Clinical trial NCT04163016
Conditions: Rheumatoid Arthritis Psoriatic Arthritis Crohn's Disease Axial Spondyloarthritis Plaque Psoriasis
Keywords: Cimzia Certolizumab Pegol Pregnant Women Crohn's Disease (CD) Rheumatoid Arthritis (RA) Psoriatic Arthritis (PsA) Plaque Psoriasis (PSO) Axial Spondyloarthritis (AxSpA) Pharmacokinetics CZP
Sponsor: UCB Biopharma SRL
Start date: 2020-06-19; Completion date: 2023-05-23
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to assess systemic certolizumab pegol (CZP) exposure, the formation of anti-CZP antibodies and safety of CZP across the course of pregnancy in study participants with chronic inflammatory diseases.

Detailed description:

Arms: arm 1: This study will include pregnant women who have decided to continue treatment with commercial certolizumab pegol (CZP) in accordance with their treating physician prior to participating in the study. Study participants will be responsible for obtaining and administering commercially available CZP under the care of their physician and according to the locally approved product label.

From all study participants blood samples will be drawn for pharmacokinetics during the study.
Interventions: intervention 1: Pharmacokinetics of certolizumab pegol
Intervention descriptions: intervention 1: The collection of blood samples for pharmacokinetics (PK) is considered interventional. Blood samples will be drawn at enrollment, predose every 4 weeks (Q4W), postdose every 8 weeks (Q8W) and postpartum predose and postdose.

Study participants will be responsible for obtaining and administering commercially available approved dosing regimens of certolizumab pegol (CZP) as prescribed by each study participant's own physician.

Protocol documents:
Prot_000.pdf: 
UCB 
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A POSTMARKETING, MULTICENTER, LONGITUDINAL, 
PROSPECTIVE, PHARMACOKINETIC, PHASE 1B STUDY IN 
PREGNANT WOMEN WITH CHRONIC INFLAMMATORY 
DISEASES TREATED WITH CIMZIA® 
(CERTOLIZUMAB PEGOL) 
 
PROTOCOL UP0085 
PHASE 1B 
 
SHORT TITLE: 
A postmarketing, multicenter, pharmacokinetic study in pregnant women with chronic 
inflammatory diseases treated with certolizumab pegol 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying number(s): 
EudraCT Number: 
2019-003410-13 
IND Number: 
11,197 
NCT Number: 
Not yet assigned 
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 
Protocol Amendment 2 
30 Aug 2022 
Substantial 
Protocol Amendment 1.1 
(France) 
01 Mar 2021 
Substantial 
Protocol Amendment 1 
29 Aug 2019 
Substantial 
Original Protocol 
31 Jul 2019 
Not applicable 
 
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Amendment 2 (30 Aug 2022)  
Overall Rationale for the Amendment 
The Sponsor wishes to clarify the adequate amount of data per participant which would classify the participant as providing 
longitudinal data over the pregnancy and postpartum periods. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Previous text: 
UCB SPRL 
 
New text: 
UCB SRL 
Updated with sponsor’s name change.  
Section 1.1, Synopsis  
Previous text:  
Enrollment is anticipated until 
approximately 10 to 12 study participants 
have complete longitudinal data sets 
(defined as a data set including all predose 
samples collected Q4W and postdose 
samples collected Q8W over the 
pregnancy period and at least 1 postpartum 
sample). 
 
New text: Enrollment will occur until a 
minimum of 10 study participants have 
longitudinal data (defined as at least 4 
quantifiable predose and 2 quantifiable 
postdose PK samples during pregnancy 
and at least 1 quantifiable postpartum 
sample) over the study period. 
To update the planned enrollment needed 
to provide a sufficient number of 
participants with adequate data.  
Section 1.2, Schema 
The post-partum period was changed to 
from 8-13 weeks to 13 weeks.  
Updated to align with the rest of the 
protocol. 
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Section 4.1, Overall design  
Previous text: 
The study will continue to enroll 
participants until approximately of 10 to 
12 complete individual longitudinal 
datasets are obtained. This is inclusive of 
PK samples (predose and postdose as 
defined in Section 1.1) obtained during the 
pregnancy along with postpartum samples. 
Study enrollment may be stopped after the 
minimum number of participants is 
reached, or the study may continue to 
enroll beyond the minimum number of 
participants if cumulated PK data are not 
deemed sufficient to meet the primary 
objective. 
New text: The study will enroll 
participants based on a minimum of 10 
study participants providing 
longitudinal data (defined as at least 4 
quantifiable predose and 2 quantifiable 
postdose PK samples during pregnancy 
and at least 1 quantifiable postpartum 
sample) over the study period. Study 
enrollment may be stopped after the 
minimum number of participants is 
reached, or the study may continue to 
enroll beyond the minimum number of 
participants if cumulated study PK data 
are not deemed sufficient to meet the 
primary objective. 
 
To update the planned enrollment needed 
to provide a sufficient number of 
participants with adequate data.  
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Section 9.1, Definition of analysis sets  
New text added: There will be 4 analysis 
sets for the study; the All Study 
Participants Screened Set, the Enrolled 
Set (ES), the Safety Set (SS) and the 
Pharmacokinetic Per Protocol Set (PK-
PPS).  
The All Study Participants Screened Set 
will consist of all study participants who 
have signed the ICF and will include all 
participants who pass screening as well 
as screen failures. This will be the 
largest analysis set. 
Updated to align with the most recent 
SAP amendment. 
Section 9.8, Sample size  
Previous text: From these 15 evaluable 
participants, it is expected approximately 
10 to 12 complete individual longitudinal 
datasets will be collected. 
New text: These 15 evaluable 
participants are expected to provide the 
minimum of 10 study participants 
providing longitudinal data as defined 
in Section 4.1. 
To update the planned enrollment needed 
to provide a sufficient number of 
participants with adequate data.  
Section 9.3.3.1 , Adverse events 
Previous text: All AEs will be coded using 
the Medical Dictionary for Regulatory 
Activities (MedDRA v19.1) and 
characterized as treatment-emergent 
according to the intake of CZP. 
New text: All AEs will be coded using 
the Medical Dictionary for Regulatory 
Activities (MedDRA v24.1 or higher) 
and characterized as treatment-
emergent according to the intake of 
CZP. 
Updated to align with the most recent 
SAP amendment. 
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Throughout the protocol 
Minor typographical edits have been 
incorporated in the protocol.  
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
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 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ...................................... 2 
SERIOUS ADVERSE EVENT REPORTING .......................................................................... 7 
1 
PROTOCOL SUMMARY ............................................................................................... 12 
1.1 Synopsis ........................................................................................................................... 12 
1.2 Schema ............................................................................................................................. 15 
1.3 Schedule of Activities ...................................................................................................... 16 
2 
INTRODUCTION ........................................................................................................... 20 
2.1 Study rationale ................................................................................................................. 20 
2.2 Background ...................................................................................................................... 20 
2.3 Benefit/risk assessment .................................................................................................... 21 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 22 
4 
STUDY DESIGN ............................................................................................................. 22 
4.1 Overall design .................................................................................................................. 22 
4.2 Scientific rationale for study design................................................................................. 24 
4.3 Justification for dose ........................................................................................................ 24 
4.4 End of study definition ..................................................................................................... 24 
5 
STUDY POPULATION .................................................................................................. 25 
5.1 Inclusion criteria .............................................................................................................. 25 
Age 
 
 ..................................................................................................................... 25 
Type of participant and disease characteristics .................................................................... 25 
Sex 
 
 ..................................................................................................................... 25 
Informed consent ................................................................................................................. 25 
5.2 Exclusion criteria ............................................................................................................. 26 
Medical conditions ............................................................................................................... 26 
Prior/concomitant therapy .................................................................................................... 26 
Prior/concurrent clinical study experience .......................................................................... 27 
Diagnostic assessments ........................................................................................................ 27 
5.3 Lifestyle restrictions ......................................................................................................... 27 
5.3.1 
Meals and dietary restrictions .............................................................................. 27 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 27 
5.3.3 
Activity ................................................................................................................ 27 
5.4 Screen failures .................................................................................................................. 27 
6 
STUDY TREATMENT ................................................................................................... 27 
6.1 Treatment administered.................................................................................................... 28 
6.2 Preparation, handling, storage, and accountability requirements .................................... 28 
6.3 Measures to minimize bias: Randomization and blinding ............................................... 28 
6.4 Treatment compliance ...................................................................................................... 28 
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6.5 Concomitant medication(s)/treatment(s).......................................................................... 28 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 29 
6.5.2 
Concomitant medications that lead to study withdrawal ..................................... 29 
6.6 Dose modification ............................................................................................................ 29 
6.7 Treatment after the end of the study ................................................................................ 30 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 30 
7.1 Discontinuation of study medication ............................................................................... 30 
7.1.1 
Temporary discontinuation .................................................................................. 30 
7.2 Participant discontinuation/withdrawal from the study ................................................... 30 
7.3 Lost to follow up .............................................................................................................. 31 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 31 
8.1 Efficacy assessments ........................................................................................................ 32 
8.2 Safety assessments ........................................................................................................... 32 
8.2.1 
Physical examination ........................................................................................... 32 
8.2.2 
Vital signs ............................................................................................................ 32 
8.2.3 
Electrocardiograms .............................................................................................. 33 
8.2.4 
Clinical safety laboratory assessments ................................................................ 33 
8.2.5 
Pregnancy outcome .............................................................................................. 33 
8.3 Adverse events ................................................................................................................. 33 
8.3.1 
Time period and frequency for collecting AE and SAE information .................. 33 
8.3.2 
Method of detecting AEs and SAEs .................................................................... 34 
8.3.3 
Follow-up of AEs and SAEs ................................................................................ 34 
8.3.4 
Regulatory reporting requirements for SAEs ...................................................... 34 
8.3.5 
Pregnancy ............................................................................................................ 34 
8.3.6 
Adverse events of special interest ........................................................................ 34 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs .................................................................................................................... 35 
8.4 Safety signal detection ..................................................................................................... 36 
8.5 Treatment of overdose ..................................................................................................... 36 
8.6 Pharmacokinetics ............................................................................................................. 36 
8.7 Pharmacodynamics .......................................................................................................... 36 
8.8 Genetics ............................................................................................................................ 37 
8.9 Biomarkers ....................................................................................................................... 37 
8.9.1 
Immunogenicity assessments ............................................................................... 37 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 37 
9.1 Definition of analysis sets ................................................................................................ 37 
9.2 General statistical considerations ..................................................................................... 37 
9.3 Planned PK, immunogenicity, and safety analyses ......................................................... 38 
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9.3.1 
Pharmacokinetic analyses .................................................................................... 38 
9.3.2 
Immunogenicity analyses .................................................................................... 39 
9.3.3 
Safety analyses ..................................................................................................... 39 
9.3.3.1 
Adverse events .......................................................................................... 39 
9.3.3.2 
Vital signs .................................................................................................. 39 
9.3.3.3 
Physical examinations ............................................................................... 39 
9.3.3.4 
Pregnancy outcome ................................................................................... 39 
9.4 Planned efficacy/outcome analyses ................................................................................. 39 
9.5 Handling of protocol deviations ....................................................................................... 39 
9.6 Handling of dropouts or missing data .............................................................................. 39 
9.7 Planned interim analysis and data monitoring ................................................................. 40 
9.8 Determination of sample size ........................................................................................... 40 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 40 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations ............................. 40 
10.1.1 
Regulatory and ethical considerations ................................................................. 40 
10.1.2 
Financial disclosure ............................................................................................. 41 
10.1.3 
Informed consent process .................................................................................... 41 
10.1.4 
Data protection ..................................................................................................... 41 
10.1.5 
Committees structure ........................................................................................... 42 
10.1.6 
Data quality assurance ......................................................................................... 42 
10.1.6.1 
Electronic Case Report Form completion ................................................. 42 
10.1.6.2 
Apps ........................................................................................................... 43 
10.1.7 
Source documents ................................................................................................ 43 
10.1.8 
Study and site closure .......................................................................................... 43 
10.1.9 
Publication policy ................................................................................................ 44 
10.2 Appendix 2: Clinical laboratory tests .............................................................................. 45 
10.3 Appendix 3: Adverse events – Definitions and procedures for recording, evaluating, 
follow-up, and reporting .................................................................................................. 46 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............. 51 
Definitions 
 ..................................................................................................................... 51 
10.5 Appendix 5: Genetics ....................................................................................................... 52 
10.6 Appendix 6: Liver safety – Suggested actions and follow-up assessments ..................... 53 
10.7 Appendix 7: Medical device incidents – Definition and procedures for recording, 
evaluating, follow-up, and reporting ................................................................................ 54 
10.8 Appendix 8: Rapid alert procedures ................................................................................ 55 
10.9 Appendix 9: Country-specific requirements .................................................................... 56 
10.10 
Appendix 10: Abbreviations and trademarks ........................................................ 57 
10.11 
Appendix 11: Protocol amendment history ........................................................... 59 
11 REFERENCES ................................................................................................................ 65 
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SPONSOR DECLARATION .................................................................................................. 66 
 
LIST OF TABLES 
Table 1‒1: 
Schedule of Activities ...................................................................................... 17 
Table 8‒1: 
Anticipated SAEs ............................................................................................. 35 
 
LIST OF FIGURES 
Figure 1‒1: 
Study Diagram ................................................................................................. 15 
 
 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: A postmarketing, multicenter, longitudinal, prospective, pharmacokinetic, 
Phase 1B study in pregnant women with chronic inflammatory diseases treated with Cimzia® 
(certolizumab pegol). 
Short title: A postmarketing, multicenter, pharmacokinetic study in pregnant women with 
chronic inflammatory diseases treated with certolizumab pegol. 
Rationale: 
Certolizumab pegol (CZP) is approved in adults for the treatment of chronic inflammatory 
diseases (such as rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and 
axial spondyloarthritis [including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis]) in multiple countries worldwide. 
Depending on the severity and condition, active disease can impact the outcome for the mother 
and infant and may necessitate therapy, even during pregnancy. For women who continue CZP 
therapy during pregnancy, there is no robust evidence available regarding the impact of 
pregnancy on pharmacokinetics (PK) during treatment with CZP. In order to ensure that women 
who require CZP treatment during pregnancy are able to achieve therapeutic steady state levels 
of CZP, it is valuable to conduct studies evaluating whether the physiologic changes underlying 
pregnancy impact the PK profile of CZP during pregnancy. 
The objective of this longitudinal, prospective, open-label PK study is to assess any changes in 
CZP (the study medication in this protocol) plasma concentrations over the course of pregnancy, 
relative to the postpartum period. 
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Objectives and endpoints: 
Objectives 
Endpoints 
Primary 
• To assess systemic CZP exposure across 
the course of pregnancy in study 
participants with chronic inflammatory 
diseases 
• Predose and postdose plasma CZP 
concentrations in women during 
pregnancy, relative to postpartum 
Secondary 
• To assess the formation of anti-CZP 
antibodies across the course of pregnancy 
• Plasma levels of anti-CZP antibodies 
throughout the study period 
• To assess the safety of CZP in study 
participants with chronic inflammatory 
diseases across the course of pregnancy 
• Adverse events from time of informed 
consent through SFU 
• Pregnancy outcome 
Other 
• To assess changes in BMI, CRP and 
albumin across the course of pregnancy 
• BMI 
• CRP levels 
• Albumin levels 
BMI=body mass index; CRP=C-reactive protein; CZP=certolizumab pegol; SFU=Safety Follow-Up 
Overall design: 
This is a Phase 1B, multicenter, longitudinal, interventional, prospective, PK, open-label study 
evaluating the impact of pregnancy on the PK of CZP. The study will recruit women who are 
already on prescribed commercial CZP with both a dosing regimen selected with guidance from 
the participant’s treating physician and an indication approved for use in their country, and who 
become pregnant and continue treatment with CZP. A postpartum predose blood sample will be 
taken 12 weeks (±1 week) after delivery, once the mother is considered to have returned to a 
pre-pregnancy physiological state, will serve as a within-participant reference sample. If 
possible, a postdose sample will be taken 1 week (±1 day) after the 12-week postpartum dose. 
This study is considered interventional due to the collection of blood samples from the women, 
which is not part of routine clinical practice. However, it is noninterventional regarding 
treatment with CZP and will only include pregnant women who decided with their treating 
physician to continue treatment with CZP prior to being recruited for and enrolled in the study. 
The study consists of a Screening Period, Sampling Period (consisting of a Pregnancy Period and 
Postpartum Period), and a Safety Follow-up (SFU) contact, as shown in Figure 1‒1 and 
described below. 
The full Schedule of Activities is provided in Table 1‒1. 
• Screening Period: Women of childbearing potential already on commercial CZP can register 
to indicate interest in the current study. After confirmation of pregnancy, the women will 
consent to participate in the study and will be eligible to enroll once CZP levels have reached 
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steady state. Confirmation of steady state is based on participant records and/or reports from 
the prescribing physician indicating that the participant has taken CZP for at least 12 weeks 
at the same dosing regimen prior to the Enrollment Visit, which must take place at 
≤10 weeks gestational age. 
• Sampling Period: 
− Pregnancy Period: PK samples will be collected prior to the subsequent dose (predose) 
every 4 weeks (Q4W) starting with the first dose after enrollment. Further, postdose 
(7 ± 1 day after dose administration) PK samples will be collected every 8 weeks (Q8W) 
throughout the pregnancy. It is expected that there will be approximately 6 predose and 
3 postdose PK samples collected per study participant (if there are no discontinuations) 
over the pregnancy. 
− Postpartum Period: A predose sample 12 weeks (±1 week) postpartum will be collected 
during the Postpartum Period. If possible, 1 additional postdose sample 1 week (±1 day) 
after the 12 weeks postpartum dose will also be collected. 
• Safety Follow-up contact: All study participants will be contacted via telephone for a 
SFU 5 weeks (±5 days) after final study visit. 
If any participant withdraws early, she will complete the SFU contact. 
The end of the study is defined as the date of the SFU/last contact of the last participant in the 
study. 
Number of participants: 
Approximately 25 to 30 participants are planned to be screened to achieve approximately 
20 enrolled study participants (ie, study participants who have provided the first blood sample). 
Enrollment will occur until a minimum of 10 study participants have longitudinal data (defined 
as at least 4 quantifiable predose and 2 quantifiable postdose PK samples during pregnancy and 
at least 1 quantifiable postpartum sample) over the study period. 
Treatment groups and duration: 
This study will include pregnant women who have decided to continue treatment with 
commercial CZP in accordance with their treating physician prior to participating in the study. 
Study participants will be responsible for obtaining and administering commercially available 
CZP under the care of their physician and according to the locally approved product label. 
The total study duration for a study participant will be a maximum of 53 weeks (40 weeks 
gestation period and up to 13 weeks (±3 days) postpartum). 
 
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1.2 
Schema 
A schematic of the study design is provided in Figure 1‒1. 
Figure 1‒1: Study Diagram 
 
CZP=certolizumab pegol; PK=pharmacokinetics; Q2W=every 2 weeks; Q4W=every 4 weeks 
a CZP dosing for at least 12 weeks before enrollment 
b First CZP dose post-enrollment 
c Timing and the number of visits across the pregnancy will vary for individual study participants 
 
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1.3 
Schedule of Activities 
The Schedule of Activities is provided in Table 1‒1. 
 
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Table 1‒1: 
Schedule of Activities 
Procedurea 
Screening 
Sampling Period 
SFU/EWD 
(via 
telephone)c 
Pregnancy Period 
Postpartum Periodb 
V1d 
V2 
(Enrollment) 
Predosee 
(Q4W) 
Postdosef 
(Q8W) 
V5 
Predosee  
 
V6 
Postdosef 
(optional) 
V7g 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics and baseline 
characteristics h 
X 
 
 
 
 
 
 
Verification of 
inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Significant 
medical/procedures history 
and concomitant diseases 
X 
 
 
 
 
 
 
Concomitant medication and 
procedures review 
X 
X 
X 
X 
X 
X 
X 
Adverse event reviewi 
X 
X 
X 
X 
X 
X 
X 
Recording of commercial 
CZP treatmentj 
X 
X 
X 
X 
X 
X 
X 
Physical examinationk 
X 
 
 
 
 
 
 
Vital signsl 
X 
 
 
 
 
 
 
Tobacco and alcohol 
consumption, and drug abuse 
X 
 
 
 
 
 
 
TB questionnairem 
X 
 
 
 
 
 
 
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Table 1‒1: 
Schedule of Activities 
Procedurea 
Screening 
Sampling Period 
SFU/EWD 
(via 
telephone)c 
Pregnancy Period 
Postpartum Periodb 
V1d 
V2 
(Enrollment) 
Predosee 
(Q4W) 
Postdosef 
(Q8W) 
V5 
Predosee  
 
V6 
Postdosef 
(optional) 
V7g 
 
TB test (if not within 
6 months)n,o 
X 
 
 
 
 
 
 
Blood sampling for plasma 
CZP PK levels 
 
X 
X 
X 
X 
X 
 
Blood sampling for plasma 
anti-CZP antibodies 
 
X 
X 
 
X 
 
 
Study participant diary 
completion/review 
X 
X 
X 
X 
X 
X 
 
Blood sampling for CRP and 
albumin 
 
X 
X 
 
X 
 
 
Weight (for BMI 
calculation) 
 
X 
X 
 
X 
 
 
Pregnancy outcome 
 
 
 
 
X 
 
 
SFU contact 
 
 
 
 
 
 
X 
BCG=Bacillus Calmette–Guérin; BMI=body mass index; CRP=c-reactive protein; CZP=certolizumab pegol; EWD=Early Withdrawal/Discontinuation; 
ICF=informed consent form; PK=pharmacokinetic; Q4W=every 4 weeks; Q8W=every 8 weeks; SFU=Safety Follow-up; TB=tuberculosis; V=Visit 
a It is expected that PK samples may not be obtainable in every case. Therefore, missing samples should not be considered major protocol deviations. 
b Postpartum samples will be collected up to 13 weeks (±3 days) postpartum. 
c The SFU telephone contact will take place 5 weeks (±5 days) after the last study visit for all study participants. 
d Visit 1 may take place at an on-site or off-site location, conducted by the investigator or appropriate designee (eg, study participant’s local healthcare 
provider). 
e Predose samples will be collected within 4 hours prior to dosing. 
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Table 1‒1: 
Schedule of Activities 
Procedurea 
Screening 
Sampling Period 
SFU/EWD 
(via 
telephone)c 
Pregnancy Period 
Postpartum Periodb 
V1d 
V2 
(Enrollment) 
Predosee 
(Q4W) 
Postdosef 
(Q8W) 
V5 
Predosee  
 
V6 
Postdosef 
(optional) 
V7g 
 
f Postdose samples will be collected 7 (±1) days after the dose has been administered. 
g The SFU will take place 5 weeks (±5 days) after the last study visit. 
h Demographic and baseline characteristics will include lifestyle, confirmation of pregnancy, height, weight and BMI. 
i Adverse events will be collected from the time of the signature on the ICF until the SFU contact. 
j The decision to treat with CZP will be made by the study participant in accordance with her treating physician prior to being recruited for the study. Study 
participants are responsible for obtaining their own supply of commercial CZP. Final dosing of CZP during the study will be recorded during the SFU. 
k Physical examinations may be performed by the study participant’s local healthcare provider, and a record of that examination is to be provided to the 
investigator as documentation. 
l Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure, and peripheral body temperature. Study participants should maintain a 
sitting position for ≥5 minutes before and during vital signs assessments. 
m Includes signs and symptoms of active TB and risk factors for exposure to TB and requires an assessment every 12 weeks. No chest x-rays or follow-up 
testing will be performed, as this study will comprise study participants who have a low risk for TB.  
n Tuberculosis test results that have been obtained within the previous 6 months prior to Screening with negative results are acceptable. Study participants 
with documented BCG vaccination and low risk of TB do not need to have TB test performed at Screening. 
o A TB test will only be offered within the study or at study exit if it has been 52 weeks since the last negative test and a test is clinically indicated. 
 
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2 INTRODUCTION 
Certolizumab pegol has been approved for use in patients with rheumatoid arthritis, psoriatic 
arthritis, plaque psoriasis, Crohn’s disease, and axial spondyloarthritis (including ankylosing 
spondylitis and non-radiographic axial spondyloarthritis) in multiple countries worldwide. 
Limited data exist on the use of CZP in pregnant women, and are not sufficient to indicate how 
the physiologic changes of pregnancy can alter the PK of CZP in pregnant women. 
2.1 
Study rationale 
Certolizumab pegol is an engineered, humanized, antigen-binding antibody fragment (Fab), with 
specificity for human tumor necrosis factor α, that is conjugated to polyethylene glycol and is 
approved in adults for the treatment of the aforementioned chronic inflammatory diseases in 
multiple countries worldwide. 
Depending on the severity and condition, active disease can impact the outcome for the mother 
and infant and may necessitate therapy, even during pregnancy. For women who continue CZP 
therapy during pregnancy, there is no robust evidence available regarding the impact of 
pregnancy on PK during treatment with CZP. In order to ensure that women who require CZP 
treatment during pregnancy are able to achieve therapeutic steady state levels of CZP, it is 
valuable to conduct studies evaluating whether the physiologic changes underlying pregnancy 
impact exposure to CZP during pregnancy. As such, this study will evaluate the PK of CZP 
during pregnancy. 
For further information regarding the study rationale see Section 4.2. 
2.2 
Background 
Autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s 
disease, and axial spondyloarthritis (including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis) affect women of childbearing age. While disease activity may spontaneously 
improve during pregnancy, approximately 50% of women with rheumatic chronic inflammatory 
diseases need effective therapeutic intervention and are faced with difficult questions regarding 
the impact of active disease on the fetus and the safety of different therapies during pregnancy. 
Depending on the severity and condition, active disease can impact the outcome for the mother 
and infant and may necessitate therapy, even during pregnancy. Published data suggest that the 
risk of adverse pregnancy outcomes in women with rheumatoid arthritis or Crohn’s disease is 
correlated with maternal disease activity and that active disease increases the risk of adverse 
pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low 
birth weight (<2500g) and small for gestational age birth. Consequently, physicians and their 
patients may decide to continue to treat disease during pregnancy. 
As described by Mariette (2018), physiologic changes during pregnancy may substantially alter 
drug PK; however, there are very limited data available on the impact of pregnancy on CZP PK. 
It is valuable to provide data about CZP levels throughout pregnancy to help women and their 
physicians make informed decisions about the dose of CZP to use during pregnancy, if a decision 
to continue treatment with CZP has been made. 
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2.3 
Benefit/risk assessment 
A clinical postmarketing prospective study (UP0017) evaluating placental transfer of CZP by 
measuring the plasma concentration of CZP from blood samples taken from infant, mother, and 
umbilical cord at delivery/birth indicated that there was minimal placental transfer of CZP from 
mother to infant. The mothers had similar CZP plasma concentrations at delivery to those of 
nonpregnant women receiving a maintenance dose regimen, and there were no detectable 
measurements of anti-CZP antibodies using the assay available at the time of the study in either 
the mothers or the infants, nor were there new safety signals. 
UP0085 will only include pregnant women who decided to continue treatment with CZP in 
accordance with their treating physician prior to participating in the study. Therefore, 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). 
Study participants will not directly benefit from participation in the study; however, the data 
obtained will enable physicians, pregnant women, and women of childbearing age to be better 
informed regarding PK of CZP when used during pregnancy. 
For more detailed information (eg, PK and safety), as well as information about the known and 
expected benefits and risks and expected adverse events (AEs) of CZP, see the current 
Investigator’s Brochure (IB). 
As per routine UCB pharmacovigilance activity, all women who are administered CZP prior to 
the estimated date of conception or at any time during their pregnancy will be asked to complete 
the UCB Pregnancy Report and Outcome Form together with their treating physician 
(see Section 10.4). This process will apply also to participants of this study and enable UCB to 
collect information on the pregnancy and its outcome. 
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3 OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To assess systemic CZP exposure across 
the course of pregnancy in study 
participants with chronic inflammatory 
diseases 
• Predose and postdose plasma CZP 
concentrations in women during 
pregnancy, relative to postpartum 
Secondary 
• To assess the formation of anti-CZP 
antibodies across the course of pregnancy 
• Plasma levels of anti-CZP antibodies 
throughout the study period 
• To assess the safety of CZP in study 
participants with chronic inflammatory 
diseases across the course of pregnancy 
• Adverse events from time of informed 
consent through SFU 
• Pregnancy outcome 
Other 
• To assess changes in BMI, CRP and 
albumin across the course of pregnancy 
• BMI 
• CRP levels 
• Albumin levels 
BMI=body mass index; CRP=C-reactive protein; CZP=certolizumab pegol; SFU=Safety Follow-Up 
4 STUDY DESIGN 
4.1 
Overall design 
This is a multicenter, longitudinal, interventional, prospective, PK, open-label study evaluating 
the impact of pregnancy on the PK of CZP. This is a Phase 1B (clinical pharmacology) 
exploratory study. The study will recruit women who are already on prescribed commercial CZP 
with a dosing regimen selected with guidance from the participant’s treating physician and for a 
given indication (approved for use in their country) and who become pregnant and continue 
treatment with CZP. A postpartum predose sample will be taken 12 weeks (±1 week) after 
delivery, once the mother is considered to have returned to a pre-pregnancy physiological state, 
will serve as a within-participant reference sample. If possible, a postdose sample will be taken 
1 week (±1 day) after the 12-week postpartum dose. 
The study is interventional due to the additional collection of blood samples from women. 
However, all other study assessments are part of routine clinical practice (with the exception of 
the diary), and the decision to continue/discontinue CZP therapy during pregnancy will be made 
between the participant and her treating physician, taking into account the potential risks to the 
mother and the benefits of CZP therapy, and according to the applicable local label.  
Study participants should have taken CZP for at least 12 weeks at their dosing regimen prior to 
enrollment and before the end of 10 weeks gestational age (see Inclusion Criterion [IC] 3). The 
study will enroll participants based on a minimum of 10 study participants providing longitudinal 
data (defined as at least 4 quantifiable predose and 2 quantifiable postdose PK samples during 
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pregnancy and at least 1 quantifiable postpartum sample) over the study period. Study enrollment 
may be stopped after the minimum number of participants is reached, or the study may continue 
to enroll beyond the minimum number of participants if the cumulative study PK data are not 
deemed sufficient to meet the primary objective. Study participants will be provided with a diary 
to record all CZP dosing dates and times over the study period. Pharmacokinetic samples (for the 
determination of CZP concentration and anti-CZP antibody titers) will be collected as detailed 
above, and samples will be collected for assessment of C-reactive protein (CRP) and albumin 
(covariates of the PK parameters). Overall safety and welfare of the mother and fetus are of 
paramount importance while performing any study-related activity. 
If a study participant has at least 1 PK sample obtained during pregnancy and then CZP dosing is 
interrupted and restarted, or dosing is modified during pregnancy, the study participant will 
continue to be followed and all samples will be obtained per protocol guidelines (including 
postpartum samples). 
If a study participant has multiple PK samples obtained during pregnancy and discontinues CZP 
during pregnancy (with the intention to restart CZP after delivery), a PK predose sample will be 
obtained at 12 weeks (±1 week) postpartum with a potential postdose sample 1 week (±1 day) 
after the predose postpartum sample. If the study participant does not take CZP for at least 
12 weeks and provides a PK sample within this window, the study participant will be 
discontinued from the study. 
The informed consent form (ICF) for this study may be available electronically and used by 
prospective study participants at a study center or a remote location. If a study participant 
consents to participate, she will enter the Screening Period and all elements of eligibility will be 
confirmed prior to entering the Sampling Period. It is anticipated that the sampling visits will be 
completed in the study participant’s home setting or at a designated convenient location in the 
presence of a qualified remote healthcare nurse. To facilitate these visits, the study participant 
should have access to a telephone. In most cases, remote healthcare nurses performing a visit to a 
study participant may complete study data forms that can be entered into the database by the 
contract research organization (CRO) or site staff. In other cases, study participants may visit a 
clinic, study site, or other health care provider’s office for assessments or to provide blood 
samples. 
Laboratory kits will be provided to the health care providers, remote healthcare nurses, and the 
study participants (as back up) for collection of CZP plasma levels, anti-CZP antibody 
assessments, CRP and albumin during collection of the final PK sample, in addition to a safety 
evaluation. Albumin was previously found to be a significant covariate in CZP population PK 
analyses, and CRP is a PK covariate and marker of inflammatory state. All samples will be 
initially delivered to a central laboratory. Pharmacokinetic samples will then be periodically 
shipped to a bioanalytical laboratory for PK and immunogenicity assessments. Samples will be 
collected for analysis of PK, immunogenicity, CRP, and albumin. At the Screening Visit, which 
may be at an on-site or off-site location and may be conducted by the investigator or appropriate 
designee (eg, study participant’s local healthcare provider), a physical examination will be 
performed, and vital signs will be measured. Additionally, tuberculosis (TB) testing will be 
performed if the study participant has not been tested within 6 months prior to Screening and has 
no associated clinical evidence of an active TB infection. Procedures and documentation will 
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comply with local Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) 
requirements. 
4.2 
Scientific rationale for study design 
Clinical studies typically exclude pregnant women and withdraw study participants once they 
become pregnant. This has created a lack of data regarding drug exposure that leaves both 
pregnant women and treating physicians without objective scientific evidence regarding dosing 
of CZP during pregnancy. Additionally, depending on the severity and condition, active disease 
can impact the outcome for the mother and infant and may necessitate therapy, even during 
pregnancy. For women who continue CZP therapy during pregnancy, there is no robust evidence 
available regarding the impact of pregnancy on PK during treatment with CZP. In order to ensure 
that women who require CZP treatment during pregnancy are able to achieve therapeutic steady 
state levels of CZP, it is valuable to conduct studies evaluating whether the physiologic changes 
underlying pregnancy impact exposure to CZP during pregnancy. This study (UP0085) will 
generate further data regarding steady state dosing of CZP during pregnancy, which can help to 
provide guidance on PK variability and the impact of pregnancy on CZP plasma levels. 
The objective of this longitudinal, prospective, open label PK study is to assess any changes in 
CZP plasma concentrations that may result from physiological changes that occur during 
pregnancy. Women who take CZP for approved indications and maintenance dosing regimens 
(200mg every 2 weeks [Q2W] or 2 x 200mg Q4W or 400mg Q2W) and who continue with CZP 
treatment after they have become pregnant will be eligible to be considered for enrollment into 
this study, which will generate important information on CZP exposure during pregnancy. To 
measure CZP plasma concentration at steady state during pregnancy and after delivery, blood 
samples will be collected predose Q4W, postdose Q8W during the pregnancy, and 1 predose 
sample 12 weeks (±1 week) postpartum (with potential postdose sample 1 week [±1 day] after 
the postpartum sample). Each study participant will serve as her own control. 
4.3 
Justification for dose 
The study will recruit pregnant women who are prescribed commercial CZP for an approved 
indication in the country where the study will be conducted. No dose adjustments or any other 
changes to treatment will be mandated by the study protocol (see Section 6.6). The commercially 
approved dosing regimens (200mg Q2W or 400mg Q4W or 400mg Q2W) will be permitted 
following the guidance of each study participant’s physician. After entry into the study, the study 
participant’s physician may modify the dosing regimen as necessary. In such cases, 
non-approved CZP dosing regimens will also be allowed, at the discretion of the study 
participant’s physician and in a manner independent of this study, as long as the regimen does 
not exceed 400mg Q2W and the dose is recorded in the diary. 
4.4 
End of study definition 
A participant is considered to have completed the study if she has completed all phases of the 
study per protocol including the final study contact (SFU). 
The end of the study is defined as the date of the SFU/last contact of the last participant in the 
study. 
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5 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
To be eligible to participate/enroll in this study, all of the following criteria must be met at the 
Screening Visit (Visit 1). Eligibility must also be confirmed at Enrollment Visit (Visit 2), ie, just 
prior to blood sampling for PK. If a participant does not initially meet the enrollment criteria, she 
may be rescreened; however, a study participant may not be enrolled for consecutive 
pregnancies. 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be ≥18 years of age at the time of signing the ICF. 
Type of participant and disease characteristics 
2. Participant must be considered reliable and capable of adhering to the protocol and visit 
schedule according to the judgment of the investigator. 
3. Participant is pregnant and ≤10 weeks gestation at the time of enrollment. 
4. Participant must have been on stable, maintenance dose CZP treatment for at least 12 weeks 
independent of and prior to being enrolled in this study, for an approved indication in 
accordance with her treating physician. 
5. Participant expects to continue CZP therapy throughout pregnancy and for at least 12 weeks 
postpartum. 
6. Participant has a negative interferon gamma release assay (IGRA) or tuberculin skin test 
(TST) within the prior 6 months, and there has been no change in the study participant’s 
clinical status, or social, family, or travel history. Participants with documented Bacillus 
Calmette–Guérin (BCG) vaccine and at low risk for TB may enroll without having a TB test 
performed. 
Sex 
7. Participants who are female. 
Informed consent 
8. Participant is capable of giving signed informed consent as described in Section 10.1 
(Appendix 1) which includes compliance with the requirements and restrictions listed in the 
ICF and in this protocol. 
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5.2 
Exclusion criteria 
Study participants are excluded from the study if any of the following criteria are met at the 
Screening Visit (Visit 1) or Enrollment Visit (Visit 2): 
Medical conditions 
1. Participant has any medical or psychiatric condition 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 recent history of alcohol or drug abuse in the investigator’s medical 
judgment. 
3. Participant has any evidence or medical history of an obstetrical or psychiatric condition, or 
she or her fetus has any medical condition or history (eg, primary or secondary 
antiphospholipid syndrome or hypercoagulable state) that, in the opinion of the investigator, 
could jeopardize or would compromise the study participant’s ability to participate in this 
study or the outcome of the pregnancy. 
4. Participant has any evidence of clinically significant anemia in the opinion of the 
investigator. 
5. Participant has had significant documented morbidity during the past 12 weeks. 
6. Participant is not permitted to enroll into the study if she meets any of the following TB 
exclusion criteria: 
− Known active TB disease 
− History of active TB involving any organ system 
− Latent TB infection 
− High risk of acquiring TB infection 
− Current nontuberculous mycobacterial (NTM) infection or history of NTM infection 
(unless proven to be fully recovered) 
7. Significant allergies to humanized monoclonal antibodies. 
8. Clinically significant multiple or severe drug allergies, or severe post-treatment 
hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear 
immunoglobulin A dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis). 
9. Current or chronic history of clinically significant liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 
Prior/concomitant therapy 
10. Study participant is taking a prohibited medication or has taken a prohibited medication as 
defined in Section 6.5.2. 
11. Live vaccine(s) within 1 month prior to Screening, or plans to receive such vaccines during 
the study. 
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Prior/concurrent clinical study experience 
12. Participant has been dosed with an investigational medicinal product (IMP), blinded IMP, or 
has received an investigational medical device or procedure within the previous 120 days or 
5 half-lives (whichever is longer) prior to Screening or is currently participating in another 
study of an IMP, blinded IMP, or will receive an investigational medical device or procedure 
(excluding noninterventional or registry studies). 
Diagnostic assessments 
13. Study participant has any clinically significant pregnancy-related clinical or test abnormality, 
as judged by the investigator. 
14. Study participant had a positive or indeterminate IGRA or TST test at Screening. In case of 
indeterminate result, a retest is allowed if time permits; 2 results of indeterminate require 
exclusion of the study participant. 
15. Study participant has a history of human immunodeficiency virus, Hepatitis B surface 
antigen (HBsAg), or Hepatitis C antibody prior to starting the study. 
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 publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened; however, a study participant may not be enrolled for consecutive pregnancies. 
Rescreened participants should be assigned the same participant number as for the initial 
Screening. 
6 STUDY TREATMENT 
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 
Treatment administered 
This study will only include pregnant women who have decided to continue treatment with CZP 
in accordance with their treating physician prior to participating in the study. The CZP is not 
provided by the Sponsor. Study participants will be responsible for obtaining and administering 
commercially available CZP under the care of their physician. 
The commercially approved dosing regimens (200mg Q2W or 400mg Q4W or 400mg Q2W) 
will be permitted following the guidance of each study participant’s physician. 
After entry into the study, the study participant’s physician may modify the dosing regimen as 
necessary. In such cases, non-approved CZP dosing regimens will also be allowed, at the 
discretion of the study participant’s physician and in a manner independent of this study, as long 
as the regimen does not exceed 400mg Q2W and the dose is recorded in the diary. Study 
participants will receive CZP in accordance with their treating physician until at least 12 weeks 
(±1 week) after delivery. 
6.2 
Preparation, handling, storage, and accountability requirements 
Study participants will be responsible for obtaining and administering commercially available 
CZP under the care of their physician. 
Commercial CZP can be self-administered by subcutaneous injection using a prefilled syringe or 
prepared and administered by a health care professional if lyophilized powder is used. 
6.3 
Measures to minimize bias: Randomization and blinding 
All study participants will receive CZP under the care of their physician; thus there is no 
opportunity for bias. Based on this study design, randomization and blinding are not possible and 
are therefore not applicable to this study. 
6.4 
Treatment compliance 
Study participants will be provided with a diary to record all CZP dosing dates and times over 
the study period. 
6.5 
Concomitant medication(s)/treatment(s) 
Unless otherwise prohibited per protocol exclusion criteria, study participants are permitted to 
continue on their prescribed medical therapy for the disease in accordance with the instructions 
of their treating physician. 
Any treatment other than commercial CZP (CZP dosing dates and times will be collected 
separately in a diary), including over-the-counter products and supplements, must be recorded in 
the study participant’s notes (source documentation) and provided on the electronic Case Report 
Form (eCRF). This record should include the name of the drug, the dose, the route, and date(s) of 
administration, and the indication for use. 
For the purposes of this study: 
• Past medications are those that are ongoing at the time of first day of the last menstrual 
period and those that started after the first day of the last menstrual period that stopped prior 
to entering the Screening Period. 
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• Prior medications are those that are ongoing at the time of first day of the last menstrual 
period and those that started after the first day of the last menstrual period prior to entering 
the Screening Period. 
• Concomitant medications are medications with at least 1 day in common with the Screening 
or Sampling Periods. 
• Prior medications may include both past medications and concomitant medications. 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
All concomitant medications are permitted, except for those noted in Section 6.5.2. 
6.5.2 
Concomitant medications that lead to study withdrawal 
The study participant must not participate in any other interventional clinical study or receive 
any unauthorized medication throughout the study period. Non-Interventional study (NIS) 
participation is allowed. 
There are no specific prohibited concomitant medications in this study, as it is not the intention 
to interfere with the physician’s decision on treatment.  However, there are certain exclusion 
criteria and withdrawal criteria associated with concomitant medication use to ensure robust and 
interpretable data.  These criteria include:   
• Any medication taken 12 weeks prior to conception with strong positive evidence of a human 
fetal risk of teratogenicity during pregnancy. 
− The study participant must be withdrawn from the study if she takes any medication 
(during the pregnancy) with strong positive evidence of a human fetal risk or other 
adverse outcomes. 
• Any biological therapeutic agent, including anti-TNFs other than CZP. 
• Any biological disease modifying drug (other than CZP), whether licensed or unlicensed, for 
the study participant’s disease during the pregnancy. 
6.6 
Dose modification 
The study will recruit pregnant women who are prescribed commercial CZP for an approved 
indication in the country where study will be conducted. No dose adjustments will be mandated 
by the study protocol. However, in the best interest of the study participant, the treating 
physician can modify the dosing regimen in accordance with local medical practice in the 
management of her disease, or the study participant might modify her dosing regimen herself and 
any changes in dosing should be recorded in the diary. In these cases, the study participant will 
still be followed per protocol since the resultant data will be informative with the data analytical 
methodologies to be employed. 
As described in Section 6.1, after entry into the study, the study participant’s physician may 
modify the dosing regimen as necessary. In such cases, non-approved CZP dosing regimens will 
also be allowed, at the discretion of the study participant’s physician and in a manner 
independent of this study, as long as the regimen does not exceed 400mg Q2W and the dose is 
recorded in the diary. 
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6.7 
Treatment after the end of the study 
Study participants may continue to be treated with commercially-available CZP in accordance 
with their treating physician following completion of the study. 
7 DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
Administration of CZP is not dictated by this protocol; therefore there are no protocol-defined 
reasons a participant should permanently discontinue CZP treatment. 
7.1.1 
Temporary discontinuation 
If a study participant has at least 1 PK sample obtained during pregnancy and then CZP dosing is 
interrupted and restarted, or dosing is modified during pregnancy, the study participant will 
continue to be followed and all samples will be obtained per protocol guidelines (including 
postpartum samples). 
If a study participant has multiple PK samples obtained during pregnancy and discontinues CZP 
during pregnancy (with the intention to restart CZP after delivery), a PK predose sample will be 
obtained at 12 weeks (±1 week) postpartum with a potential postdose sample 1 week (±1 day) 
after the predose postpartum sample. If the study participant does not take CZP for at least 
12 weeks and provides a PK sample within this window, the study participant will be 
discontinued from the study. 
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 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, 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. 
Participants should be withdrawn from the study if any of the following events occur: 
1. Participant develops an illness that would interfere with her continued participation. 
2. Participant is noncompliant with the study procedures or medications in the opinion of the 
investigator. 
3. Participant takes concomitant medications that lead to study withdrawal as defined in this 
protocol (Section 6.5.2). 
4. Participant withdraws her consent. 
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5. The sponsor or a regulatory agency requests withdrawal of the participant. 
6. If the study participant has a spontaneous abortion, the study participant will be discontinued 
from the study and a postpartum sample will not be obtained. 
7. If the study participant ceases CZP during pregnancy, and upon restarting after delivery does 
not take CZP for at least 12 weeks and provides a PK sample within the window defined in 
Section 7.1.1, the study participant will be discontinued from the study. 
8. If the study participant is given a dose of CZP exceeding 400mg Q2W, the study participant 
will be discontinued from the study. 
Study participants should consult with their treating physician to determine the best method of 
ceasing administration of CZP based on recommendations located on the manufacturer’s label. 
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 she repeatedly misses scheduled visits and is 
unable to be contacted by the investigator. 
The following actions must be taken if a participant misses a required study visit: 
• The investigator must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (at least 1 phone call and 1 written message 
to the participant), and document his/her effort (date and summary of the phone call and copy 
of the written message in the source documents), to complete the final evaluation. All results 
of these evaluations and observations, together with a narrative description of the reason(s) 
for removing the participant, must be recorded in the source documents. The eCRF must 
document the primary reason for withdrawal. 
Should the participant continue to be unreachable, she will be considered to have withdrawn 
from the study with a primary reason of lost to follow up documented in the eCRF. 
8 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities 
(see Section 1.3). 
Protocol waivers or exemptions are not allowed. 
It will be the responsibility of the treating physician to determine if the participant should 
continue or discontinue treatment. The sponsor should be informed immediately regarding safety 
concerns upon occurrence or awareness to determine if the participant should continue or 
discontinue participation in the study. 
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Adherence to the study design requirements, including those specified in the Schedule of 
Activities (see Section 1.3), is essential and required for study conduct. 
All Screening evaluations 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 (see Section 1.3). 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Study participants will be provided with a diary to record all CZP dosing dates and times over 
the study period. 
8.1 
Efficacy assessments 
Not applicable. 
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 physical examination will take place at Screening, as specified in Section 1.3, and may be 
performed by the study participant’s local healthcare provider, and a record of that examination 
provided to the investigator as documentation. 
A physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, abdomen (liver and spleen). 
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 
Peripheral body temperature, pulse rate, respiratory rate, and systolic and diastolic blood 
pressure will be assessed. 
Blood pressure and pulse measurements will be assessed with the study participant in a sitting 
position with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television and/or cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
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intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded on 
the eCRF. 
8.2.3 
Electrocardiograms 
Electrocardiograms will not be recorded in this study. 
8.2.4 
Clinical safety laboratory assessments 
No clinical safety laboratory assessments will be performed in this study. 
8.2.5 
Pregnancy outcome 
Information regarding pregnancy outcome and maternal hospitalization/delivery will be 
collected. The investigator should update the Pregnancy Report and Outcome form, as necessary, 
and send it to the Sponsor. 
Additional information regarding collection of pregnancy-related data is located in Appendix 4 
(Section 10.4). 
8.3 
Adverse events 
The definitions of an AE and SAE can be found in Appendix 3 (Section 10.3). 
Adverse events 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 CZP or study procedures, or that caused the participant to 
discontinue the study (see Section 7). 
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 at the time 
points 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 eCRF. 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 CZP), up to 
35 days (±5 days) after the final blood sample is obtained 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 CZP must be reported to UCB, regardless of 
the time between the event and the end of the study. 
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The method of recording, evaluating, and assessing causality of AEs and SAEs 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 
nonleading 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 nonserious 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 CZP 
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 CZP under clinical investigation. The Sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
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 a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
Details of the pregnancies for all study participants will be collected from enrollment into the 
study and up to the SFU. UCB standing guidance for collection of data pertaining to pregnancy 
and pregnancy outcomes will be used during this study for the collection of such data 
(Section 8.2.5). Information regarding collection of pregnancy-related data is located in 
Appendix 4 Section 10.4.  
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and 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 to be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. 
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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 ≥3x upper limit of normal (ULN) alanine 
aminotransferase or aspartate aminotransferase with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN alkaline phosphatase, with no alternative explanation for the 
biochemical abnormality (ie, without waiting for any additional etiologic investigations 
to have been concluded). Follow-up information should then be reported if an alternative 
etiology is identified during investigation and monitoring of the participant. 
• Serious infections including opportunistic infections 
• Malignancies including lymphoma 
• Congestive heart failure 
• Demyelinating-like disorders 
• Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leucopenia 
• Serious bleeding events 
• Lupus and lupus-like syndrome 
• Serious skin reactions (eg, Stevens Johnson Syndrome, toxic epidermal necrosis, and 
erythema multiforme). 
8.3.7 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs 
Anticipated SAEs are anticipated to occur in the population studied in this protocol at some 
frequency that is independent of drug exposure. A summary of anticipated SAEs is presented in 
Table 8‒1 (Appendix 3). 
This list does not change the investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 8.3.1 and Section 10.3 (Appendix 3). 
Table 8‒1: 
Anticipated SAEs 
Population 
Anticipated SAE(s) 
Rheumatoid arthritis 
Rheumatoid arthritis 
Crohn’s disease 
Crohn’s disease 
Perianal abscess 
Abdominal pain 
Ankylosing spondylitis 
Ankylosing spondylitis 
Psoriatic arthritis 
Psoriatic arthritis 
Plaque psoriasis 
Plaque psoriasis 
SAE=serious adverse event 
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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 CZP 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 CZP, medically 
qualified personnel at UCB may identify additional safety measures (eg, AEs, vital signs) for 
which data will be periodically reviewed during the course of the study. 
8.5 
Treatment of overdose 
Excessive dosing (beyond that prescribed per the local label) will be recorded by the study 
participant in the diary and also recorded in the eCRF.  The dosing documentation will be 
reviewed and verified by the investigator and/or home health nurse. Any SAE or nonserious AE 
associated with excessive dosing must be followed as any other SAE or nonserious AE. 
Overdose events are only considered AEs or SAEs if there are associated clinical signs and 
symptoms or if the act of taking the excess CZP 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 
treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
commercial 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 
commercial CZP if requested by the Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
8.6 
Pharmacokinetics 
Plasma and whole blood samples of approximately 5mL will be collected for measurement of 
plasma concentrations of CZP as specified in the Schedule of Activities (Section 1.3). 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. Each plasma sample will be divided for PK and 
immunogenicity analyses. Samples collected for analyses of CZP plasma concentration may also 
be used to evaluate safety or efficacy aspects related to concerns arising during or after the study. 
8.7 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
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8.8 
Genetics 
Genetics are not evaluated in this study. 
8.9 
Biomarkers 
Immunogenicity assessments will be the only biomarkers evaluated in this study. Additionally, 
serum CRP and albumin are being measured as these markers have previously been found to be 
influential determinants in the description of CZP population PK. 
8.9.1 
Immunogenicity assessments 
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. 
The detection and characterization of antibodies to CZP will be performed using a validated 
assay method by or under the supervision of the Sponsor. All samples collected for detection of 
antibodies to CZP will be used to assess the effect on CZP exposure. 
9 STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
9.1 
Definition of analysis sets 
There will be 4 analysis sets for the study; the All Study Participants Screened Set, the Enrolled 
Set (ES), the Safety Set (SS) and the Pharmacokinetic Per Protocol Set (PK-PPS).  
The All Study Participants Screened Set will consist of all study participants who have signed 
the ICF and will include all participants who pass screening as well as screen failures. This will 
be the largest analysis set.  
The Enrolled Set (ES) will include all study participants who are confirmed as having signed the 
ICF to participate in the study and have provided the first blood sample. 
The Safety Set (SS) will include all enrolled study participants who received at least 1 dose of 
CZP after Screening. 
The Pharmacokinetic Per-Protocol Set (PK-PPS) is a subset of the SS, consisting of those study 
participants who had no important protocol deviations affecting the CZP plasma concentration 
and for whom a sufficient number of samples are available. 
9.2 
General statistical considerations 
All analyses will be performed using statistical analysis system (SAS®, SAS Institute, Cary, NC, 
USA) Version 9.4 or higher using validated program code according to relevant UCB standard 
operating procedures. 
In general, summary statistics (n [number of available measurements], arithmetic mean, standard 
deviation [SD], median, minimum, and maximum) for quantitative variables and frequency 
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tables for qualitative data will be presented. The arithmetic mean and SD will be replaced by the 
geometric mean and coefficient of variation (CV), respectively, for quantitative PK data. Any 
further deviations from this general approach will be outlined in the SAP. 
Baseline characteristics will be summarized based on the ES. Adverse event data collected will 
be summarized based on the SS. For PK measurements, the data will be summarized based on 
the PK-PPS. 
For summaries of plasma concentration data, baseline will be defined as the predose 
measurement 12 weeks (±1 week) postpartum. 
9.3 
Planned PK, immunogenicity, and safety analyses 
Details regarding study participant disposition and characteristics will be provided in the SAP. 
9.3.1 
Pharmacokinetic analyses 
All PK analyses will be performed on the PK-PPS. The individual plasma concentrations of CZP 
will be summarized over the course of pregnancy by trimester and dosing time point (predose or 
postdose) using graphs and descriptive statistics (number of observations [n], geometric mean, 
lower and upper 95% confidence intervals [CI], geometric CV, arithmetic mean, SD, CV, 
median, minimum, and maximum values). 
For the calculation of descriptive statistics, a plasma concentration below the lower limit of 
quantification (LLOQ) will be substituted by LLOQ/2. The geometric and arithmetic means and 
associated SD, lower and upper limits of 95% CI, and CV will be calculated only if at least 
two-thirds of the individual data at a specific sampling point are measured, are above or equal to 
LLOQ, and N≥4. 
The CZP plasma concentrations (primary variable) will be analyzed using a linear mixed effect 
model (disease phenotype, time point, trimester [trimester 1, 2, 3, or postpartum] and whether the 
sample was predose or postdose [binary indicator] may be used as fixed effects, and the random 
effect will be study participant). Mean differences with 95% CI of CZP plasma concentrations 
between samples taken during pregnancy and baseline (predose measurement at 12 weeks 
(±1 week) postpartum and potential postdose sample 1 week [±1 day] after the predose 
postpartum sample) will be estimated within this mixed effect model using contrasts. A forest 
plot of mean trough CZP plasma concentrations with 95% CI of each sampling time point during 
pregnancy and postpartum will be displayed. Data analysis may be conducted on 
log-transformed data (and back-transformed results displayed). Then, the change from baseline 
in CZP plasma concentrations across trimesters will be adjusted for the clinical covariates of 
albumin, body mass index (BMI), CRP (or any other relevant covariates) and disease phenotype 
using a multivariate linear mixed-effects model. The resulting coefficient b-estimate represents 
the change in CZP plasma concentrations for a unit increase in that predictor. 
Pharmacokinetic data from this study will also be analyzed using population PK methodologies, 
which will enable derivation of (posthoc) PK parameters throughout the study periods, as well as 
enable accounting for individual variations in dosing regimens and times. 
Any additional analyses may be defined in the SAP. 
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9.3.2 
Immunogenicity analyses 
Immunogenicity (anti-CZP antibody levels) will be assessed through summary tables, figures 
and listings of individual results by study participant. All analyses will be performed using the 
SS, unless otherwise specified. For all tabulations, percentages will be calculated based on the 
number of study participants with nonmissing data. More details will be provided in the SAP. 
9.3.3 
Safety analyses 
All safety analyses will be performed using the SS. All safety variables will be summarized by 
study part (each sampling point or postpartum). 
9.3.3.1 
Adverse events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA v24.1 
or higher) and characterized as treatment-emergent according to the intake of CZP. 
The occurrence and incidence of treatment-emergent adverse events (TEAEs) will be 
summarized by MedDRA system organ class and preferred term. The occurrence and incidence 
of TEAEs will also be summarized by intensity and by relationship to CZP. Adverse events 
leading to discontinuation and SAEs will also be summarized. 
9.3.3.2 
Vital signs 
Measured values of vital signs (blood pressure [systolic and diastolic], respiratory rate, pulse 
rate, and peripheral body temperature) at Screening will be summarized descriptively. 
9.3.3.3 
Physical examinations 
Physical examination abnormalities will be listed. 
9.3.3.4 
Pregnancy outcome 
Pregnancy outcome by study participant will be included in a listing. 
9.4 
Planned efficacy/outcome analyses 
Not applicable. 
9.5 
Handling of protocol deviations 
No protocol deviation is permitted, either in retrospect or prospect. 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the key safety or PK outcomes (if applicable) for an 
individual study participant. The criteria for identifying important protocol deviations will be 
defined within the important protocol deviations document. Important protocol deviations will be 
reviewed as part of the ongoing data cleaning process and data evaluation. All important 
deviations will be identified and documented prior to database lock to confirm exclusion from 
analysis sets. 
9.6 
Handling of dropouts or missing data 
There will be no special procedures for handling missing data. All imputation of missing or 
partial dates for safety assessments, as well as handling values below the LLOQ in the PK data, 
will be detailed in the SAP. 
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9.7 
Planned interim analysis and data monitoring 
Not applicable. 
9.8 
Determination of sample size 
Because no formal hypothesis testing will be conducted, the sample size of 15 study participants 
is deemed sufficient for a small exploratory Phase 1B study. It is expected that up to 25 to 
30 women will need to be screened to ensure that approximately 20 study participants are 
enrolled, in order to allow for approximately 15 evaluable study participants. These 15 evaluable 
participants are expected to provide the minimum of 10 study participants providing longitudinal 
data as defined in Section 4.1. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
This 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, IB, 
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. 
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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 CRO agreements, as applicable. 
10.1.3 
Informed consent process 
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 her legal representative, and by the person who conducted the informed consent 
discussion (investigator or designee). The participant or 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 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 United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization form. 
The participant may withdraw her consent to participate in the study at any time. A participant is 
considered as enrolled in the study when she has signed the ICF. An eCRF must not be started, 
nor may any study specific procedure be performed for a given participant, without having 
obtained 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 
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to 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 her personal study-related data will be used by the 
Sponsor in accordance with local data protection laws. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that 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. 
10.1.5 
Committees structure 
Not applicable. 
10.1.6 
Data quality assurance 
All participant data relating to the study will be recorded on the eCRF 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 
eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
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 eCRF by authorized site personnel are accurate, complete, and verifiable 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 are to be retained by the investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of CZP. These documents should be retained for 
a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (Committee for Proprietary Medicinal Products [CPMP]/ICH/135/95, 2002 
[Section 4.9.5]). The investigator will contact UCB for authorization prior to the destruction of 
any study records or in the event of accidental loss or destruction of any study records. The 
investigator will also notify UCB should he/she relocate or move the study-related files to a 
location other than that specified in the Sponsor’s trial master file. 
10.1.6.1 
Electronic Case Report Form completion 
The investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
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Any change or correction to the eCRF 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 eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
10.1.6.2 
Apps 
Not applicable. 
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, or 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). 
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, 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. 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, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study medication development 
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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 
No clinical safety laboratory tests will be performed in this study. CRP and albumin will be 
assessed as described in Section 8.9. 
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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, 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 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 fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
d. Results in 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. 
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e. 
Is a congenital anomaly/birth defect 
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 eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical records 
to UCB in lieu of completion of the UCB/AE/SAE eCRF 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 IB 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 a 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 eCRF. 
• 
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 by telephone. 
• 
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 
All study participants will be pregnant females (IC 3). 
• The investigator will collect pregnancy information on any pregnant female participating in 
this study. 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 at least 
12 weeks after the delivery date. In certain circumstances, UCB may request that follow up is 
continued for a period longer than 12 weeks. Any termination 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 
pregnancy related SAE considered reasonably related to CZP 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. 
Pregnancy and neonatal outcomes will be followed via Pregnancy Report and Outcome Forms 
which is the standard methodology for follow-up of all reported pregnancies and is a routine 
process unrelated to study procedure. 
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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 
No safety laboratory assessments will be performed in this study; as such, no evaluation of liver 
safety will be conducted. 
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10.7 
Appendix 7: Medical device incidents – 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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10.10 
Appendix 10: Abbreviations and trademarks 
AE 
adverse event 
BCG 
Bacillus Calmette–Guérin 
BMI 
body mass index 
CI 
confidence interval 
CPMP 
Committee for Proprietary Medicinal Products 
CRO 
contract research organization 
CRP 
C-reactive protein 
CV 
Coefficient of variation 
CZP 
certolizumab pegol 
eCRF 
electronic Case Report Form 
ES 
Enrolled Set 
EWD 
Early Withdrawal or Discontinuation 
Fab 
antibody fragment 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
IB 
Investigator’s Brochure 
IC 
inclusion criterion 
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 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NTM 
nontuberculous mycobacterial 
PK 
pharmacokinetics 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
Q8W 
every 8 weeks 
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RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
statistical analysis system 
SD 
standard deviation 
SFU 
Safety Follow-up 
SS 
Safety Set 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TST 
tuberculin skin test 
ULN 
upper limit of normal 
 
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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 (Aug 29 2019) 
 
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Amendment 1 (29 Aug 2019)  
Overall Rationale for the Amendment 
The purpose of this substantial amendment is to implement pre-review feedback received from the Central IRB US (Advarra) dated 
31 Jul 2019. 
The first version of the protocol was not formally submitted. 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
EudraCT number 2019-003410-13 has been 
added. 
EudraCT number was omitted in original 
protocol. 
Section 4.1 
Previous text:  
This study is considered interventional due to 
the collection of blood samples from the 
women, which is not part of routine clinical 
practice. However, it is noninterventional 
regarding treatment with CZP and will only 
include pregnant women who decided with 
their treating physician to continue treatment 
with CZP prior to being recruited for and 
enrolled in the study. Study participants who 
start CZP treatment after confirmation of 
pregnancy will not be eligible to participate in 
the study. Study participants are responsible 
for procuring their own supply of commercial 
CZP as it is not provided as part of the study. 
New text:  
The study is interventional due to the 
additional collection of blood samples from 
women. However, all other study 
assessments are part of routine clinical 
practice (with the exception of the diary), 
and the decision to continue/discontinue 
CZP therapy during pregnancy will be 
made between the participant and her 
To clarify the text and to describe further that 
there is no intention to interfere with treating 
physician’s decisions on the care of their 
patient 
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treating physician, taking into account the 
potential risks to the mother and the 
benefits of CZP therapy, and according to 
the applicable local label. 
Section 6.5 
Added text: Unless otherwise prohibited per 
protocol exclusion criteria, study participants 
are permitted to continue on their prescribed 
medical therapy for the disease in accordance 
with the instructions of their treating physician 
To clarify the intention is for study 
participants to continue their prescribed 
therapy for their disease unless prohibited per 
protocol exclusion criteria. 
Section 6.5.2 
Section heading changed from: 
Prohibited concomitant treatments 
(medications and therapies) 
 
To: 
Concomitant medications that lead to study 
withdrawal 
To further clarify that the intention is not to 
interfere with the physician’s decision. 
 
 
 
Section 6.5.2 
Previous text: 
The study participant must not participate in 
any other interventional clinical study or 
receive any unauthorized medication 
throughout the Study Period. 
 
New text: 
The study participant must not participate 
in any other interventional clinical study or 
receive any unauthorized medication 
throughout the study period. Non-
Interventional study (NIS) participation is 
allowed. 
To allow for non-interventional study 
participation where applicable. 
Previous text:  
There are certain exclusion criteria and 
withdrawal criteria associated with 
To further clarify that there is no intention to 
interfere with the treating physician’s decision 
on treatment of their patient and to add 
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concomitant medication use; to protect the 
safety of the study participant and to ensure 
robust and interpretable data, there is no 
intention to interfere with the physician’s 
decision on treatment.  
The following concomitant medications are 
prohibited during the study: 
 
New text:  
There are no specific prohibited 
concomitant medications in this study, as it 
is not the intention to interfere with the 
physician’s decision on treatment.  
However, there are certain exclusion 
criteria and withdrawal criteria associated 
with concomitant medication use to ensure 
robust and interpretable data.  These 
criteria include:.   
language to describe that the use of any 
medications listed in section 6.5.2 would 
result in withdrawal from the study. 
Section 7.2 
Previous text: 
3. Participant takes prohibited concomitant 
medications as defined in this protocol 
(Section 6.5.2). 
New Text: 
3. Participant takes prohibited concomitant 
medications that lead to study withdrawal as 
defined in this protocol (Section 6.5.2). 
To align the withdrawal criteria with updates 
made in Section 6.5.2 
Section 8 
Previous text: 
Immediate safety concerns should be 
discussed with the sponsor immediately upon 
occurrence or awareness to determine if the 
participant should continue or discontinue 
CZP.   
 
To clarify it is the treating physician’s 
responsibility to determine if the patient 
continues or is discontinues treatment. 
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New text 
It will be the responsibility of the treating 
physician to determine if the participant 
should continue or discontinue treatment.   
The sponsor should be informed 
immediately regarding safety concerns 
upon occurrence or awareness to determine 
if the participant should continue or 
discontinue participation in the study. 
Section 8.3.5 
Previous text: 
Women who become pregnant while taking 
CZP, and choose not to participate in the 
study, will still have their pregnancy followed 
per normal UCB guidance on pregnancy 
reporting. 
 
New Text: 
Information regarding collection of 
pregnancy-related data is located in 
Appendix 4 section 10.4 
To align text with Section 10.4 
Section 8.5 
Previous text:  
Excessive dosing (beyond that prescribed in 
the protocol and including overdose) should 
be recorded in the Drug Accountability 
module of the eCRF 
 
New text: 
Excessive dosing (beyond that prescribed 
per the local label) will be recorded by the 
study participant in the diary and also 
recorded in the eCRF.  The dosing 
documentation will be reviewed and 
To clarify that dosing will be captured by the 
study participant in the diary and verified by 
the investigator and/or home health nurse in 
addition to documented in the eCRF. 
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verified by the investigator and/or home 
health nurse 
Deleted text: 
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. 
To clarify that dosing decisions are the 
responsibility of the treating physician 
Section 10.4 
Previous text: 
Women who become pregnant while taking 
CZP, and choose not to participate in the 
study, will still have their pregnancy followed 
per normal UCB guidance on pregnancy 
reporting. 
New text: 
Pregnancy and neonatal outcomes will be 
followed via Pregnancy Report and 
Outcome Forms which is the standard 
methodology for follow-up of all reported 
pregnancies and is a routine process 
unrelated to study procedure. 
 
To clarify how pregnancy and neonatal 
outcomes will be followed-up. 
Throughout 
Change of "study treatment" to "CZP") 
Deleted reference to ‘study treatment’ and 
clarified that this refers to CZP. 
 
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11 REFERENCES 
CIMZIA© Prescribing information accessed at 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125160s270lbl.pdf on 15 Jul 2019. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Mariette X, Förger F, Abraham B, et al. Lack of placental transfer of certolizumab pegol during 
pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann 
Rheum Dis. 2018:77(2):228-233. 
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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:
UP0085-protocol-amend-2
Version:
1. 0
Document Number:
CLIN-000202273
Title:
A postmarketing, multicenter, longitudinal, prospective, pharmacokinetic, Phase 1B study
Approved Date:
31 Aug 2022
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 30-Aug-2022 21:22:47 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Medical
Date of Signature: 31-Aug-2022 08:07:51 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 31-Aug-2022 15:32:42 GMT+0000
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SAP_001.pdf: 
UCB 
 
22 JUN 2023 
Statistical Analysis Plan 
CERTOLIZUMAB PEGOL 
UP0085 
 
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STATISTICAL ANALYSIS PLAN 
Study: UP0085 
Product: CERTOLIZUMAB PEGOL 
A POSTMARKETING, MULTICENTER, LONGITUDINAL, 
PROSPECTIVE, PHARMACOKINETIC, PHASE 1B STUDY IN 
PREGNANT WOMEN WITH CHRONIC INFLAMMATORY 
DISEASES TREATED WITH CIMZIA® (CERTOLIZUMAB PEGOL) 
 
 
SAP/Amendment Number Date 
Final SAP 
SAP Amendment 1 
06 DEC 2019 
15 DEC 2021 
SAP Amendment 2 
22 JUN 2023 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 7 
2 
PROTOCOL SUMMARY ................................................................................................. 7 
2.1 
Study objectives ............................................................................................................. 7 
2.1.1 
Primary objective ................................................................................................... 7 
2.1.2 
Secondary objectives ............................................................................................. 7 
2.1.3 
Other objectives ..................................................................................................... 7 
2.2 
Study variables ............................................................................................................... 7 
2.2.1 
Primary Outcome variable ..................................................................................... 7 
2.2.1.1 
Secondary Outcome variables ..................................................................... 8 
2.2.1.2 
Other Outcome variables ............................................................................. 8 
2.3 
Study design and conduct .............................................................................................. 8 
2.3.1 
Schema ................................................................................................................. 10 
2.4 
Determination of sample size ....................................................................................... 10 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 10 
3.1 
General presentation of summaries and analyses ........................................................ 10 
3.1.1 
Summary statistics specific to PK data ................................................................ 12 
3.1.2 
Unit conversion for height, weight and BMI formula ......................................... 13 
3.2 
General study level definitions .................................................................................... 13 
3.2.1 
Analysis time points ............................................................................................ 13 
3.2.1.1 
Relative day ............................................................................................... 13 
3.2.2 
Study periods ....................................................................................................... 14 
3.3 
Definition of Baseline values ....................................................................................... 15 
3.4 
Protocol deviations....................................................................................................... 15 
3.5 
Analysis sets................................................................................................................. 15 
3.5.1 
All Study Participants Set .................................................................................... 15 
3.5.2 
Enrolled Set ......................................................................................................... 15 
3.5.3 
Safety Set ............................................................................................................. 16 
3.5.4 
Pharmacokinetic Per Protocol Set ....................................................................... 16 
3.6 
Treatment assignment and treatment groups ............................................................... 16 
3.7 
Center pooling strategy ................................................................................................ 16 
3.8 
Coding dictionaries ...................................................................................................... 16 
3.9 
Changes from protocol-defined analyses ..................................................................... 16 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 17 
4.1 
Adjustments for covariates .......................................................................................... 17 
4.2 
Handling of dropouts or missing data .......................................................................... 17 
4.2.1 
Handling of missing data for AE ......................................................................... 17 
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4.2.2 
Handling of missing data for prior and concomitant medications ....................... 18 
4.2.3 
Handling of values below the LLOQ in PK data ................................................. 19 
4.3 
Interim analyses and data monitoring .......................................................................... 19 
4.4 
Multicenter studies ....................................................................................................... 19 
4.5 
Multiple comparisons/multiplicity ............................................................................... 19 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 19 
5.1 
Disposition of study participants ................................................................................. 19 
5.2 
Protocol deviations....................................................................................................... 19 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 20 
6.1 
Demographics .............................................................................................................. 20 
6.2 
Other Baseline characteristics ...................................................................................... 20 
6.3 
Medical history and concomitant diseases ................................................................... 20 
6.4 
Medical conditions leading to CZP use ....................................................................... 20 
6.5 
Prior and concomitant medications .............................................................................. 21 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 21 
8 
EFFICACY ANALYSES ................................................................................................ 21 
9 
PHARMACOKINETIC AND IMMUNOGENICITY ANALYSES .............................. 22 
9.1 
Statistical analysis of the primary outcome variable ................................................... 22 
9.1.1 
Derivations of primary outcome variable ............................................................ 22 
9.1.2 
Primary analysis of the primary outcome variable .............................................. 22 
9.1.3 
Primary summaries of the primary outcome variable .......................................... 22 
9.1.4 
Exploratory analysis of the primary outcome variable ........................................ 23 
9.2 
Immunogenicity ........................................................................................................... 23 
9.2.1 
Anti-drug antibodies sample status category definitions ..................................... 23 
9.2.2 
Anti-drug antibodies participant titer classification ............................................ 24 
9.2.3 
ADA titer and classification summaries and analyses ......................................... 24 
10 ANALYSIS OF OTHER OUTCOME VARIABLES ..................................................... 25 
10.1 
Other outcome variables .............................................................................................. 25 
11 SAFETY ANALYSES ..................................................................................................... 25 
11.1 
Pregnancy outcome ...................................................................................................... 25 
11.2 
Infant illnesses ............................................................................................................. 25 
11.3 
Adverse events ............................................................................................................. 25 
11.3.1 
Identification of opportunistic infections ............................................................. 26 
11.4 
Clinical laboratory evaluations .................................................................................... 28 
11.5 
Vital signs, physical findings, and other observations related to safety ...................... 28 
11.5.1 
Vital signs ............................................................................................................ 28 
11.5.2 
Physical Findings ................................................................................................. 28 
12 REFERENCES ................................................................................................................ 29 
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13 APPENDICES ................................................................................................................. 30 
13.1 
AMENDMENT 1......................................................................................................... 30 
13.1.1 
Coding Dictionaries (Section 3.8) ....................................................................... 30 
13.1.2 
Handling of partial missing dates for AEs (Section 4.2) ..................................... 30 
13.1.3 
Exclusion of TB summary from baseline analyses (Section 6.2) ........................ 30 
13.1.4 
Definition of past and prior medications (Section 6.5) ........................................ 30 
13.1.5 
Exclusion of TEAE tables (Section 11.3) ............................................................ 31 
13.2 
AMENDMENT 2......................................................................................................... 32 
13.2.1 
Sample size (Section 2.3 and Section 2.4) ........................................................... 32 
13.2.2 
Handling of small samples in summary tables (Section 3.1) ............................... 33 
13.2.3 
Addition of Not Dosed column (Section 3.1) ...................................................... 33 
13.2.4 
Summary statistics specific to PK model (Section 3.1.1) .................................... 33 
13.2.5 
Conversion formulas and BMI calculation (Section 3.1.2) ................................. 33 
13.2.6 
Definition of gestational week (Section 3.2.2) .................................................... 34 
13.2.7 
Definition of postpartum as the reference point for PK analyses (Section 3.3) .. 34 
13.2.8 
All Study Participants Set definition (Section 3.5.1) ........................................... 34 
13.2.9 
Enrolled Set definition (Section 3.5.2) ................................................................ 35 
13.2.10 
Safety Set definition (Section 3.5.3) .................................................................... 35 
13.2.11 
Pharmacokinetic Per Protocol Set definition (Section 3.5.4 and Section 9.1.1).. 35 
13.2.12 
Additional changes from protocol-specified analyses (Section 3.9) ................... 35 
13.2.13 
Summary of Medical Condition Leading to CZP Use (Section 6.4) ................... 35 
13.2.14 
Past and prior medications (Section 6.5) ............................................................. 36 
13.2.15 
PK random effects model description (Section 9.1.2) ......................................... 36 
13.2.16 
PK Graphical Displays (Section 9.1.3) ................................................................ 37 
13.2.17 
Anti-Drug Antibody Methods (Section 9.2.1, Section 9.2.2, and Section 9.2.3) 37 
13.2.18 
TEAE of interest (Section 11.3) .......................................................................... 39 
13.2.19 
Identification of Opportunistic Infections (Section 11.3.1) ................................. 39 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 41 
 
LIST OF FIGURES 
Figure 1-1: 
Study Diagram ................................................................................................. 10 
 
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LIST OF ABBREVIATIONS 
ADA                       
anti-CZP antibody 
AE                                 
adverse event                           
ASPS 
All Study Participants Set 
BLQ                                  
below the limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CSR                                
Clinical Study Report 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSR                           
Clinical Study Report 
CV                       
coefficient of variation 
CZP                                   
certolizumab pegol 
DAP                          
Data Analysis Plan 
DEM                               
Data Evaluation Meeting 
eCRF 
electronic Case Report Form 
ES                               
Enrolled Set 
FDA 
Food and Drug Administration 
HLT 
Higher Level Term 
ICC 
Intraclass Correlation Coefficient 
ICF 
informed consent form 
ICH                                   
International Council for Harmonization 
IVF 
in vitro fertilization 
LLOQ                          
lower limit of quantification 
MedDRA                       
Medical Dictionary for Regulatory Activities 
MRD 
minimum required dilution 
MSR 
minimum significant ratio 
OI 
opportunistic infections 
PD                                
Pharmacodynamics 
PK                             
pharmacokinetic 
PK-PPS            
Pharmacokinetic Per Protocol Set 
PT 
preferred term 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
Q8W 
every 8 weeks 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
standard deviation 
SFU 
Safety Follow-up 
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SMQ 
standardized MedDRA query 
SOC 
system organ class 
SS 
Safety Set 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TFLs 
Tables, Listings and Figures 
 
 
 
 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) provides the necessary information to perform the final 
statistical analysis for study UP0085. It also defines the summary tables, figures and listings 
(TFLs) to be generated for the final clinical study report. 
The SAP is based on the final Protocol Amendment 2 (30 AUG 2022). All references to study 
protocol hereafter refer to this version of the protocol, and, unless otherwise specified, the study 
will be analyzed as described in this version of the protocol. If a future protocol amendment 
necessitates a substantial change to the statistical analysis of the study data, or if analysis 
definitions must be modified or updated, this SAP will be amended accordingly.   
The content of this SAP is compatible with the International Council for Harmonization 
(ICH)/Food and Drug Administration (FDA) E9 Guidance documents (Phillips et al, 2003). 
The study assesses any changes in certolizumab pegol (CZP) plasma concentrations over the 
course of pregnancy, relative to the postpartum period. CZP is approved in adults for the 
treatment of chronic inflammatory diseases. It is valuable to evaluate whether the physiologic 
changes underlying pregnancy impact the pharmacokinetic (PK) profile of CZP during 
pregnancy in order to ensure that women who require CZP treatment during pregnancy are able 
to achieve therapeutic steady state levels of CZP.  
Revision(s) of this SAP will not be required for any subsequent amendments to the protocol 
which do not change the analyses described in this SAP. 
 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
To assess systemic CZP exposure across the course of pregnancy in study participants with 
chronic inflammatory diseases 
2.1.2 
Secondary objectives 
• To assess the formation of anti-CZP antibodies (ADA) across the course of pregnancy 
• To assess the safety of CZP in study participants with chronic inflammatory diseases across 
the course of pregnancy 
2.1.3 
Other objectives 
• To assess changes in body mass index (BMI), C-reactive protein (CRP) and albumin across 
the course of pregnancy 
2.2 
Study variables 
2.2.1 
Primary Outcome variable 
Predose and postdose plasma CZP concentrations in women during pregnancy, relative to 
postpartum 
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2.2.1.1 
Secondary Outcome variables 
• Plasma levels of ADA throughout the study period 
• Treatment-emergent adverse events from time of informed consent through Safety Follow-up 
(SFU) 
• Pregnancy outcome 
2.2.1.2 
Other Outcome variables 
• BMI 
• CRP levels 
• Albumin levels 
2.3 
Study design and conduct 
This is a Phase 1B, multicenter, longitudinal, interventional, prospective, PK, open-label study 
evaluating the impact of pregnancy on the PK of CZP. The study will recruit women who are 
already on prescribed commercial CZP with both a dosing regimen selected with guidance from 
the participant’s treating physician and an indication approved for use in their country, and who 
become pregnant and continue treatment with CZP. A postpartum predose blood sample taken 
12 weeks (±1 week) after delivery, once the mother is considered to have returned to a 
pre-pregnancy physiological state, will serve as a within-participant reference sample. If 
possible, a postdose sample will be taken 1 week (±1 day) after the 12-week postpartum dose. 
This study is considered interventional due to the collection of blood samples from the women, 
which is not part of routine clinical practice. However, it is noninterventional regarding 
treatment with CZP and will only include pregnant women who decided with their treating 
physician to continue treatment with CZP prior to being recruited for and enrolled in the study. 
The study consists of a Screening Period, Sampling Period (consisting of a Pregnancy Period and 
Postpartum Period), and SFU contact, as shown in Figure 1-1 and described below. 
The full Schedule of Activities is provided in the protocol (Table 1-1). 
• Screening Period:  
Women of childbearing potential already on commercial CZP can register to indicate interest 
in the current study. After confirmation of pregnancy, the women will consent to participate 
in the study and will be eligible to enroll once CZP levels have reached steady state. 
Confirmation of steady state is based on participant records and/or reports from the 
prescribing physician indicating that the participant has taken CZP for at least 12 weeks at 
the same dosing regimen prior to the Enrollment Visit, which must take place at ≤10 weeks 
gestational age. 
• Sampling Period: 
− Pregnancy Period:  
PK samples will be collected prior to the subsequent dose (predose) every 4 weeks 
(Q4W) starting with the first dose after enrollment. Further, postdose (7 ± 1 day after 
dose administration) PK samples will be collected every 8 weeks (Q8W) throughout the 
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pregnancy. It is expected that there will be approximately 6 predose and 3 postdose 
PK samples collected per study participant (if there are no discontinuations) over the 
pregnancy. 
− Postpartum Period:  
A predose sample 12 weeks (±1 week) postpartum will be collected during the 
Postpartum Period. If possible, 1 additional postdose sample 1 week (±1 day) after the 12 
weeks postpartum dose will also be collected. 
• Safety Follow-up contact:  
All study participants will be contacted via telephone for a SFU 5 weeks (±5 days) after final 
study visit. 
If any participant withdraws early, she will complete the SFU contact. 
The end of the study is defined as the date of the SFU/last contact of the last participant in the 
study. 
Number of participants: 
Approximately 25 to 30 participants are planned to be screened to achieve approximately 
20 enrolled study participants (i.e., study participants who have provided the first blood sample). 
Enrollment will occur until a minimum of 10 study participants have longitudinal data (defined 
as at least 4 quantifiable predose and 2 quantifiable postdose PK samples during pregnancy and 
at least 1 quantifiable postpartum sample) over the study period.  
Treatment groups and duration: 
This study will include pregnant women who have decided to continue treatment with 
commercial CZP in accordance with their treating physician prior to participating in the study. 
Study participants will be responsible for obtaining and administering commercially available 
CZP under the care of their physician and according to the locally approved product label. 
The total study duration for a study participant will be a maximum of 53 weeks (40 weeks 
gestation period and up to 13 weeks (±3 days) postpartum). 
 
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2.3.1 
Schema 
A schematic of the study design is provided in Figure 1-1. 
Figure 1-1: Study Diagram 
 
CZP=certolizumab pegol; PK=pharmacokinetics; Q2W=every 2 weeks; Q4W=every 4 weeks 
a CZP dosing for at least 12 weeks before enrollment 
b First CZP dose post-enrollment 
c Timing and the number of visits across the pregnancy will vary for individual study participants 
2.4 
Determination of sample size 
Because no formal hypothesis testing will be conducted, the sample size of 15 study participants 
is deemed sufficient for a small exploratory Phase 1B study. It is expected that up to 25 to 30 
women will need to be screened to ensure that approximately 20 study participants are enrolled, 
in order to allow for approximately 15 evaluable study participants. These 15 evaluable 
participants are expected to provide the minimum of 10 study participants providing longitudinal 
data (defined as at least 4 quantifiable predose and 2 quantifiable postdose PK samples during 
pregnancy and at least 1 quantifiable postpartum sample) over the study period.  
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, study participant data listings, and statistical 
output will be performed using SAS® Version 9.3 or higher. All tables and listings will use 
Courier New font size 9. 
Descriptive statistics will be displayed to provide an overview of the study results.  
For categorical parameters, the number and percentage of study participants in each category will 
be presented. Unless otherwise noted, the denominator for percentages will be based on the 
number of study participants included in the respective analysis set. Study participants with 
missing PK/ADA data will be addressed in Section 4.2.3.  Other missing data can generally be 
accounted for using one of the following approaches:  
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• Percentages will be summarized based on all study participants in the analysis set and a 
“Missing” category (corresponding to study participants with missing data for the variable 
being summarized) will be included as the last row in the list of categories being 
summarized.   
• Percentages will be based only on those study participants with observed data for the variable 
being summarized. As the denominator may be different from the number of study 
participants in the analysis set being considered, the denominator should be displayed in the 
table. The general format for displaying this will be “n/Nsub (%)”, where n=number 
participants in a category and Nsub=total number of participants with observed data. 
The approach to be considered will be further specified in the relevant section of the variable of 
interest. 
Unless otherwise noted, all percentages will be displayed to one decimal place. No percentage 
will be displayed for zero counts, and no decimal place will be presented when the percentage is 
100%.  
Unless stated otherwise, continuous endpoints will be summarized by timepoints.  
For continuous parameters, descriptive statistics will include number of study participants with 
available measurements (n), arithmetic mean, standard deviation (SD), median, minimum, and 
maximum (unless otherwise stated).  If n=3, only n, mean, median, minimum and maximum will be 
displayed.  If n<3, only n, minimum and maximum will be displayed.  For both cases, any summary 
statistics that are not displayed will be replaced with ‘NA’ and explained in a footnote. 
Decimal places for descriptive statistics will always apply the following rules: 
• “n” will be an integer. 
• Mean, SD, and median will use 1 additional decimal place compared to the original raw 
value from the Case Report Form (CRF). 
• Coefficient of variance (CV [%]) will be presented with 1 decimal place. 
• Minimum and maximum will have the same number of decimal places as the original raw 
value. 
If the number of decimal places reported in the raw data is varied then either the maximum raw 
number of reported decimal places or 3 will be used, whichever is the lowest, as a guide for the 
descriptive statistics. 
Unless stated otherwise, statistical tests will be performed 2-sided and p-values will be rounded 
to 4 decimal places. P-values less than 0.0001 will be presented as “<0.0001” and p-values 
greater than 0.9999 will be presented as “>0.9999.” Statistical comparison will be performed at 
the 0.05 level of significance. 
The SAS® outputs supportive of any statistical model (i.e., all excluding the descriptive analyses) 
will be provided as a separate PDF document in addition to TFLs. These outputs will be included 
in the ‘Documentation of Statistical Methods’ section of the clinical study report. 
The abbreviation for certolizumab pegol is CZP and will be used in tables and listings headers. 
Unless otherwise specified, in the TFLs study participants on Certolizumab pegol will be 
displayed in columns by dosing regimen and all study participants as: 
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• “Not Dosed” 
• “CZP 200mg Q2W” 
• “CZP 400mg Q2W” 
• “CZP 400mg Q4W” 
• “All Dosed Participants” 
An additional “Other” category will be added to the tables in case there are dosing regimens 
outside those listed.  The “Not Dosed” category includes participants who enrolled but did not 
record a CZP dose relative to any PK samples prior to discontinuation.  The “All Dosed 
Participants” category includes participants in CZP 200mg Q2W, CZP 400mg Q2W and CZP 
400mg Q4W combined. 
Study Participants will be grouped according to the commercial CZP dosing regimen that was in 
effect at enrollment (actual dose).  Any participant with a dose reduction or increase will be 
summarized in the initial dosing regimen group. 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. The following general rules will apply to all repeated and unscheduled 
measurements:  
• Unscheduled measurements will not be used in the descriptive statistics. 
• For repeated measurements only the scheduled latest value can be used in the calculation of 
the descriptive statistics. 
Unless otherwise stated, listings will be sorted by dosing regimen, study participant number, 
variable (if applicable) and visit (if applicable, including timing relative to dosing if applicable). 
All listings will include repeat and unscheduled measurements; such measurements will appear 
in chronological order together with the scheduled visits, i.e., a repeated measurement will 
appear directly after the visit and time relative to dosing for which the repeat measurement was 
performed. In all the listings dates will be presented in the format ‘YYYY-MM-DD’ and times 
will be presented in 24h clock format as ‘hh:mm’. 
3.1.1 
Summary statistics specific to PK data 
For CZP Plasma concentrations, geometric mean, geometric coefficient of variation (geometric 
CV (%)), 95% CI for the geometric mean (assuming log-normally distributed data) will only be 
calculated if at least ⅔ of the values of interest are above the LLOQ (0.032 ug/mL). If this is not 
the case, only median, minimum and maximum will be presented.  
The 95% CI for the geometric mean will be calculated by obtaining the lower and upper 95% CI 
for the arithmetic mean on the log-transformed data and back-transforming to obtain the 
respective values for the geometric CI. 
The geometric CV (%) will be calculated using the following formula: 
𝐶𝑉= √𝑒𝑆𝐷𝑙𝑛
2 −1 
where 𝑆𝐷𝑙𝑛 represents the standard deviation of the log-transformed plasma concentration 
values. 
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The intraclass correlation coefficient (ICC) will be calculated using the following formula: 
𝜌=
𝜎𝑟
2
𝜎𝑟2 + 𝜎𝜖2 
Where 𝜎𝑟
2 represents the variance of the random effect and 𝜎𝜖
2 represents the variance of the 
residual in the linear mixed effects model as described in Section  9.1.2.  
3.1.2 
Unit conversion for height, weight and BMI formula 
Even if BMI is available in the database, BMI (in kg/m2) will be recalculated during analysis 
based on height (in m) and weight (in kg) values collected in the database, and the calculated 
values will be used in the statistical analysis.   
If height is recorded in inches, the height conversion is: 
Height (m) = 0.0254*Height (inches) 
If weight is recorded in pounds, the weight conversion is: 
Weight (kg) = 0.45359237*Weight(lb) 
The formula for BMI (kg/m2) calculation is: 
BMI = Weight (kg)
(Height (m))2 
 
3.2 
General study level definitions 
3.2.1 
Analysis time points 
3.2.1.1 
Relative day 
The relative day will be included in some listings and will be calculated as described below. The 
way that relative day is calculated depends on when the given event occurs relative to the date of 
first day of enrolment into the study.  
Relative day 1 is the date of first day of enrolment into the study. 
• If the study participant is not discontinued from the study and the event start (stop) date 
occurred on or after the first day of enrolment into the study, but prior to the SFU visit date, 
relative day is calculated as start (stop) date of the event minus date of first day of enrolment 
into the study + 1.  
• If the study participant is discontinued from the study and the event start (stop) date occurred 
on or after the first day of enrolment into the study, but prior to the stop date, relative day is 
calculated as start (stop) date of the event minus date of first day of enrolment into the study 
+ 1.  
• If the study participant completes the SFU visit and the event start (stop) date occurred after 
the SFU visit date, the relative day to the most recent CZP dose is calculated as start (stop) 
date of the event minus most recent CZP dose date. The relative day in this situation should 
be preceded by a ‘+’ 
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• If the study participant does not complete the SFU visit and the event start (stop) date 
occurred after the study stop date, the relative day to the most recent CZP dose is calculated 
as start (stop) date of the event minus most recent CZP dose date. The relative day in this 
situation should be preceded by a ‘+’ 
• If the event start (stop) date occurred before the first day of enrolment into the study, the 
relative day is calculated as start (stop) date of the event minus first day of enrolment into the 
study. The relative day in this situation should be preceded by a ‘-’. 
Relative day will only be computed for fully completed dates and will be left blank for partial 
dates. 
3.2.2 
Study periods 
The study consists of a Screening Period, Sampling Period (consisting of a Pregnancy Period and 
Postpartum Period), and a Safety Follow-up (SFU) contact, as described below. Gestational 
week (i.e., week of gestational age) is determined from the time since the first day of the last 
menstrual period or, if the participant had undergone in vitro fertilization (IVF), from the date of 
birth and gestational age recorded for the pregnancy outcome and then back-calculated to get the 
gestational week for each PK sample. 
• Screening Period: Starts at the confirmation of pregnancy at screening and ends at the start of 
the enrolment date (Participant having taken CZP for at least 12 weeks at the same dosing 
regimen prior to the Enrollment Visit, which must take place at ≤10 weeks gestational age).  
• Sampling Period: The total study duration for a study participant will be a maximum of 53 
weeks (40 weeks gestation period and up to 13 weeks (±3 days) postpartum). 
− Pregnancy Period: Starts at enrolment and ends on the day of delivery. Pregnancy may 
take the entire length of the gestation period (up to 40 weeks). 
− Postpartum Period:  Starts the day after the date of delivery and ends after the final 
postpartum sample is taken.  
− Trimesters: Defined using the gestational week and distinguished as first (up to 12 weeks 
and 6 days’ gestation), second (13–28 weeks and 6 days’ gestation), and third (any time 
at or after 29 weeks’ gestation) 
• Safety Follow-up contact: The SFU visit will be defined for all study participants who 
complete the study, or for study participants who discontinue early including those who 
discontinue from CZP. For participants who complete the study, the SFU will be conducted 5 
weeks (+/-5 days) after final study visit. For participants who discontinue, the SFU visit will 
still be completed. 
In case that the SFU date is not available, the last contact date will be used as end of the SFU 
period. A participant is considered to have completed the study if she has completed all phases of 
the study per protocol including the final study contact (SFU).  
The end of the study is defined as the date of the SFU/last contact of the last participant in the 
study. 
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3.3 
Definition of Baseline values 
For summaries of all participant demographic data, Baseline value for a study participant is 
defined as the latest measurement for that study participant up to and including the day of 
enrolment into the study, unless otherwise stated. If a Baseline assessment is taken on the same 
day as study enrolment, it is eligible to be used as the Baseline value, even in the case that the 
time of the assessment is recorded as taking place after the time of study enrolment. However, 
such cases should be rare as study center personnel are instructed to do all assessments at the 
Baseline visit prior to enrolment. If a Baseline measurement is missing or not collected, and a 
Screening value is available, the Screening value will be utilized as Baseline instead. If no 
measurement is available prior to study enrolment, then the Baseline value is treated as missing.  
For summaries of CRP, Albumin, BMI and anti-CZP antibody data, the postpartum measurement 
will be used as the reference point based on the postpartum measurement collected at Visit 5.  If 
there was no sample collected at Visit 5, then the last available postpartum sample will be used.  
If the postpartum measurement is missing or not collected (i.e., the postpartum value is not 
available), then the reference value is treated as missing. 
For summaries of plasma concentration, the postpartum measurements will be used as the 
reference point instead of the day of enrolment based on both the predose and postdose 
postpartum PK samples. If either the predose or postdose postpartum PK measurement is missing 
or not collected, (i.e., the postpartum value is not available), then the respective reference value 
is treated as missing.   
3.4 
Protocol deviations 
No protocol deviation is permitted, either in retrospect or prospect. 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the key safety or PK outcomes (if applicable) for an 
individual study participant. The criteria for identifying important protocol deviations will be 
defined within the important protocol deviations document. Important protocol deviations will be 
reviewed as part of the ongoing data cleaning process and data evaluation. All important 
deviations will be identified and documented prior to database lock to confirm exclusion from 
analysis sets.  
3.5 
Analysis sets 
There will be 4 analysis sets for the study: the All Study Participants Set (ASPS), the Enrolled 
Set (ES), the Safety Set (SS) and the Pharmacokinetic Per Protocol Set (PK-PPS).  
3.5.1 
All Study Participants Set 
This will be the largest analysis set, consisting of all study participants who have signed the 
Informed Consent Form (ICF) and will include all participants who pass screening as well as 
screen failures.  For participants who fail screening and subsequently re-screen, only the 
successful screening record(s) will be included in the ASPS. 
3.5.2 
Enrolled Set 
The ES will include all study participants who are confirmed as having signed the ICF to 
participate in the study and have provided the first blood sample. For participants who re-enroll 
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after discontinuation, both enrollments will be included, and tables and listings will provide the 
participant identifiers in a footnote. 
3.5.3 
Safety Set 
The SS will include all enrolled study participants who are dosing with commercial CZP per 
protocol at Screening. 
3.5.4 
Pharmacokinetic Per Protocol Set 
The Pharmacokinetic Per-Protocol Set (PK-PPS) is a subset of the SS, consisting of those study 
participants for whom at least one predose or postdose sample is available which was not 
impacted by an important protocol deviation. 
3.6 
Treatment assignment and treatment groups 
The study will include pregnant women who have decided to continue treatment with 
commercial CZP in accordance with their treating physician prior to participating in the study. 
The commercially approved dosing regimens (200mg Q2W or 400mg Q2W or 400mg Q4W) 
will be permitted following the guidance of each study participant’s physician.  
After enrolment into the study, the study participant’s physician may modify the dosing regimen 
as necessary. In such cases, non-approved CZP dosing regimens will also be allowed, at the 
discretion of the study participant’s physician and in a manner independent of this study, as long 
as the regimen does not exceed 400mg Q2W and the dose is recorded in the diary. All dosing 
regimens outside the commercially approved will be categorized as other. 
3.7 
Center pooling strategy 
No center pooling is planned for this study. 
3.8 
Coding dictionaries 
All medications other than CZP will be classified by WHO Anatomical Therapeutic Chemical 
(ATC) Classification, presenting Anatomical Main Group (ATC Level 1), Pharmacological 
Subgroup (ATC level 3), and preferred term, using version MAR/2021 or later of the World 
Health Organization Drug Dictionary (WHO-DD), according to UCB standard operating 
procedures. Medical procedures will not be coded. 
All adverse events (AEs) will be considered as treatment emergent adverse events (TEAEs) and 
will be classified by primary system organ class (SOC), high level term (HLT) and preferred 
term (PT) using MedDRA® version 24.1 or later. UCB Standard Operating Procedures will be 
followed.  
3.9 
Changes from protocol-defined analyses 
The following change from the protocol have been implemented in the SAP: 
• The protocol stated the secondary outcome variable of ‘adverse events from time of 
informed consent through Safety Follow-up’, this will now be ‘Treatment-emergent 
adverse events from time of informed consent through Safety Follow-up’. 
• The protocol defines ‘baseline’ for plasma concentration data as the predose 
measurement 12 weeks (±1 week) postpartum. In the SAP, tables and figures, the name 
for the reference point was changed to ‘postpartum’.  
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• Clarification was added to the Enrolled Set definition to include participants who re-
enrolled.  The SS definition was updated to include all participants with ongoing CZP 
dosing at screening.  PK-PPS definition was clarified to include participants for whom at 
least one predose or postdose sample is available which was not impacted by an 
important protocol deviation. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
The following covariates will be included in the primary analysis model specified in Section 
9.1.2: 
• disease phenotype  
• gestational week 
• trimester and  
• dose point  
The covariates will be defined as: disease phenotype (rheumatoid arthritis, psoriatic arthritis, 
psoriasis, Crohn’s disease, axial spondyloarthritis and ankylosing spondylitis) a 6-category 
variable, gestational week (that is, at the time point when sample is collected) as a continuous 
variable, trimester (trimester 1, 2, 3, or postpartum) as a 4-category variable, and dose point 
(predose or postdose) as a binary variable. In case of overfitting, disease phenotype will be 
excluded from the model. 
4.2 
Handling of dropouts or missing data 
There will be no special procedures for handling missing outcome data. Only the imputation of 
missing or partial dates for safety assessments, as well as handling values below the LLOQ in the 
PK data will be conducted. 
4.2.1 
Handling of missing data for AE 
All AEs will be considered TEAEs in this study. For analyses of TEAEs, a complete date must 
be established to correctly identify the TEAE as occurring during the pregnancy period or not. 
For purposes of imputing missing components of partially reported start and stop dates for 
TEAEs, the algorithms listed below will be followed.  
Although the algorithms for pregnancy period or not depend on the onset date, imputation rules 
are provided for stop date as well, as these may be needed for certain statistical analyses, such as 
an analysis of TEAE prevalence or TEAE duration. 
Start and stop dates of TEAEs will be displayed as reported in the study participant data listings 
(i.e., no imputed values will be displayed in data listings). 
Imputation of Partial Start Dates 
• If only the month and year are specified and the month and year of study enrolment is not the 
same as the month and year of TEAE onset, then use the 1st of the month 
• If only the month and year are specified and the month and year of study enrolment is the 
same as the month and year of TEAE onset, then use the date/time of study enrolment 
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• If only the year is specified, and the year of study enrolment is the same as the year of TEAE 
onset, then use the date/time of study enrolment 
• If the TEAE onset date is completely unknown, then use the date of study enrolment 
Imputation of 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 31st of that year 
• If the imputed stop date is after last contact date, use last contact date. 
• If the TEAE is resolved and the stop date is completely unknown, then do not impute the stop 
date 
Other imputation 
In addition, the following will apply for presenting TEAE in summary tables: 
• if the intensity of an TEAE is unknown, it will be considered as severe.  
• If the relationship to CZP is missing, it will be considered as related.  
For seriousness, no imputation rule will be applied, the worst-case approach will be applied for 
the analysis of Serious TEAEs (i.e., the missing seriousness will be considered as serious if 
missing). 
4.2.2 
Handling of missing data for prior and concomitant medications 
Any medications with incomplete start and end dates/times will be handled according to the 
following rules for classification as prior and concomitant and for the calculation of relative 
study days. In the event of ambiguity or incomplete data which makes it impossible to determine 
whether a medication was concomitant or not, the medication will be considered as concomitant. 
Such imputations will only be performed for these classifications and calculations; in the listings 
all data will be shown as recorded on the electronic case report form (eCRF). 
Imputation of Partial Start Dates 
• If only the month and year are specified and the month and year of study enrolment is not the 
same as the month and year of the start date, then use the 1st of the month 
• If only the month and year are specified and the month and year of study enrolment is the 
same as the month and year of the start, then use the date of study enrolment 
• If only the year is specified, and the year of study enrolment is not the same as the year of the 
start date, then use January 1 of the year of the start date 
• If only the year is specified, and the year of study enrolment is the same as the year of the 
start date, then use the date of study enrolment 
• If the start date is completely unknown, and the stop date is unknown or not prior to the date 
of first dose after enrollment, then use the date of study enrollment 
Imputation of Partial Stop Dates 
• If only the month and year are specified, then use the last day of the month 
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• If only the year is specified, then use December 31 of that year 
• If the imputed stop date is after last contact date, use last contact date. 
• If the stop date is completely unknown, do not impute the stop date 
4.2.3 
Handling of values below the LLOQ in PK data 
Unless otherwise stated, PK measured values below the limit of quantification (BLQ) will be 
reported as the values of LLOQ/2 (0.016 ug/mL) for the summary statistics and figures but as 
BLQ for listings. No imputation will be used for missing samples. 
4.3 
Interim analyses and data monitoring 
No interim analyses or data monitoring is planned. 
4.4 
Multicenter studies 
No exploration of treatment by center interaction will be investigated. 
4.5 
Multiple comparisons/multiplicity 
 No adjustments for multiplicity or multiple comparisons are planned. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Disposition of study participants 
Study participant disposition will be summarized for the ASPS. In this summary, the dates of 
first study participant screened and date of last study participant last visit, number of screened 
study participants, and the number of study participants included in each analysis set (ES, SS, 
PK-PPS) will be presented for all participants and by dosing regimen overall and for each site.  
The disposition of study participants into dosing regimen groups and analysis sets (ES, SS and 
PK-PPS) will also be summarized on the ES. 
Reasons for screen failures (as collected on the Study Termination Screen Failure of the case 
report form (CRF) page) will be summarized for the ASPS who failed to be enrolled.  
The number and percentage of study participants will be summarized using the ES. The primary 
reason for study discontinuation as collected on the Study Termination CRF page will be 
provided in this table.  
Finally, the number of enrolled study participants who discontinued the study due to TEAEs will 
be summarized. 
Study disposition and termination details will be listed for the ASPS. Additional listings on the 
ES will be created on study discontinuation, study participant analysis sets and visit dates. A 
listing will also be provided for study participants who did not meet the study eligibility criteria. 
5.2 
Protocol deviations 
A summary displaying the number and percentage of study participants with an important 
protocol deviation will be provided on the ES, including a summary of study participants 
excluded from the PK-PPS due to important protocol deviations.  
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A by-study participant listing of important protocol deviations will be provided for all study 
participants in the ES. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
The following demographic variables measured at Baseline to be summarized for the ES are: age 
(years), country, race, height (cm), body weight (kg) and BMI (kg/m2). Age and BMI will be 
summarized as continuous variables only. Gender, confirmation of pregnancy and ethnicity will 
only be listed. 
By-study participant listings on demographics will be provided for the ASPS.  
6.2 
Other Baseline characteristics 
Other baseline characteristics to be summarized are lifestyle characteristics based on SS.  
Details of tuberculosis (TB) testing will not be summarized. TB testing will be performed if the 
study participant has not been tested within 6 months prior to Screening and has no associated 
clinical evidence of an active TB infection. However, this data is not captured in the electronic 
database and hence no summary table or listing will be produced. 
6.3 
Medical history and concomitant diseases 
Previous medical history is defined as conditions that have resolved prior to study entry.  
Ongoing medical history is defined as conditions that are ongoing at the time of study entry. 
Previous and on-going medical history will be summarized together by MedDRA System Organ 
Class (SOC) and Preferred Term (PT), by dosing regimen and overall including the number and 
percentage of study participants with each condition. The table summaries will be ordered 
alphabetically for SOC and in terms of decreasing frequency for PT within SOC. In the event of 
ties, PT will be ordered alphabetically.  
The summaries will be presented on the SS.  
Medical history will be listed by dosing regimen and study participant including the reported 
term, PT, and SOC for the ES. A glossary of all medical history conditions will be presented 
including the reported term, PT and SOC.  
Medical procedures and medical procedure history will be listed for all study participants on the 
ES. 
6.4 
Medical conditions leading to CZP use 
Medical conditions identified as the primary condition for CZP use will be summarized using the 
number and percentage for the SS.  Primary medical conditions for Cimzia use as well as other 
medical conditions reported on the electronic Case Report Form (eCRF) but not identified as 
primary will be included in a listing.  The medical condition decodes (MHDECOD) for the 
listing include: 
- 
Psoriatic arthropathy 
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- 
Psoriasis 
- 
Rheumatoid arthritis 
- 
Arthritis 
- 
Ankylosing spondylitis 
- 
Axial spondyloarthritis 
- 
Spondylitis 
- 
Crohn’s disease 
- 
Juvenile idiopathic arthritis 
6.5 
Prior and concomitant medications 
Study participants are permitted to continue on their prescribed medical therapy for the disease in 
accordance with the instructions of their treating physician. 
Any treatment other than commercial CZP (CZP dosing dates and times will be collected 
separately in a diary), including over-the-counter products and supplements, must be recorded in 
the study participant’s notes (source documentation) and provided on the eCRF. This record 
should include the name of the drug, the dose, the route, and date(s) of administration, and the 
indication for use. 
For the purposes of this study: 
• Past medications are those that are ongoing at the time of the first day of the last menstrual 
period and those that started after the first day of the last menstrual period and stopped prior 
to entering the screening period.  For participants with IVF, past medications are those that 
are ongoing 12 weeks prior to screening or started within 12 weeks prior to screening and 
stopped prior to entering the screening period. 
• Prior medications are those that are ongoing at the time of the first day of the last menstrual 
period and those that started after the first day of the last menstrual period but prior to 
entering the screening period.  For participants with IVF, prior medications are those that are 
ongoing 12 weeks prior to screening or started within 12 weeks prior to screening.  
• Concomitant medications are medications with at least 1 day in common with the screening 
period or sampling periods.  
• Prior medications may include both past medications and concomitant medications.  
The number and percentage of study participants taking past, prior and concomitant medications 
will be summarized for the SS.  
A by-study participant listing of all past, prior and concomitant medications will be provided on 
ES. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Study participants will be provided with CZP outside the study; hence compliance will not be 
measured. 
8 
EFFICACY ANALYSES 
Not applicable. 
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9 
PHARMACOKINETIC AND IMMUNOGENICITY ANALYSES 
9.1 
Statistical analysis of the primary outcome variable 
9.1.1 
Derivations of primary outcome variable 
The primary endpoint will be summarized and listed using the PK-PPS.  Individual samples 
marked ‘Excluded from analysis’ according to the PD review log ‘Action for analysis’ column 
will be deselected from the primary analysis. 
Predose and postdose plasma CZP concentrations in women during pregnancy, relative to 
postpartum, will be analyzed as measured. Data analysis may be conducted on log transformed 
data (and back-transformed results displayed) where necessary. 
9.1.2 
Primary analysis of the primary outcome variable 
The CZP plasma concentrations (primary variable) will be analyzed using a linear mixed effects 
model with fixed effects for disease phenotype, gestational week, trimester [trimester 1, 2, 3, or 
postpartum] and whether the sample was predose or postdose [binary indicator], and the random 
effect will be study participant. Within this model trimesters will be defined as follows: trimester 
1 (≤12 weeks and 6 days’ gestation), trimester 2 (13–28 weeks and 6 days’ gestation), trimester 3 
(≥29 weeks’ gestation) and postpartum.  
A compound symmetry covariance structure will be used, as this was decided to be the most 
appropriate structure given the context of this data.  In case of overfitting, disease phenotype will 
be excluded from the model. 
Adjusted mean differences with 95% CI of CZP plasma concentrations between samples taken 
each pregnancy trimester and postpartum will be estimated within this linear mixed effects 
model using contrasts. These adjusted mean differences and 95% CIs will be displayed 
graphically in a forest plot. 
ICC may be provided to describe the consistency of CZP absorption from the same participant 
based on the linear mixed effects model as described in Section  3.1.1. 
Data analyses may be conducted on log-transformed data, based on visual inspection of the data. 
This will be based on visual inspection of histograms, boxplots and quantile-quantile plots for 
each dosing regimen which will be included as part of the statistical appendices. If the data show 
a departure from normality, data analysis will be conducted on log transformed data (and back-
transformed results displayed). 
9.1.3 
Primary summaries of the primary outcome variable 
The individual plasma concentrations of CZP (ug/mL) will be summarized over the course of 
pregnancy by dosing regimen and by trimester or dosing time point (predose or postdose) using 
graphs and descriptive statistics (number of observations [n], geometric mean, lower and upper 
95% confidence intervals [CI], geometric CV, arithmetic mean, SD, median, minimum, and 
maximum values). 
The graphs to be produced by dosing regimen include: 
1. Individual CZP plasma concentration plots using gestational week with predose and 
postdose values plotted side by side,  
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2. Spaghetti plots of CZP plasma concentrations using gestational week with predose and 
postdose values plotted side by side, and  
3. Geometric Mean plots by dosing regimen and sample time relative to dose, i.e., 
separately for predose and postdose.  The time points will be based on trimester as 
defined in Section  3.2.2, including the postpartum period.  The plot will show both a 
linear and semi-logarithmic scale side by side.  The average predose (or postdose) results 
within trimester per participant will be used to calculate the geometric mean and 95% CI 
for all participants combined. 
For the calculation of descriptive statistics, a plasma concentration below the lower limit of 
quantification (LLOQ) will be substituted by LLOQ/2. The geometric and arithmetic means and 
associated SD, lower and upper limits of 95% CI, and CV will be calculated only if at least two 
thirds of the individual data at a specific sampling point are measured, are above or equal to 
LLOQ, and n≥4.  If n<4, a subset of summary statistics will be displayed as described in Section 
3.1. 
9.1.4 
Exploratory analysis of the primary outcome variable 
The linear mixed effects model from the primary analysis will also be fitted to the predose and 
postdose CZP plasma concentrations separately.  Adjusted means and 95% CI for each model 
will be included in the forest plot. 
CZP plasma concentrations will additionally be analyzed adjusting for CRP, albumin and BMI. 
These analyses will be conducted using the same linear mixed effects model used for the primary 
analysis with CRP, albumin and BMI as a covariate in 3 separate models. Results from these 
models should be interpreted with caution, due to the small sample size and relatively large 
number of covariates. Summary tables showing the mean differences and 95% CIs of each 
trimester vs post-partum estimated from the model contrasts will be presented. 
9.2 
Immunogenicity 
All immunogenicity analyses will be performed using the SS.  
9.2.1 
Anti-drug antibodies sample status category definitions 
Anti-drug antibodies (ADA) will be measured using a three-tiered assay approach: screening, 
confirmatory and titration assay.  
Samples will first be evaluated in the screening assay (reported as ‘negative screen’ or ‘positive 
screen’), followed by analysis of screened positive samples in the confirmatory assay to confirm 
the true positivity of the samples (reported as ‘negative immuno-depletion’ or ‘positive immuno-
depletion’). Samples that are confirmed as positive in the confirmatory assay will be evaluated in 
a titration assay to quantify the ADA level and will be reported as titer (reciprocal dilution factor 
including minimum required dilution [MRD]).  
The ADA sample status will be determined for each visit where samples were collected for ADA 
analysis (both scheduled and any unscheduled visits). 
- 
Sample values that are either ‘negative screen’ or the combination of ‘positive screen’ and 
‘negative immunodepletion’ will be defined as ADA negative if corresponding CZP 
concentrations are equal or below the validated drug tolerance limit of the ADA assay (100 
ug/mL CZP) allowing detection of 100ng/mL ADA. 
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- 
Sample values that are either ‘negative screen’ or the combination of ‘positive screen’ and 
‘negative immunodepletion’ but with corresponding CZP concentrations above the 
validated drug tolerance limit of the ADA assay will be defined as ADA inconclusive. 
- 
Sample values that are ‘positive screen’ and ‘positive immunodepletion’ will be defined as 
ADA positive. 
- 
Samples that could not be tested for ADA status due to inadequate sample volume, 
mishandling, or errors in sample collection, processing, storage, etc., will be defined as 
Missing. 
9.2.2 
Anti-drug antibodies participant titer classification 
Once determined positive, a study participant’s highest titer will be used to categorize (“titer 
classification”) the study participant as follows: 
• Positive ≤32 
• Positive >32 - ≤128 
• Positive >128 - ≤512 
• Positive >512 - ≤1024 
• Positive >1024 - ≤4096 
• Positive >4096 
9.2.3 
ADA titer and classification summaries and analyses 
The fold difference increase from postpartum value, i.e., the minimum significant ratio (MSR) 
determined during assay validation, will be reported in the relevant tables, listings and figures. It 
reflects the fold difference in titer level that is considered higher than the assay variation in titer 
determination. 
The following summaries, figures and listings will be produced using the MSR and will be 
presented using the SS: 
• 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 
dosing regimen.  
• Spaghetti plots of the individual time course plots of ADA titer (y-axis) by time (x-axis) for 
participants with at least one ADA positive sample status, with one line representing one study 
participant. Separate plots will be presented for each dosing regimen. Plots may be presented 
using a semi-logarithmic scale for the ADA titers (ADA negative samples will therefore be 
excluded from the plot).  Time will be presented using gestational week. 
• Summary statistics of ADA titers (mean, min, max, geomean) per time point and dosing 
regimen. 
• Summary of titer classification for all study participants who test positive at any visit will be 
presented by category.  
• The ADA results will be listed including the results from the screening assay, confirmatory 
assay, and titration assay (titer level), the ADA sample status, the drug concentration with 
indication if the drug level exceeds the ADA assay tolerance for detecting 100 ng/ml ADA or 
alternative level as defined above (Y/N). 
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In addition, the following figures will be produced to illustrate the impact of ADA on PK: 
• Spaghetti plots of the individual CZP plasma concentrations (each participant corresponding 
to a line) over time will be produced on a linear and semi-logarithmic scale according to 
ADA titer classification. Gestational week should be indicated below the x-axis.  
• Time course plots of individual CZP plasma concentrations (one plot per participant) 
superimposed with the participant’s corresponding ADA titer over the course of the study 
will be presented.  Plots may be presented using a semi-logarithmic scale for the ADA titers 
(ADA negative samples will therefore be excluded from the plot).  Time will be presented 
using gestational week. 
10 
ANALYSIS OF OTHER OUTCOME VARIABLES 
10.1 
Other outcome variables 
The other outcome variables to be presented are: 
• CRP levels 
• Albumin levels 
• BMI 
All three parameters will be listed on the SS only and will be used for the exploratory CZP 
model.  
11 
SAFETY ANALYSES 
All safety analyses will be performed using the SS.  
11.1 
Pregnancy outcome 
Pregnancy outcome by study participant will be included in a listing. 
11.2 
Infant illnesses 
Illnesses reported for each infant by study participant will be included in a listing. 
11.3 
Adverse events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA v24.1 
or later version) and characterized as treatment emergent. 
The occurrence and incidence of TEAEs will be summarized by MedDRA system organ class 
and preferred term. The TEAEs will also be summarized by intensity and by relationship to CZP. 
TEAEs leading to discontinuation and serious TEAEs will also be summarized. 
The following TEAE tables will be produced: 
• Incidence of TEAEs Overview 
• Incidence of TEAEs by SOC, HLT and PT 
• Serious TEAEs  
• Non-serious TEAEs 
• TEAEs leading to death 
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• TEAEs leading to hospitalization or death 
• TEAEs leading to study discontinuation 
• Incidence of TEAEs by Maximum Severity 
• Incidence of TEAEs by Maximum relationship 
• Incidence of TEAEs by Trimester 
The following TEAE of interest will be summarized in stand-alone tables:  
• Serious infections including opportunistic infections (see Section  11.3.1) 
• Malignancies or unspecified tumours including lymphoma 
• Malignant Tumours 
• Demyelinating-like disorders 
• Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leucopenia 
• Serious bleeding events 
For the following AEs of interest, no additional tables will be provided, as these are included in 
 the standard AE summaries: 
• Congestive heart failure 
• Lupus and lupus-like syndrome 
• Serious skin reactions (e.g., Stevens Johnson Syndrome, toxic epidermal necrosis, and 
erythema multiforme). 
Separate tables will be created to summarize each of the above TEAEs of interest by system 
organ class, high level term, and PT, where the TEAEs of interest are identified using 
standardized MedDRA queries (SMQ).  An additional review cycle to confirm the targeted 
events will be implemented for opportunistic infections as described in Section 11.3.1. 
All TEAEs and serious TEAEs will be listed using the SS. Details of serious TEAEs, TEAEs 
leading to death or study discontinuation will be listed.  For results disclosure on public registries 
(e.g., ClinicalTrials.gov), TEAEs and serious TEAEs will be published. 
11.3.1 
Identification of opportunistic infections 
A summary of opportunistic infections (including tuberculosis) will include all TEAEs identified 
using UCB-defined search criteria. 
Identification Process 
The steps below outline 2 ways (both programmatically and after manual review) in which 
opportunistic infections (or potential opportunistic infections) can be identified using 
standardized MedDRA queries (SMQ): 
Step 1 [programmatic identification]: All TEAEs from ‘Opportunistic infections (SMQ)’ with a 
narrow scope are considered as automatically identified opportunistic infection, regardless of 
seriousness. 
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Step 2 [manual identification]: All other TEAE in the ‘Opportunistic infections (SMQ)’ with a 
broad scope will be evaluated on a case-by-case basis by the study physician to determine 
whether it is a true opportunistic infection (OI) of interest or not. 
Review Process 
A final listing for opportunistic infections (in the format described below) will be produced and 
reviewed by the study physician prior to finalizing the database. 
The study programming team will produce an Excel listing of all AEs from the ADaM domain 
for participants with at least 1 TEAE falling within the broad scope of the ‘Opportunistic 
infections (SMQ)’ allowing a review of all the participants’ AEs to establish OI of interest. The 
Excel listing will contain the following columns (using the descriptions below as the column 
headings in the Excel listing): 
• Study ID 
• Unique Participant ID 
• AE Term (Verbatim) 
• AE Preferred Term 
• AE System Organ Class 
• AE High Level Term 
• AE Low Level Term 
• Date of Onset 
• Outcome of Adverse Event 
• Date of Outcome 
• TEAE Flag 
• Serious Adverse Event? 
• Relationship to Study Medication  
• Intensity 
• Action Taken with IMP 
• Opportunistic Infection – Automatic; code and scope (Y/N) 
• Opportunistic Infection – Manual Review; code and scope (Y/N) 
• Flag for previously reviewed? (NEW/OLD) 
• Data Cut Date 
• Opportunistic Infection – Final Adjudication (Y/N) 
Note the following about the final 5 variables in this listing: 
• Opportunistic Infection – Automatic: This is flagged as “Y” if the criteria for automatic 
selection as described in “Step 1” of the identification process are met. 
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• Opportunistic Infection – Manual Review: This is flagged as “Y” if the criteria for case-by-
case selection as described in “Step 2” of the identification process are met. 
• Flag – This has a value of either “NEW” or “OLD”. It is marked as “NEW” if the event is 
appearing for the first time in that run of the listing. Otherwise, if it has appeared previously, 
it is marked as “OLD”. Unique records are determined by USUBJID AESPID for purposes 
of identifying whether an event has been modified from a previous run. 
• Date – Only for cases where Flag is “NEW”, this field will be populated with the data cut 
date for that particular run of the listing. 
• Opportunistic Infection – Final Adjudication – For new events, this is always left blank by 
the programmers. It will be completed by the study physician for every event that appears in 
the listing. For events adjudicated as opportunistic, the field will be populated with a “Y”.  
Following the review by the study physician, the Opportunistic Infection – Final Adjudication 
column will be completed (as described above), and the spreadsheet will be returned to the study 
programming team via e-mail.  The decisions documented in the returned file will be merged 
with AE data for final reporting in a summary table and flagged in the All Adverse Events 
listing. 
11.4 
Clinical laboratory evaluations 
Clinical laboratory evaluations will not be conducted. CRP and albumin will be assessed as 
described in Section 10.1. 
11.5 
Vital signs, physical findings, and other observations related to 
safety 
11.5.1 
Vital signs 
Measured values of vital signs will be summarized descriptively and reported using the SS. 
• Systolic Blood Pressure (mmHg) 
• Diastolic Blood Pressure (mmHg) 
• Pulse Rate (bpm) 
• Temperature (°C) 
• Respiratory Rate (breaths per min) 
If any vital signs are repeated then the last or latest dated assessment will be used for tabulation 
purposes. 
All vital signs will be summarized by dosing regimen and listed using the SS. 
11.5.2 
Physical Findings 
Physical examination abnormalities will be listed using the SS. 
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12 
REFERENCES 
Phillips A, Haudiquet V. ICH E9 guideline ‘Statistical principles for clinical trials: a case study’. 
Stat Med. 2003;22(1):1-11; discussion 13-7. 
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13 
APPENDICES 
13.1 
AMENDMENT 1 
Rationale for the amendment 
The major purpose of this SAP amendment was to implement changes to align with more recent 
standards and make further clarifications for programming.  
The main SAP amendments can be summarized as follows: 
• Change of WHO Anatomical Therapeutic Chemical (ATC) Classification, presenting 
Anatomical Main Group (ATC Level 1), Pharmacological Subgroup (ATC level 3), and 
preferred term version to MAR/2021 
• Change to MedDRA 24.1.  
• Updates to prior and concomitant medication definitions 
• Update to partial dates imputation 
• Exclusion of selected TEAE tables from analysis 
13.1.1 
Coding Dictionaries (Section 3.8) 
• Dictionary versions updated 
13.1.2 
Handling of partial missing dates for AEs (Section 4.2) 
• If the imputed stop date is after last contact date, use last contact date. 
13.1.3 
Exclusion of TB summary from baseline analyses (Section 6.2) 
Paragraph updated to: 
Other baseline characteristics to be summarized are lifestyle characteristics. Details of 
tuberculosis (TB) testing will not be summarized. TB testing will be performed if the study 
participant has not been tested within 6 months prior to Screening and has no associated clinical 
evidence of an active TB infection. However, these data are not captured in the electronic 
database and hence no summary table or listing will be produced. 
13.1.4 
Definition of past and prior medications (Section 6.5) 
• Past medications are those that are ongoing at the time of first day of the last menstrual 
period and those that started after the first day of the last menstrual period and stopped prior 
to entering the screening period.  
• Prior medications are those that are ongoing at the time of first day of the last menstrual 
period and those that started after the first day of the last menstrual period prior to entering 
the screening period.  
• Concomitant medications are medications with at least 1 day in common with the screening 
period or sampling periods.  
• Prior medications may include both past medications and concomitant medications.  
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13.1.5 
Exclusion of TEAE tables (Section 11.3) 
For the following AEs of interest, no additional tables will be provided, as these are included in 
 the standard AE summaries: 
• Congestive heart failure 
• Lupus and lupus-like syndrome 
• Serious skin reactions (e.g., Stevens Johnson Syndrome, toxic epidermal necrosis, and 
erythema multiforme). 
 
 
 
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13.2 
AMENDMENT 2 
Rationale for the amendment 
The major purpose of this SAP amendment was to align text with protocol amendment 2 and 
with more recent standards, and to make further clarifications for programming.  
The main SAP amendments can be summarized as follows: 
• Change of sample size text to reflect the minimum required number of participants 
• Inclusion of a Not Dosed group for the participant who withdrew from the study prior to 
dosing during the pregnancy period and change from ‘All Participants’ to ‘All Dosed 
Participants’ to avoid counting this participant twice. 
• Clarification of the calculation of geometric CI and ICC 
• Clarification of the definition of gestational week 
• Rewording of the reference point for plasma concentration  
• Updated the definitions of the ES, SS and PK-PPS  
• Handling of missing dates for imputation rules 
• Addition of a section to describe the summary of medical conditions leading to CZP use 
along with dictionary terms to use for identifying the medical conditions.  
• Clarification of which PK graphs will be produced 
• Details of anti-drug antibody status and classification definitions and summaries 
• Addition of a listing to display infant illnesses 
• Cosmetic and grammatical corrections 
• Addition of a section for the identification of opportunistic infections 
 
13.2.1 
Sample size (Section 2.3 and Section 2.4) 
Section 2.3 text updated to: 
 
Enrollment will occur until a minimum of 10 study participants have longitudinal data (defined 
as at least 4 quantifiable predose and 2 quantifiable postdose PK samples during pregnancy and 
at least 1 quantifiable postpartum sample) over the study period. 
 
Section 2.5 text updated to: 
 
These 15 evaluable participants are expected to provide the minimum of 10 study participants 
providing longitudinal data (defined as at least 4 quantifiable predose and 2 quantifiable postdose 
PK samples during pregnancy and at least 1 quantifiable postpartum sample) over the study 
period. 
 
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13.2.2 
Handling of small samples in summary tables (Section 3.1) 
A rule was added: 
If n=3, only n, mean, median, minimum and maximum will be displayed.  If n<3, only n, minimum 
and maximum will be displayed.  For both cases, any summary statistics that are not displayed will 
be replaced with ‘NA’ and explained in a footnote. 
13.2.3 
Addition of Not Dosed column (Section 3.1) 
Section 3.1 dosing regimen labels updated to: 
 
• “Not Dosed” 
• “CZP 200mg Q2W” 
• “CZP 400mg Q2W” 
• “CZP 400mg Q4W” 
• “All Dosed Participants” 
An additional “Other” category will be added to the tables in case there are dosing regimens 
outside those listed.  The “Not Dosed” category includes participants who enrolled but did not 
record a CZP dose relative to any PK samples prior to discontinuation.  The “All Dosed 
Participants” category includes participants in CZP 200mg Q2W, CZP 400mg Q2W and CZP 
400mg Q4W combined. 
Study Participants will be grouped according to the commercial CZP dosing regimen that was in 
effect at enrollment (actual dose).  Any participant with a dose reduction or increase will be 
summarized in the initial dosing regimen group. 
13.2.4 
Summary statistics specific to PK model (Section 3.1.1) 
Section 3.1.1 header and text updated to: 
The 95% CI for the geometric mean will be calculated by obtaining the lower and upper 95% CI 
for the arithmetic mean on the log-transformed data and back-transforming to obtain the 
respective values for the geometric CI. 
The intraclass correlation coefficient (ICC) will be calculated using the following formula: 
𝜌=
𝜎𝑟
2
𝜎𝑟2 + 𝜎𝜖2 
Where 𝜎𝑟
2 represents the variance of the random effect and 𝜎𝜖
2 represents the variance of the 
residual in the linear mixed effects model as described in Section 4.1. 
 
13.2.5 
Conversion formulas and BMI calculation (Section 3.1.2) 
This formula was removed from Section 6.1 and added to Section 3.1.2 including conversion 
factors for height and weight: 
Even if BMI is available in the database, BMI (in kg/m2) will be recalculated during analysis 
based on height (in m) and weight (in kg) values collected in the database, and the calculated 
values will be used in the statistical analysis.   
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If height is recorded in inches, the height conversion is: 
Height (m) = 0.0254*Height (inches) 
If weight is recorded in pounds, the weight conversion is: 
Weight (kg) = 0.45359237*Weight(lb) 
The formula for BMI (kg/m2) calculation is: 
BMI = Weight (kg)
(Height (m))2 
 
13.2.6 
Definition of gestational week (Section 3.2.2) 
Text updated to: 
 
Gestational week (i.e., week of gestational age) is determined from the time since the first day of 
the last menstrual period or, if the participant had undergone in vitro fertilization (IVF), from the 
date of birth and gestational age recorded for the pregnancy outcome and then back-calculated to 
get the gestational week. 
13.2.7 
Definition of postpartum as the reference point for PK analyses 
(Section 3.3) 
Text updated to: 
For summaries of CRP, Albumin and anti-CZP antibody data, the postpartum measurement will 
be used as the reference point instead of the day of enrolment, based on the postpartum 
measurement collected at Visit 5.  If there was no sample collected at Visit 5, then the last 
available postpartum sample will be used.  If the postpartum measurement is missing or not 
collected (i.e., the postpartum value is not available), then the reference value is treated as 
missing. 
For summaries of plasma concentration, the postpartum measurements will be used as the 
reference point instead of the day of enrolment, based on both the predose and postdose 
postpartum PK samples. If either the predose or postdose postpartum PK measurement is missing 
or not collected, (i.e., the postpartum value is not available), then the respective reference value 
is treated as missing.   
 
13.2.8 
All Study Participants Set definition (Section 3.5.1) 
The word ‘Screened’ was removed from the label and clarification on handling re-screened 
participants was added: 
This will be the largest analysis set, consisting of all study participants who have signed the 
Informed Consent Form (ICF) and will include all participants who pass screening as well as 
screen failures.  For participants who fail screening and subsequently re-screen, only the 
successful screening record(s) will be included in the ASPS. 
 
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13.2.9 
Enrolled Set definition (Section 3.5.2) 
Clarification was added to include participants who re-enrolled: 
The ES will include all study participants who are confirmed as having signed the ICF to 
participate in the study and have provided the first blood sample. For participants who re-enroll 
after discontinuation, both enrollments will be included in the Enrolled Set.  Tables and listings 
using the ES will list the participant identifiers in a footnote. 
 
13.2.10 
Safety Set definition (Section 3.5.3) 
Clarification was added to include all enrolled participants: 
The SS will include all enrolled study participants who are dosing with commercial CZP per 
protocol at Screening. 
 
13.2.11 
Pharmacokinetic Per Protocol Set definition (Section 3.5.4 and 
Section 9.1.1) 
Section 3.5.4 text updated to: 
 
The Pharmacokinetic Per-Protocol Set (PK-PPS) is a subset of the SS, consisting of those study 
participants for whom at least one predose or postdose sample is available which was not 
impacted by an important protocol deviation. 
Section 9.1.1 text updated to: 
The primary endpoint will be summarized and listed using the PK-PPS.  Individual samples 
marked ‘Excluded from analysis’ according to the PD review log ‘Action for analysis’ column 
will be deselected from the primary analysis. 
 
13.2.12 
Additional changes from protocol-specified analyses (Section 3.9) 
Two changes were added: 
• The protocol defines ‘baseline’ for plasma concentration data as the predose 
measurement 12 weeks (±1 week) postpartum. In the SAP, tables and figures, the name 
for the reference point was changed to ‘postpartum’.  
• The Safety Set definition was modified to include all enrolled participants.  These are 
participants who have been on a stable dose of commercial CZP per inclusion criteria 
regardless of whether the participant had the scheduled dosing administered during the 
Sampling Period according to Table 1-1 of the protocol. 
 
13.2.13 
Summary of Medical Condition Leading to CZP Use (Section 6.4) 
Text updated to: 
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Medical conditions identified as the primary condition for CZP use will be summarized using the 
number and percentage for the SS.  Primary medical conditions for Cimzia use as well as other 
medical conditions reported on the electronic Case Report Form (eCRF) but not identified as 
primary will be included in a listing.  The medical condition decodes (MHDECOD) for the 
listing include: 
- 
Psoriatic arthropathy 
- 
Psoriasis 
- 
Rheumatoid arthritis 
- 
Arthritis 
- 
Ankylosing spondylitis 
- 
Axial spondyloarthritis 
- 
Spondylitis 
- 
Crohn’s disease 
- 
Juvenile idiopathic arthritis 
13.2.14 
Past and prior medications (Section 6.5) 
The definitions of ‘past’ and ‘prior’ were clarified for participants with IVF: 
• Past medications are those that are ongoing at the time of the first day of the last menstrual 
period and those that started after the first day of the last menstrual period and stopped prior 
to entering the screening period.  For participants with IVF, past medications are those that 
are ongoing 12 weeks prior to screening or started within 12 weeks prior to screening and 
stopped prior to entering the screening period. 
• Prior medications are those that are ongoing at the time of the first day of the last menstrual 
period and those that started after the first day of the last menstrual period but prior to 
entering the screening period.  For participants with IVF, prior medications are those that are 
ongoing 12 weeks prior to screening or started within 12 weeks prior to screening.  
 
13.2.15 
PK random effects model description (Section 9.1.2) 
Header updated to describe the model, and text updated to: 
The CZP plasma concentrations (primary variable) will be analyzed using a linear mixed effects 
model with fixed effects for disease phenotype, gestational week, trimester [trimester 1, 2, 3, or 
postpartum] and whether the sample was predose or postdose [binary indicator], and the random 
effect will be study participant. Within this model trimesters will be defined as follows: trimester 
1 (≤12 weeks and 6 days’ gestation), trimester 2 (13–28 weeks and 6 days’ gestation), trimester 3 
(≥29 weeks’ gestation) and postpartum.  
A compound symmetry covariance structure will be used, as this was decided to be the most 
appropriate structure given the context of this data.  In case of overfitting, disease phenotype will 
be excluded from the model. 
Adjusted mean differences with 95% CI of CZP plasma concentrations between samples taken 
each pregnancy trimester and postpartum will be estimated within this linear mixed effects 
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model using contrasts. These adjusted mean differences and 95% CIs will be displayed 
graphically in a forest plot. 
ICC may be provided to describe the consistency of CZP absorption from the same participant 
based on the linear mixed effects model as described in Section 3.1.1.  
Data analyses may be conducted on log-transformed data, based on visual inspection of the data. 
This will be based on visual inspection of histograms, boxplots and quantile-quantile plots for 
each dosing regimen which will be included as part of the statistical appendices. If the data show 
a departure from normality, data analysis will be conducted on log transformed data (and back-
transformed results displayed). 
13.2.16 
PK Graphical Displays (Section 9.1.3) 
Section header inserted and text for graphics updated to: 
 
The graphs to be produced by dosing regimen include: 
1. Individual CZP plasma concentration plots using gestational week with predose and 
postdose values plotted side by side,  
2. Spaghetti plots of CZP plasma concentrations using gestational week with predose and 
postdose values plotted side by side, and  
3. Geometric Mean plots by dosing regimen and sample time relative to dose, i.e., 
separately for predose and postdose.  The time points will be based on trimester as 
defined in Section 3.2.2, including the postpartum period.  The plot will show both a 
linear and semi-logarithmic scale side by side.  The average predose (or postdose) results 
within trimester per participant will be used to calculate the geometric mean and 95% CI 
for all participants combined. 
 
13.2.17 
Anti-Drug Antibody Methods (Section 9.2.1, Section 9.2.2, and 
Section 9.2.3) 
Section 9.2.1 text updated to: 
Anti-drug antibodies (ADA) will be measured using a three-tiered assay approach: screening, 
confirmatory and titration assay.  
Samples will first be evaluated in the screening assay (reported as ‘negative screen’ or ‘positive 
screen’), followed by analysis of screened positive samples in the confirmatory assay to confirm 
the true positivity of the samples (reported as ‘negative immuno-depletion’ or ‘positive immuno-
depletion’). Samples that are confirmed as positive in the confirmatory assay will be evaluated in 
a titration assay to quantify the ADA level and will be reported as titer (reciprocal dilution factor 
including minimum required dilution [MRD]).  
The ADA sample status will be determined for each visit where samples were collected for ADA 
analysis (both scheduled and any unscheduled visits).  
Section 9.2.2 text updated to: 
 
Once determined positive, a study participant’s highest titer will be used to categorize (“titer 
classification”) the study participant as follows: 
• Positive ≤32 
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• Positive >32 - ≤128 
• Positive >128 - ≤512 
• Positive >512 - ≤1024 
• Positive >1024 - ≤4096 
• Positive >4096 
 
Section 9.2.3 text updated to: 
 
The fold difference increase from postpartum value, i.e., the minimum significant ratio (MSR) 
determined during assay validation, will be reported in the relevant tables, listings and figures. It 
reflects the fold difference in titer level that is considered higher than the assay variation in titer 
determination. 
 
The following summaries, figures and listings will be produced using the MSR and will be 
presented using the SS: 
• 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 
dose regimen.  
• Spaghetti plots of the individual time course plots of ADA titer (y-axis) by time (x-axis) for 
participants with at least one ADA positive sample status, with one line representing one study 
participant. Separate plots will be presented for each dose regimen. Plots may be presented 
using a semi-logarithmic scale for the ADA titers (ADA negative samples will therefore be 
excluded from the plot).  Time will be presented using gestational week. 
• Summary statistics of ADA titers (mean, min, max, geomean) per time point and dose 
regimen. 
• Summary of titer classification for all study participants who test positive at any visit will be 
presented by category.  
• The ADA results will be listed including the results from the screening assay, confirmatory 
assay, and titration assay (titer level), the ADA sample status, the drug concentration with 
indication if the drug level exceeds the ADA assay tolerance for detecting 100 ng/ml ADA or 
alternative level as defined above (Y/N). 
In addition, the following figures will be produced to illustrate the impact of ADA on PK: 
• Spaghetti plots of the individual CZP plasma concentrations (each participant corresponding 
to a line) over time will be produced on a linear and semi-logarithmic scale according to 
ADA titer classification.  Gestational week should be indicated below the x-axis.  
• Time course plots of individual CZP plasma concentrations (one plot per participant) 
superimposed with the participant’s corresponding ADA titer over the course of the study 
will be presented.  Plots may be presented using a semi-logarithmic scale for the ADA titers 
(ADA negative samples will therefore be excluded from the plot).  Time will be presented 
using gestational week. 
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13.2.18 
TEAE of interest (Section 11.3) 
Clarification was added: 
Separate tables will be created to summarize each of the above TEAEs of interest by system 
organ class, high level term, and PT, where the TEAEs of interest are identified using 
standardized MedDRA queries (SMQ).  An additional review cycle to confirm the targeted 
events will be implemented for opportunistic infections as described in Section 11.3.1. 
All TEAEs and serious TEAEs will be listed using the SS. Details of serious TEAEs, TEAEs 
leading to death or study discontinuation will be listed.  For results disclosure on public registries 
(e.g., ClinicalTrials.gov), TEAEs and serious TEAEs will be published. 
 
13.2.19 
Identification of Opportunistic Infections (Section 11.3.1) 
Text added: 
A summary of opportunistic infections (including tuberculosis) will include all TEAEs identified 
using UCB-defined search criteria. 
Identification Process 
The steps below outline 2 ways (both programmatically and after manual review) in which 
opportunistic infections (or potential opportunistic infections) can be identified using 
standardized MedDRA queries (SMQ): 
Step 1 [programmatic identification]: All TEAEs from ‘Opportunistic infections (SMQ)’ with a 
narrow scope are considered as automatically identified opportunistic infection, regardless of 
seriousness. 
Step 2 [manual identification]: All other TEAE in the ‘Opportunistic infections (SMQ)’ with a 
broad scope will be evaluated on a case-by-case basis by the study physician to determine 
whether it is a true opportunistic infection (OI) of interest or not. 
Review Process 
A final listing for opportunistic infections (in the format described below) will be produced and 
reviewed by the study physician prior to finalizing the database. 
The study programming team will produce an Excel listing of all AEs from the ADaM domain 
for participants with at least 1 TEAE falling within the broad scope of the ‘Opportunistic 
infections (SMQ)’ allowing a review of all the participants’ AEs to establish OI of interest. The 
Excel listing will contain the following columns (using the descriptions below as the column 
headings in the Excel listing): 
• Study ID 
• Unique Participant ID 
• AE Term (Verbatim) 
• AE Preferred Term 
• AE System Organ Class 
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• AE High Level Term 
• AE Low Level Term 
• Date of Onset 
• Outcome of Adverse Event 
• Date of Outcome 
• TEAE Flag 
• Serious Adverse Event? 
• Relationship to Study Medication  
• Intensity 
• Action Taken with IMP 
• Opportunistic Infection – Automatic; code and scope (Y/N) 
• Opportunistic Infection – Manual Review; code and scope (Y/N) 
• Flag for previously reviewed? (NEW/OLD) 
• Data Cut Date 
• Opportunistic Infection – Final Adjudication (Y/N) 
Note the following about the final 5 variables in this listing: 
• Opportunistic Infection – Automatic: This is flagged as “Y” if the criteria for automatic 
selection as described in “Step 1” of the identification process are met. 
• Opportunistic Infection – Manual Review: This is flagged as “Y” if the criteria for case-by-
case selection as described in “Step 2” of the identification process are met. 
• Flag – This has a value of either “NEW” or “OLD”. It is marked as “NEW” if the event is 
appearing for the first time in that run of the listing. Otherwise, if it has appeared previously, 
it is marked as “OLD”. Unique records are determined by USUBJID AESPID for purposes 
of identifying whether an event has been modified from a previous run. 
• Date – Only for cases where Flag is “NEW”, this field will be populated with the data cut 
date for that particular run of the listing. 
• Opportunistic Infection – Final Adjudication – For new events, this is always left blank by 
the programmers. It will be completed by the study physician for every event that appears in 
the listing. For events adjudicated as opportunistic, the field will be populated with a “Y”.  
Following the review by the study physician, the Opportunistic Infection – Final Adjudication 
column will be completed (as described above), and the spreadsheet will be returned to the study 
programming team via e-mail.  The decisions documented in the returned file will be merged 
with AE data for final reporting in a summary table and flagged in the All Adverse Events 
listing. 
 
 
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UCB 
 
22 JUN 2023 
Statistical Analysis Plan 
CERTOLIZUMAB PEGOL 
UP0085 
 
Confidential 
Page 41 of 41 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
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This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Approval Signatures
Name:
up0085-sap amendment-2
Version:
1. 0
Document Number:
CLIN-000225640
Title:
SAP Amendment 2
Approved Date:
23 Jun 2023
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 22-Jun-2023 21:49:59 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 23-Jun-2023 11:38:27 GMT+0000
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