb+ (see definition above) (this includes participant who have negative and positive 
results at baseline) 
A participant will be classified as overall negative if at all post Baseline visits the ADAb status is 
negative (this includes study participants who have positive and negative results at Baseline) 
A participant will be classified as having classification of ADA status as stated in below 
Table 5‒2 . 
Table 8‒2 
: 
Classification of ADA status 
1. 
Pre ADA negative and treatment-
emergent ADA negative  
Study participants who were negative at Baseline and 
negative at all sampling points post treatment till time 
point of interest 
2. 
Pre ADA negative and treatment-
(emergent)  induced ADA 
positive 
Study participants who were negative at Baseline and 
positive at any sampling point post treatment. This 
group also included study participants who had a 
missing pre-treatment sample (either missing or 
insufficient volume) with 1 or more positive post-
treatment samples. 
3. 
Pre ADA positive and treatment-
emergent reduced ADA  
Study participants who were positive at Baseline, and 
negative at all sampling points post treatment till time 
point of interest 
4. 
Pre ADA positive and treatment-
emergent unaffected ADA 
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 a predefined fold difference from the Baseline 
value of 4.11). 
5. 
Pre ADA positive and treatment-
emergent ADA 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 4.11 from 
Baseline value which is defined within the validation of 
the assay). 
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6. 
ADA inconclusive 
Study participant for who the ADA participant status 
cannot be defined due to missing or inconclusive 
samples (this will include study participants from the SS 
for whom no ADA samples were collected). 
Inconclusive [1]: Study participant that had negative 
ADA status at Baseline and post-Baseline samples 
missing per schedule or inconclusive, while others post-
Baseline samples are ADA negative up to the time point 
of interest.  
Inconclusive [2]:  Participants who do not satisfy any of 
the above criteria 
7. 
Treatment emergent ADA 
positive 
Combination of 2 and 5 
8. 
Pre-treatment ADA positive  
Combination of 3, 4 and 5 
 
 
Analysis: 
Immunogenicity will be assessed through summary tables and figures and listing of individual 
results by study participant. All analyses will be run on the SS, unless specified otherwise. For 
all tabulations, percentages will be calculated based on the number of study participants with 
non-missing data. 
Individual participant concentration-time profiles of CZP will be displayed graphically in 
linear and semi-logarithmic scale and grouped by MTX use at screening .  
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). 
Summary table displaying the number and percentage of study participants with a positive 
ADA, negative ADA, inconclusive or missing ADA sample status at the time of each visit by 
treatment group. [Note that in case of presence of pre-ADA, no differentiation can be made 
between pre-ADA and treatment emergent ADA (either newly induced or boosted ADA). 
Note this table is not be used for incidence interpretation]. 
Based on the overall ADA study participant classification above from Table 10, the 
following will be determined and presented: summary tables displaying the number and 
percentage of study participants in each of ADA participant status categories (1–8), with the 
denominator being the total number of study participants having an individual ADA 
participant category defined during the corresponding analysis period and treatment 
group. (All study participants will be assigned to a category in this table and should not be 
confused with ADA incidence that is defined below). 
Incidence and prevalence: 
• Total prevalence of pre-Ab overall and by treatment group.  Total prevalence of pre-
Ab: n/NN % number of participants that have a pre-ADA positive ADA sample status, 
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with NN being the denominator defined as all participants having an evaluable baseline 
ADA sample.  
Overall ADA incidence and by treatment group, Treatment-Emergent Anti-CZP Antibody 
Positivity Activity for combined results of treatment-boosted ADA-positive participants 
and treatment induced ADA-positive participants. n/N % of participants that are 
treatment emergent, with N being the denominator defined as all participants except the 
participants categorized as inconclusive. 
Number and percentage of study participant Baseline Anti-CZP status and Treatment-
Emergent Anti-CZP Antibody Status will be summarized during the entire study. The 
change in category from Baseline ADAb status including ADAb-, ADAb+, Missing and 
total will be presented in shift tables at each post-Baseline treatment treatment-emergent 
anti-CZP antibody status. 
Treatment Treatment-Emergent Anti-CZP Antibody Status will be categorized as below: 
− Negative : Treatment Treatment-Emergent Anti-CZP Antibody Status is ADAb- 
− Positive <512 : Treatment Treatment-Emergent Anti-CZP Antibody Status is 
ADAb+ and ADAb titer is less than 512. 
− Positive 512-<=1024: Treatment Treatment-Emergent Anti-CZP Antibody Status is 
ADAb+ and ADAb titer is greater than 512 and less and equal 1024. 
− Positive>1024: Treatment Treatment-Emergent Anti-CZP Antibody Status is 
ADAb+ and ADAb titer is greater than 1024. 
− Any positive : Study participants having treatment-emergent ADAb+. 
− Total : total Treatment Treatment-Emergent Anti-CZP Antibody Status 
Number and percentage of study participant Anti-CZP titer by visit will be summarized 
during the entire study. ADAb titer will be categorized as below: 
− Negative : The ADAb status is ADAb- 
− <=32 : The ADAb titer result is less than or equal to 32. 
− >32-128: The ADAb titer result is greater than 32 and less than or equal to 128. 
− >128-512: The ADAb titer result is greater than 128 and less than or equal to 512. 
− >512-1024: The ADAb titer result is greater than 512 and less than or equal to 1024. 
− >1024-4096: The ADAb titer result is greater than 1024 and less than or equal to 
4096. 
− >4096: The ADAb titer result is greater than 4096. 
A listing will be presented showing the CZP concentrations and ADAb measurements in the 
same output in adjacent columns, based on the SS. The listing will include the CZP 
concentration and ADAb status (positive or negative) and screening assay results (PS or NS) and 
confirmatory assay results if applicable (NI or PI), together with the titer if applicable. In 
addition, the time since the administration of study medication will be reported (in days). ADAb 
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samples that are negative but have drug concentration above the drug tolerance characteristics of 
the assay will be flagged. 
Time course plots of all individual CZP plasma concentrations profiles (each participant 
corresponding to a line) (spaghetti plot) with identification of the individual ADA 
participant category  using different colors ( categories 1, 3,4 and 7. If not sufficient 
participants in category 3 and 4, these could be combined for this plot). These plots will be 
produced on a linear and semilogarithmic scale and multi-panel per treatment group. 
Individual samples with positive ADA sample status will be visualized using a symbol or a 
red dot. Dosing nominal time points should be indicated below the x-axis. A similar plot 
may be considered for PD endpoints.  The plot may be stratified based on MTX use at 
baseline/screening.  
 
Change #9 
Section  6.1.2 Protocol deviations 
A by-participant listing of important protocol deviations will be provided using the ASP.  
Has been changed to: 
A by-participant listing of important protocol deviations will be provided using the SS.  
A by-site participant listing of COVID-19 related important protocol deviations will be 
provided using the SS.  
 
Change #10 
Section  6.1.4 History of Rheumatoid Arthritis 
• Duration of RA (years) will be calculated as: 
− 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛=
(𝐷𝑎𝑡𝑒 𝑜𝑓 screening −𝐷𝑎𝑡𝑒 𝑜𝑓 diagnosis 𝑜𝑓 RA )
365.25
 
 
Has been changed to: 
• Duration of RA (years) will be calculated as: 
− Duration or RA (first persistent symptoms)= (screening date - first persistent 
symptoms)/365.25 
 
− Duration of RA (since date of diagnosis)=(screening date - date of IMP 
Administration diagnosis)/365.25. 
 
Change #11 
Section  6.1.7 AEs of Special Interest (AESIs) 
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Table 8‒1:Adverse Events of Special Interest (AESIs) 
AESIs term and other  
AE subsets 
Extraction way 
Term of SMQ (for SMQ extraction only) or 
other search strategy 
AESIs: Infections, 
including serious 
opportunistic infections 
and tuberculosis 
1) Serious infections 
 
 
2) Opportunistic 
infections including 
tuberculosis, manual 
 
2) UCB defined search criteria for opportunistic 
infections including Tuberculosis 
 
 
AESIs: Malignancies, 
including lymphoma 
1) SMQ 
2) SMQ 
1) SMQ=”Malignant or unspecified tumours” 
2) SMQ=”Malignant tumours” 
Note: Non melanomic skin cancer will also be 
summarized  by using HLT= “Skin neoplasms 
malignant and unspecified (excluding  
melanoma)” 
AESIs: Congestive heart 
failure 
1) Congestive heart 
failure, manual 
 
2) Major adverse 
cardiovascular events 
(MACE) 
2) UCB defined search criteria1) 
AESIs: Demyelinating-
like disorders 
Manual 
Medical review of TEAE table 
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AESIs term and other  
AE subsets 
Extraction way 
Term of SMQ (for SMQ extraction only) or 
other search strategy 
AESIs: Aplastic anemia, 
pancytopenia, 
thrombocytopenia, 
neutropenia, and 
leucopenia 
SMQ 
SMQ=”Haematopoietic cytopenias” on subset of 
serious TEAEs 
AESIs: Serious bleeding 
events 
SMQ 
SMQ=”Haemorrhages” on subset of serious 
TEAEs 
AESIs: Lupus and lupus-
like syndrome 
Manual 
Medical review of TEAE table 
AESIs: Serious skin 
reactions (eg, Stevens-
Johnson Syndrome, toxic 
epidermal necrosis, and 
erythema multiforme) 
Manual 
Medical review of serious TEAE table 
1) 
Will include fatal and serious non-fatal myocardial infarctions, cerebrovascular events and congestive heart failures based on 
MedDRA terms and medical reviews. 
 
 
Has been changed to: 
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RA0138 
 
 
 
 
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Page 55 of 56 
 
Table 8‒1:Adverse Events of Special Interest (AESIs) 
AESIs term and other  
AE subsets 
Extraction way 
Term of SMQ (for SMQ extraction only) or 
other search strategy 
AESIs: Infections, 
including serious 
opportunistic infections 
and tuberculosis 
1) Serious infections 
 
 
2) Opportunistic 
infections including 
tuberculosis, manual 
 
2) UCB defined search criteria for opportunistic 
infections including Tuberculosis 
 
 
AESIs: Malignancies, 
including lymphoma 
1) SMQ 
2) SMQ 
1) SMQ=”Malignant or unspecified tumours” 
2) SMQ=”Malignant tumours” 
Note: Non melanomic skin cancer will also be 
summarized  by using HLT= “Skin neoplasms 
malignant and unspecified (excluding  
melanoma)” 
AESIs: Congestive heart 
failure 
1) Congestive heart 
failure, manual 
 
2) Major adverse 
cardiovascular events 
(MACE) 
2) UCB defined search criteria1) 
AESIs: Demyelinating-
like disorders 
SMQ 
SMQ = “Demyelination (SMQ)” 
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AESIs term and other  
AE subsets 
Extraction way 
Term of SMQ (for SMQ extraction only) or 
other search strategy 
AESIs: Aplastic anemia, 
pancytopenia, 
thrombocytopenia, 
neutropenia, and 
leucopenia 
SMQ 
SMQ=”Haematopoietic cytopenias” on subset of 
serious TEAEs 
AESIs: Serious bleeding 
events 
SMQ 
SMQ=”Haemorrhages” on subset of serious 
TEAEs 
AESIs: Lupus and lupus-
like syndrome 
Manual 
Medical review of TEAE table 
AESIs: Serious skin 
reactions (eg, Stevens-
Johnson Syndrome, toxic 
epidermal necrosis, and 
erythema multiforme) 
Manual 
Medical review of serious TEAE table 
1) 
Will include fatal and serious non-fatal myocardial infarctions, cerebrovascular events and congestive heart failures based on 
MedDRA terms and medical reviews. 
 
 
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Approval Signatures
Name:
RA0138-sap-amend
Version:
1. 0
Document Number:
CLIN-000203063
Title:
RA0138-sap-amend_30AUG2022
Approved Date:
30 Aug 2022
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Qualified Person
Date of Signature: 30-Aug-2022 13:39:13 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 30-Aug-2022 13:41:19 GMT+0000
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