Clinical trial NCT03928743
Conditions: Ankylosing Spondylitis
Keywords: Ankylosing spondylitis AS Bimekizumab Axial spondyloarthritis
Sponsor: UCB Biopharma SRL
Start date: 2019-04-25; Completion date: 2022-08-08
Enrollment: 332 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to demonstrate the efficacy, safety and tolerability of bimekizumab administered subcutaneously (sc) compared to placebo in the treatment of subjects with active ankylosing spondylitis (AS).

Detailed description:

Arms: arm 1: Subjects randomized to this arm will receive bimekizumab during the Double-Blind Treatment Period and the Maintenance Period. arm 2: Subjects randomized to this arm will receive placebo during the Double-Blind Treatment Period and receive bimekizumab during the Maintenance Period.
Interventions: intervention 1: Bimekizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will receive bimekizumab at pre-specified time-points. intervention 2: Subjects will receive placebo at pre-specified time-points during the Double-Blind Treatment Period.

Protocol documents:
Prot_000.pdf: 
UCB 
 
16 Feb 2021 
Clinical Study Protocol 
Bimekizumab 
AS0011 
 
 
 
Confidential 
Page 1 of 187 
PROTOCOL AS0011 AMENDMENT 4 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY EVALUATING THE 
EFFICACY AND SAFETY OF BIMEKIZUMAB IN SUBJECTS 
WITH ACTIVE ANKYLOSING SPONDYLITIS 
PHASE 3 
EudraCT Number: 2017-003065-95 
IND Number: 128708 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Protocol/Amendment number 
Date 
Type of amendment 
Final protocol 
26 Nov 2018 
Not applicable 
Protocol Amendment 0.1 (Japan) 
26 Feb 2019 
Not applicable 
Protocol Amendment 0.2 (Germany) 
23 Apr 2019 
Nonsubstantial 
Protocol Amendment 1 
11 Sep 2019 
Substantial 
Protocol Amendment 1.1 (Japan) 
13 Sep 2019 
Substantial 
Protocol Amendment 1.2 (Germany) 
18 Sep 2019 
Substantial 
Protocol Amendment 2 
17 Oct 2019 
Substantial 
Protocol Amendment 2.1 (Japan) 
24 Oct 2019 
Substantial 
Protocol Amendment 2.2 (Germany) 
29 Oct 2019 
Substantial 
Protocol Amendment 3 
16 Dec 2019 
Nonsubstantial 
Protocol Amendment 3.1 (Japan) 
16 Dec 2019 
Nonsubstantial 
Protocol Amendment 3.2 (Germany) 
16 Dec 2019 
Nonsubstantial 
Protocol Amendment 4 
16 Feb 2021 
Substantial 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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16 Feb 2021 
Clinical Study Protocol 
Bimekizumab 
AS0011 
 
 
 
Confidential 
Page 2 of 187 
STUDY CONTACT INFORMATION 
Sponsor 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim am Rhein 
GERMANY 
Phone: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim am Rhein 
GERMANY 
Phone: 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB BIOSCIENCES Ltd. 
208 Bath Road 
Slough SL1 3WE 
UNITED KINGDOM 
Phone: 
 
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16 Feb 2021 
Clinical Study Protocol 
Bimekizumab 
AS0011 
 
 
 
Confidential 
Page 3 of 187 
Clinical Monitoring Contract Research Organization 
Name: 
PAREXEL International (IRL) Limited-Ireland 
Address: 
Ireland Limited at 70 Sir John Rogerson’s Quay 
Dublin 2 
Ireland 
Phone: 
+353 (1) 477 3171 
Fax: 
+353 (1) 477 3308 
  
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16 Feb 2021 
Clinical Study Protocol 
Bimekizumab 
AS0011 
 
 
 
Confidential 
Page 4 of 187 
SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
All SAEs will be reported and transmitted to Patient Safety through the eCRF 
system. The numbers below are to be used to send ancillary documentation only 
(discharge summaries, death certificates, etc) or in the event that the electronic 
reporting (eCRF) is not available. 
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  
 
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16 Feb 2021 
Clinical Study Protocol 
Bimekizumab 
AS0011 
 
 
 
Confidential 
Page 5 of 187 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 12 
1 
SUMMARY ..................................................................................................................... 17 
2 
INTRODUCTION ........................................................................................................... 18 
2.1 Axial spondyloarthritis ..................................................................................................... 18 
2.1.1 
axSpA epidemiology ........................................................................................... 18 
2.1.2 
Current treatments for axSpA .............................................................................. 19 
2.2 Bimekizumab ................................................................................................................... 19 
2.2.1 
Nonclinical ........................................................................................................... 19 
2.2.2 
Clinical ................................................................................................................. 20 
2.2.2.1 
Completed studies ..................................................................................... 20 
2.2.2.2 
Ongoing studies ......................................................................................... 20 
3 
STUDY OBJECTIVE(S) ................................................................................................. 21 
3.1 Primary objective ............................................................................................................. 21 
3.2 Secondary objectives ....................................................................................................... 21 
3.3 Other objectives ............................................................................................................... 21 
4 
STUDY VARIABLES ..................................................................................................... 21 
4.1 Primary variable ............................................................................................................... 21 
4.1.1 
Primary efficacy variable ..................................................................................... 21 
4.2 Secondary variables ......................................................................................................... 21 
4.2.1 
Secondary efficacy variables ............................................................................... 21 
4.2.2 
Secondary safety variables .................................................................................. 22 
4.3 Other variables ................................................................................................................. 22 
4.3.1 
Other efficacy variables ....................................................................................... 22 
4.3.2 
Other safety variables .......................................................................................... 24 
4.3.3 
Pharmacokinetic variable ..................................................................................... 24 
4.3.4 
Pharmacogenomic variables ................................................................................ 24 
4.3.5 
Immunological variables ..................................................................................... 24 
5 
STUDY DESIGN ............................................................................................................. 25 
5.1 Study description ............................................................................................................. 25 
5.1.1 
Screening Period/Baseline ................................................................................... 25 
5.1.1.1 
Within-study rescreening/retesting requirements ...................................... 26 
5.1.1.2 
Cross-study screening requirements .......................................................... 26 
5.1.2 
Treatment Period ................................................................................................. 27 
5.1.2.1 
Double-Blind Treatment Period ................................................................ 27 
5.1.2.2 
Maintenance Period ................................................................................... 28 
5.1.3 
Early Termination Visit ....................................................................................... 28 
5.1.4 
Safety Follow-Up Visit ........................................................................................ 28 
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Bimekizumab 
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5.1.5 
Study duration per subject ................................................................................... 29 
5.1.6 
Planned number of subjects and site(s) ............................................................... 29 
5.1.7 
Anticipated regions and countries ....................................................................... 29 
5.2 Schedule of study assessments ......................................................................................... 29 
5.3 Schematic diagram ........................................................................................................... 35 
5.4 Rationale for study design and selection of dose ............................................................. 36 
5.4.1 
Study design ......................................................................................................... 36 
5.4.2 
Dose selection ...................................................................................................... 36 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 36 
6.1 Inclusion criteria .............................................................................................................. 36 
6.2 Exclusion criteria ............................................................................................................. 38 
6.3 Withdrawal criteria .......................................................................................................... 41 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 44 
7 
STUDY TREATMENTS ................................................................................................. 45 
7.1 Description of investigational medicinal products .......................................................... 45 
7.2 Treatment(s) to be administered ...................................................................................... 45 
7.2.1 
Double-Blind Treatment Period .......................................................................... 45 
7.2.2 
Maintenance Period ............................................................................................. 46 
7.3 Packaging ......................................................................................................................... 46 
7.4 Labeling ........................................................................................................................... 46 
7.5 Handling and storage requirements.................................................................................. 46 
7.6 Drug accountability .......................................................................................................... 46 
7.7 Procedures for monitoring subject compliance ................................................................ 47 
7.8 Concomitant medications/treatments ............................................................................... 47 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 54 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 54 
7.8.3 
Nonbiologic rescue therapy ................................................................................. 54 
7.8.4 
Vaccines ............................................................................................................... 54 
7.9 Blinding ............................................................................................................................ 54 
7.9.1 
Procedures for maintaining and breaking the treatment blind ............................. 54 
7.9.1.1 
Maintenance of study treatment blind ....................................................... 54 
7.9.1.2 
Breaking the treatment blind in an emergency situation ........................... 55 
7.10 Randomization and numbering of subjects ...................................................................... 55 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 55 
8.1 Screening (Visit 1) ........................................................................................................... 56 
8.2 Baseline (Visit 2, Day 1, first dose of IMP) .................................................................... 57 
8.3 Double-Blind Treatment Period ....................................................................................... 59 
8.3.1 
Week 1 (±3 days) (Visit 3) .................................................................................. 59 
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Bimekizumab 
AS0011 
 
 
 
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8.3.2 
Week 2 (±3 days) (Visit 4) .................................................................................. 59 
8.3.3 
Week 4 (±3 days) (Visit 5) .................................................................................. 59 
8.3.4 
Week 8 (±3 days) (Visit 6) .................................................................................. 60 
8.3.5 
Week 12 (±3 days) (Visit 7) ................................................................................ 61 
8.3.6 
Week 16 (±3 days) (Visit 8) ................................................................................ 61 
8.4 Maintenance Period ......................................................................................................... 63 
8.4.1 
Week 20 (±4 days) (Visit 9) ................................................................................ 63 
8.4.2 
Week 24 (±4 days) (Visit 10) .............................................................................. 63 
8.4.3 
Week 28 (±4 days) (Visit 11) .............................................................................. 64 
8.4.4 
Week 32 (±4 days) (Visit 12) .............................................................................. 64 
8.4.5 
Week 36 (±4 days) (Visit 13) .............................................................................. 65 
8.4.6 
Week 40 (±4 days) (Visit 14) .............................................................................. 66 
8.4.7 
Week 44 (±4 days) (Visit 15) .............................................................................. 66 
8.4.8 
Week 48 (±4 days) (Visit 16) .............................................................................. 66 
8.4.9 
Week 52 (±4 days) (Visit 17) .............................................................................. 67 
8.5 Early Termination Visit (if applicable) ............................................................................ 68 
8.6 Safety Follow-Up Visit (-3 days/+7 days) ....................................................................... 69 
8.7 Unscheduled Visit ............................................................................................................ 69 
9 
ASSESSMENT OF EFFICACY ...................................................................................... 70 
9.1 ASAS20, 40, ASAS 5/6 response, and ASAS-PR ........................................................... 70 
9.2 ASQoL ............................................................................................................................. 71 
9.3 Inflammation – BASDAI (mean of Questions 5 and 6) .................................................. 71 
9.4 BASDAI ........................................................................................................................... 71 
9.5 Physical function – BASFI .............................................................................................. 72 
9.6 SF-36 72 
9.7 MOS-12 ............................................................................................................................ 73 
9.8 PGADA ............................................................................................................................ 73 
9.9 Total and nocturnal spinal pain ........................................................................................ 73 
9.10 FACIT-Fatigue subscale .................................................................................................. 73 
9.11 EQ-5D-3L ........................................................................................................................ 73 
9.12 TJC and SJC (44/44) ........................................................................................................ 74 
9.13 WPAI-SHP v2.0 ............................................................................................................... 74 
9.14 CRP 74 
9.15 ASDAS ............................................................................................................................ 75 
9.16 MASES ............................................................................................................................ 75 
9.17 BASMI ............................................................................................................................. 75 
9.18 PhGADA .......................................................................................................................... 76 
9.19 Occurrence of extra-articular manifestations ................................................................... 76 
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Bimekizumab 
AS0011 
 
 
 
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9.20 Imaging evaluation ........................................................................................................... 76 
9.20.1 
Sacroiliac joint x-ray (AP Pelvis Joint Film for modified New York Criteria) ... 76 
9.20.2 
Spine x-ray ........................................................................................................... 77 
9.20.3 
Sacroiliac joint and spine MRI assessment substudy .......................................... 77 
10 ASSESSMENT OF PHARMACOKINETIC AND PHARMACOGENOMIC 
VARIABLES ................................................................................................................... 78 
10.1 Pharmacokinetic variables ............................................................................................... 78 
10.2 Pharmacogenomic variables ............................................................................................ 79 
11 ASSESSMENT OF IMMUNOLOGICAL VARIABLES ............................................... 79 
12 ASSESSMENT OF SAFETY .......................................................................................... 80 
12.1 Adverse events ................................................................................................................. 80 
12.1.1 
Definitions ........................................................................................................... 80 
12.1.1.1 
Adverse event ............................................................................................ 80 
12.1.1.2 
Serious adverse event ................................................................................ 80 
12.1.1.3 
Adverse events of special interest ............................................................. 82 
12.1.1.4 
Other safety topics of interest .................................................................... 83 
12.1.2 
Procedures for reporting and recording adverse events ....................................... 83 
12.1.2.1 
Description of adverse events .................................................................... 83 
12.1.2.2 
Rule for repetition of an adverse event...................................................... 83 
12.1.2.3 
Additional procedures for reporting serious adverse events ..................... 83 
12.1.3 
Follow up of adverse events ................................................................................ 84 
12.2 Pregnancy ......................................................................................................................... 84 
12.3 Suspected transmission of an infectious agent ................................................................. 85 
12.4 Overdose of investigational medicinal product ............................................................... 86 
12.5 Safety signal detection ..................................................................................................... 86 
12.6 Laboratory measurements ................................................................................................ 86 
12.6.1 
Evaluation of PDILI ............................................................................................ 88 
12.6.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 92 
12.6.1.2 
Immediate action: determination of IMP discontinuation ......................... 92 
12.6.1.3 
Testing: identification/exclusion of alternative etiology ........................... 93 
12.6.1.4 
Follow-up evaluation ................................................................................. 95 
12.7 Other safety measurements .............................................................................................. 95 
12.7.1 
Vital signs ............................................................................................................ 95 
12.7.2 
Body weight and height ....................................................................................... 96 
12.7.3 
Physical examination ........................................................................................... 96 
12.7.4 
12-lead electrocardiogram ................................................................................... 96 
12.7.5 
Assessment and management of TB and TB risk factors .................................... 96 
12.7.5.1 
Tuberculosis assessment by IGRA .......................................................... 100 
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Bimekizumab 
AS0011 
 
 
 
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12.7.5.2 
Chest x-ray for tuberculosis .................................................................... 100 
12.7.5.3 
Tuberculosis questionnaire ...................................................................... 100 
12.7.5.4 
Tuberculosis management ....................................................................... 100 
12.7.6 
Pregnancy testing ............................................................................................... 101 
12.7.7 
PHQ-9 ................................................................................................................ 101 
12.7.8 
Assessment of suicidal ideation and behavior ................................................... 101 
13 OTHER STUDY MEASUREMENTS .......................................................................... 102 
13.1 Demography ................................................................................................................... 102 
13.2 Medical and ankylosing spondylitis history .................................................................. 102 
13.3 Prior and concomitant medications ................................................................................ 102 
14 STUDY MANAGEMENT AND ADMINISTRATION ............................................... 102 
14.1 Adherence to protocol .................................................................................................... 102 
14.2 Monitoring ..................................................................................................................... 102 
14.2.1 
Definition of source data ................................................................................... 103 
14.2.2 
Source data verification ..................................................................................... 103 
14.3 Data handling ................................................................................................................. 104 
14.3.1 
Case Report Form completion ........................................................................... 104 
14.3.2 
Database entry and reconciliation ...................................................................... 104 
14.3.3 
Subject Screening and Enrollment log/Subject Identification Code list............ 104 
14.4 Termination of the study ................................................................................................ 104 
14.5 Archiving and data retention .......................................................................................... 105 
14.6 Audit and inspection ...................................................................................................... 105 
14.7 Good Clinical Practice ................................................................................................... 105 
15 STATISTICS ................................................................................................................. 106 
15.1 Definition of analysis sets .............................................................................................. 106 
15.2 General statistical considerations ................................................................................... 106 
15.3 Planned efficacy analyses .............................................................................................. 107 
15.3.1 
Analysis of the primary and secondary efficacy variables ................................ 107 
15.3.1.1 
Analysis of the primary efficacy variable ............................................... 108 
15.3.1.2 
Analyses of the secondary efficacy variables .......................................... 110 
15.3.2 
Analyses of other efficacy variables .................................................................. 111 
15.3.3 
Subgroup analyses ............................................................................................. 112 
15.4 Planned safety analyses .................................................................................................. 112 
15.4.1 
Safety analyses ................................................................................................... 112 
15.5 Planned other analyses ................................................................................................... 113 
15.5.1 
Pharmacokinetic analyses .................................................................................. 113 
15.5.2 
Immunological analyses .................................................................................... 113 
15.6 Handling of protocol deviations ..................................................................................... 113 
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Clinical Study Protocol 
Bimekizumab 
AS0011 
 
 
 
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15.7 Handling of dropouts or missing data ............................................................................ 113 
15.8 Planned interim analysis and data monitoring ............................................................... 114 
15.8.1 
Interim analyses ................................................................................................. 114 
15.8.2 
Data monitoring and Adjudication Committees ................................................ 115 
15.9 Determination of sample size ......................................................................................... 115 
15.9.1 
Power calculation for primary endpoint ............................................................ 115 
15.9.2 
Power calculations for secondary endpoints in the hierarchical testing ............ 116 
16 ETHICS AND REGULATORY REQUIREMENTS .................................................... 117 
16.1 Informed consent ........................................................................................................... 117 
16.2 Subject identification cards ............................................................................................ 118 
16.3 Institutional Review Boards and Independent Ethics Committees ................................ 118 
16.4 Subject privacy ............................................................................................................... 119 
16.5 Protocol amendments ..................................................................................................... 119 
17 FINANCE, INSURANCE, AND PUBLICATION ....................................................... 119 
18 REFERENCES .............................................................................................................. 120 
19 APPENDICES ............................................................................................................... 125 
19.1 ASAS classification criteria for axial SpA .................................................................... 125 
19.2 Modified New York (mNY) Classification Criteria for AS .......................................... 126 
19.3 Protocol Amendment 1 .................................................................................................. 127 
19.4 Protocol Amendment 2 .................................................................................................. 161 
19.5 Protocol Amendment 3 .................................................................................................. 163 
19.6 Protocol Amendment 4 .................................................................................................. 164 
20 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 186 
21 SPONSOR DECLARATION ........................................................................................ 187 
 
LIST OF TABLES 
Table 5‒1: 
Cross-study screening requirements ................................................................ 27 
Table 5-2: 
Schedule of study assessments......................................................................... 30 
Table 7‒1: 
Overview on dosing during the Double-Blind Treatment Period .................... 45 
Table 7‒2: 
Exclusionary, concomitant, and rescue medication ......................................... 48 
Table 9‒1: 
Tenderness and swelling grading ..................................................................... 74 
Table 12‒1: 
Anticipated serious adverse events for the population of subjects with AS .... 82 
Table 12‒2: 
Laboratory measurements ................................................................................ 87 
Table 12‒3: 
Required investigations and follow-up for PDILI ........................................... 89 
Table 12‒4: 
PDILI laboratory measurements ...................................................................... 94 
Table 12‒5: 
PDILI information to be collected ................................................................... 95 
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Clinical Study Protocol 
Bimekizumab 
AS0011 
 
 
 
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Table 19‒1: 
ASAS classification criteria for axial SpA (for subjects with chronic back 
pain of at least 3 months and age at onset <45 years) .................................... 125 
Table 19‒2: 
Modified New York (mNY) Classification Criteria for AS .......................... 126 
 
LIST OF FIGURES 
Figure 5‒1: 
Schematic diagram: study overview ................................................................ 35 
Figure 12‒1: Schematic diagram of TB test results and study eligibility ............................. 98 
Figure 12‒2: Schematic diagram of TB test results during the study ................................... 99 
Figure 15‒1: Sequential testing procedure of primary/secondary efficacy endpoints ........ 108 
 
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Clinical Study Protocol 
Bimekizumab 
AS0011 
 
 
 
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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AP 
Anterior Posterior 
AS 
ankylosing spondylitis 
ASAS 
Assessment of SpondyloArthritis International Society 
ASAS20, 40, 5/6 
Assessment of SpondyloArthritis International Society 20%, 40%, 5 out of 6 
response criteria 
ASAS-PR 
Assessment of SpondyloArthritis International Society partial remission 
ASDAS-CRP 
Ankylosing Spondylitis Disease Activity Score-C-reactive protein 
ASDAS-MI 
Ankylosing Spondylitis Disease Activity Score major improvement 
ASspiMRI-a 
Ankylosing Spondylitis spine Magnetic Resonance Imagine-activity 
ASQoL 
Ankylosing Spondylitis Quality of Life 
AST 
aspartate aminotransferase 
axSpA 
axial spondyloarthritis 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index 
BASFI 
Bath Ankylosing Spondylitis Functional Index 
BASMI 
Bath Ankylosing Spondylitis Metrology Index 
BP 
blood pressure 
CAT 
Computed Axial Tomography 
CDC  
Centers for Disease Control  
CDMS 
clinical data management system 
CHO 
Chinese Hamster Ovarian 
CI 
confidence interval 
CMV 
cytomegaly virus 
COVID-19 
coronavirus disease 2019 
COX-2 inhibitor 
cyclooxygenase 2 inhibitor 
CPM 
Clinical Project Manager 
CPMP 
Committee for Proprietary Medicinal Products 
CRO 
contract research organization 
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Bimekizumab 
AS0011 
 
 
 
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CRP 
C-reactive protein 
eC-SSRS 
electronic Columbia-Suicide Severity Rating Scale 
CZP 
certolizumab pegol 
DMARD 
disease-modifying antirheumatic drug 
DMC 
Data Monitoring Committee 
DVU 
disco-vertebral unit 
EAM 
extra-articular manifestation 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ePRO 
electronic Patient-Reported Outcomes 
EDC 
electronic data capture 
EQ-5D-3L 
European Qol-5 Dimensions 3-Level 
ES 
Enrolled Set 
ET 
Early Termination 
EULAR 
European League Against Rheumatism 
FACIT 
Functional assessment of chronic illness therapy 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GMP 
Good Manufacturing practice 
HbcAb  
hepatitis B core antibody 
HbsAg  
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCQ 
hydroxychloroquine 
HCV 
hepatitis C virus 
HD 
high disease 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HRQoL 
health-related quality of life 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
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Bimekizumab 
AS0011 
 
 
 
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ID 
inactive disease 
IEC 
Independent Ethics Committee 
IGRA 
Interferon-Gamma Release Assay 
IL 
interleukin 
im 
intramuscular 
IMP 
investigational medicinal product 
IMS 
International Menopause Society 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
iv 
intravenous 
IXRS 
interactive voice or web response system  
LEF 
leflunomide 
LD 
low disease 
LTB 
latent tuberculosis 
LTBI 
latent tuberculosis infection  
MAR 
missing at random 
MASES 
Maastricht Ankylosing Spondylitis Enthesitis Index 
MCID 
minimal clinically important difference 
MCMC 
Markov-Chain Monte Carlo 
MCP 
metacarpophalangeals 
MCS 
mental component summary 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MNAR 
missing not at random 
mNY 
Modified New York (criteria) 
MOS 
Medical Outcomes Study 
MRI 
magnetic resonance imaging 
MTX 
methotrexate 
nr-axSpA 
nonradiographic axial spondyloarthritis 
NRI 
nonresponder imputation 
NRS 
Numeric Rating Scale 
NSAID 
nonsteroidal anti-inflammatory drug 
NTMB 
nontuberculous mycobacteria 
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Bimekizumab 
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OC 
observed cases 
OMERACT 
Outcome Measures in Rheumatology Clinical Trials 
PASI  
Psoriasis Area and Severity Index  
PCS 
physical component summary 
PD 
pharmacodynamics 
PDILI 
potential drug-induced liver injury 
PFS 
prefilled syringe 
PGADA 
Patient’s Global Assessment of Disease Activity 
PhGADA 
Physician’s Global Assessment of Disease Activity 
PHQ-9 
Patient Health Questionnaire 9 
PIP 
proximal interphalangeal 
PK 
pharmacokinetics 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PPS 
Per-Protocol Set 
PRN 
as needed 
PS 
Patient Safety 
PsA 
psoriatic arthritis 
PSO 
psoriasis 
Q4W 
every 4 weeks  
r-axSpA 
radiographic axSpA 
RA 
rheumatoid arthritis 
RNA 
ribonucleic acid 
RS 
Randomized Set 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
subcutaneous(ly) 
SD 
standard deviation 
SF-36 
Short-Form 36-item Health Survey 
SFU 
Safety Follow-Up 
SJC 
swollen joint count 
SpA 
spondyloarthritis 
SPARCC 
Spondyloarthritis Research Consortium of Canada 
SPARTAN 
Spondyloarthritis Research and Treatment Network 
SS 
Safety Set 
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Bimekizumab 
AS0011 
 
 
 
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SSZ 
sulfasalazine 
STIR 
short-tau-inversion recovery 
t½ 
half-life 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TJC 
tender joint count 
TNFα 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
VAS 
visual analog scale 
vHD 
very high disease 
WHO 
World Health Organization 
WPAI-SHP 
Work Productivity and Activity Impairment Questionnaire-specific health 
problem 
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1 
SUMMARY 
This is a multicenter, Phase 3, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of bimekizumab in subjects with active ankylosing spondylitis (AS), a 
subtype of axial spondyloarthritis (axSpA) with radiographic evidence of disease (also known as 
radiographic axSpA [r-axSpA]). To be eligible to participate in this study, subjects must be 
adults with a diagnosis of active AS, determined by documented radiologic evidence (x-ray) 
fulfilling the Modified New York (mNY) criteria for AS (1984) (Section 19.2), including at least 
3 months of symptoms and age at symptom onset <45 years, and moderate-to-severe active 
disease at Baseline as defined by both of the following: 
• Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 AND spinal pain ≥4 on a 
0 to 10 numeric rating scale (NRS) (from BASDAI Item 2). 
As bimekizumab will be evaluated in axSpA, UCB will also perform a randomized, 
double-blind, placebo-controlled Phase 3 study (AS0010) in subjects with nonradiographic axial 
spondyloarthritis (nr-axSpA) in parallel to the present study in AS (AS0011).  
The primary objective of AS0011 is to demonstrate the efficacy of bimekizumab administered 
subcutaneously (sc) every 4 weeks (Q4W) compared with placebo in the treatment of subjects 
with active AS. The secondary objectives of the study are listed in Section 3.2, and other 
objectives are listed in Section 3.3.  
The primary efficacy variable for this study is the Assessment of SpondyloArthritis International 
Society 40% response criteria (ASAS 40) response at Week 16. The secondary and other 
efficacy variables are listed in Section 4.2.1 and Section 4.3.1, respectively. 
Safety variables are listed in Section 4.2.2 (secondary safety variables) and Section 4.3.2 (other 
safety variables). The pharmacokinetic (PK), pharmacogenomic, and immunological variables 
are listed in Section 4.3.3, Section 4.3.4, and Section 4.3.5 respectively. 
AS0011 will evaluate the efficacy, safety, and PK of bimekizumab in adult subjects with 
active AS at a dose level of bimekizumab 160mg Q4W administered by sc injection.  
The overall study design consists of a Screening Period (minimum of approximately 14 days 
[unless a screenfailed subject from AS0010 will be screened in AS0011] to ≤35 days), a 52-week 
Treatment Period consisting of a 16-week Double-Blind Treatment Period, a 36-week 
Maintenance Period, and a Safety Follow-Up (SFU) Visit 20 weeks after the final dose of the 
investigational medicinal product (IMP) (ie, Week 48 for subjects who completed AS0011; for 
subjects not entering the extension study or who discontinue early, including those withdrawn 
from study treatment). The maximum study duration per subject will be 73 weeks.  
Approximately 300 subjects will be randomly assigned in a 2:1 ratio to the following treatment 
groups: bimekizumab 160mg sc Q4W (200 subjects) or placebo (100 subjects). Subjects 
receiving placebo during the Double-Blind Treatment Period will be re-allocated to 
bimekizumab treatment at Week 16 after all study assessments have been completed. These 
subjects will receive bimekizumab 160mg sc at Week 16 and Q4W thereafter (Section 7.2).  
A detailed schedule of study assessments is presented in Table 5-2 and a study schematic 
diagram is presented in Figure 5‒1. 
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Nonbiologic rescue therapy will be at the Investigator’s discretion as add-on therapy to 
bimekizumab at any time from Week 20 or later. Details are provided in Table 7‒2. 
Subjects completing Week 52 who meet the eligibility criteria may be enrolled in an extension 
study to continue to receive bimekizumab treatment.  
2 
INTRODUCTION 
2.1 
Axial spondyloarthritis 
Spondyloarthritis (SpA) is an umbrella term applied to a family of rheumatic diseases (including 
axial spondyloarthritis [axSpA], psoriatic arthritis [PsA], reactive arthritis, the arthritis of 
inflammatory bowel disease [IBD], and undifferentiated SpA) that have features in common with 
each other and distinct from other inflammatory arthritides, particularly rheumatoid arthritis 
(RA).  
The ASAS working group established classification criteria to distinguish 2 broad categories of 
SpA: peripheral SpA and axSpA (Rudwaleit et al, 2011; Rudwaleit, 2010; Rudwaleit et al, 
2009b). This division is based on the body part predominantly involved in the inflammatory 
process. Therefore, peripheral SpA includes diseases affecting mainly peripheral joints, such as 
reactive arthritis and PsA, whereas axSpA comprises those diseases with mainly axial 
involvement (sacroiliac joints and spine), including AS (also known as r-axSpA) diagnosed with 
definite radiographic changes of the sacroiliac joint and nr-axSpA.  
Patients with axSpA have inflammatory back pain. The disease typically originates in the 
sacroiliac joints, then progresses to the spine. In the sacroiliac joints and the spine, active 
inflammation results in erosions, sclerosis, and fatty lesions seen on magnetic resonance imaging 
(MRI). However, the most characteristic feature is new bone formation leading to ankylosis of 
the sacroiliac joints and syndesmophytes attached to the vertebral bodies. As a result of extended 
syndesmophyte formation, over time the spine may become fused (bamboo spine). Objective 
signs of inflammation (such as enthesitis, dactylitis, peripheral arthritis, or uveitis), genetic 
features (such as the presence of human leukocyte antigen [HLA] B27), and laboratory 
parameters (such as elevated C-reactive protein [CRP]) may also be present (Braun, 2012; 
Rudwaleit et al, 2009a; Braun and Sieper, 2007). Disability in axSpA is related to both the 
degree of inflammatory activity, causing pain, stiffness, fatigue, and poor quality of sleep, and to 
the degree of bony ankylosis, causing loss of spinal mobility. Patients with AS show 
radiographic progression of disease with x-ray identified sacroiliitis, while "bamboo spine" may 
develop when the outer fibers of the fibrous ring of the intervertebral discs ossify, which results 
in the formation of marginal syndesmophytes between adjoining vertebrae. 
2.1.1 
axSpA epidemiology  
Axial SpA is a chronic inflammatory disease that impacts a substantial proportion of the 
population. Limited evidence exists regarding the global occurrence of axSpA with a prevalence 
of 0.20 to 0.25% in Europe and North America, and a wider range in Asia (0.06 to 0.20%) 
(Stolwijk et al, 2016); however, recent data suggest that the prevalence is similar to that of RA in 
the US (axSpA: 0.7% to 1.4%; RA: 0.5% to 1.0%) (Reveille et al, 2012; Myasoedova et al, 2010; 
Helmick et al, 2008). Axial SpA comprises those diseases with mainly axial involvement 
(sacroiliac joints and spine), including AS and nr-axSpA. 
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2.1.2 
Current treatments for axSpA 
Nonsteroidal anti-inflammatory drugs are used as first-line treatment and are effective for the 
symptoms (pain and stiffness) of axSpA (van der Heijde et al, 2017; Ward et al, 2015; 
Poddubnyy, 2013; Poddubnyy et al, 2012), but many patients lose or never have clinically 
meaningful response and structural damage often progresses despite their use. Conventional 
disease-modifying antirheumatic drugs (DMARDs, eg, methotrexate [MTX] and sulfasalazine 
[SSZ]) have no proven efficacy in axial disease, but may benefit patients with peripheral joint 
disease (Haibel et al, 2007; Braun et al, 2006; Haibel et al, 2005). Therefore, DMARDs are 
recommended only in patients with predominantly peripheral manifestations (Braun et al, 2011). 
Patients who are intolerant of or have inadequately responded to NSAIDs, or those in whom 
NSAIDs are contraindicated, have approved treatment options such as tumor necrosis factor 
alpha (TNFα) inhibitors (van der Heijde, 2017; Ward et al, 2015).  
Recently, the interleukin (IL)-17 cytokine family has been identified as a therapeutic target in 
axSpA and secukinumab, an IL-17A monoclonal antibody, has recently been approved as a 
treatment option in active AS. 
2.2 
Bimekizumab 
Bimekizumab (UCB4940) is an engineered, humanized full-length monoclonal antibody of IgG1 
subclass of approximately 150,000 Dalton, which is expressed in a genetically engineered 
Chinese Hamster Ovarian (CHO) cell line. Bimekizumab has high affinity for human IL-17A 
and human IL-17F and selectively and potently inhibits the activity of both isoforms in vitro. 
Interleukin-17A and IL-17F are key proinflammatory cytokines believed to play important roles 
in autoimmune and inflammatory diseases. Therefore, bimekizumab permits an evaluation of the 
potential for additional efficacy, which may be conferred by dual inhibition of both cytokines, in 
patients suffering from diseases in which both cytokines are active. Bimekizumab is being 
developed for the treatment of patients with inflammatory diseases such as PsA, psoriasis (PSO), 
axSpA and hidradenitis suppurativa.  
2.2.1 
Nonclinical 
There is increasing evidence of the role of IL-17F in various inflammatory diseases. 
Simultaneous inhibition of IL-17A and IL-17F has been shown to be more efficacious than 
inhibition of IL-17A alone in in vitro models. Intravenously or sc administered bimekizumab 
was well tolerated in repeat-dose toxicology studies in Cynomolgus monkeys with dosing up to 
200mg/kg/week for up to 26 weeks. The findings of note varied from study to study, but were all 
compatible with decreased muco-epidermal immunity induced by the inhibition of IL-17A and F 
signaling. They consisted in diarrhea related to infectious enteritis, asymptomatic proliferation of 
a protozoan commonly found in the cynomolgus monkey, Balantidium coli, superficial 
dermatitis associated with increased bacterial load on the skin (mainly Gram positive cocci, 
including Staphylococcus aureus), and abscesses.  
Infection-related safety findings in a nonhuman primate can be highly variable from study to 
study and have limited ability to accurately predict the incidence and type of infection that can be 
expected in humans, especially because nonhuman primates bear different commensal flora and 
show different sensitivity to different pathogens. Immunomodulators can increase the 
susceptibility of monkeys to potential pathogens that are endemic in nonhuman primate 
populations and usually remain clinically undetectable or are mild and self-limiting in 
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immunocompetent animals. Moreover, infections associated with the gastrointestinal (GI) tract 
that result in chronic enterocolitis are a persistent and widespread colony problem in nonhuman 
primates, often multifactorial in origin.  
The nonclinical studies have highlighted the already known risk of infection linked to decreased 
muco-epidermal immunity that needs to be carefully monitored in the clinic, but are unlikely to 
predict the risk of infection in humans based on dose and exposure for the aforementioned 
reasons. To date, similar findings have not been seen in studies in humans. 
Preliminary results from the embryofetal and postnatal study conducted in the Cynomolgus 
monkey indicate no effects of bimekizumab on the gestation, gestation duration, or the 
parturition of pregnant females. No bimekizumab-related effects were noted in infants at birth, 
during postnatal development, or on infant survival rate. Toxicokinetic data confirmed 
dose-related exposure of maternal animals during the pregnancy and the lactation phase, and of 
infants at birth and during the postnatal phase. 
Additional information on the nonclinical data for bimekizumab is available in the current 
version of the Investigator’s Brochure (IB). 
2.2.2 
Clinical  
2.2.2.1 
Completed studies 
Twenty clinical studies of bimekizumab have been completed: UP0008 in 39 subjects with 
mild-to-moderate plaque PSO, RA0124 in 30 healthy volunteers, PA0007 in 53 subjects with 
PsA, UP0031 in 12 healthy volunteers, UP0033 in 189 healthy volunteers, UP0034 in 56 healthy 
volunteers, UP0042 in 48 Japanese and Caucasian healthy volunteers, UP0074 in 37 healthy 
volunteers, RA0123 in 159 subjects with moderate-to-severe RA, PS0010 in 250 subjects with 
moderate-to-severe chronic plaque PSO and the corresponding extension study (PS0011), 
PS0016 in 49 subjects with moderate-to-severe chronic plaque PSO and the corresponding 
extension study (PS0018), UC0011 in 23 subjects with moderate-to-severe active ulcerative 
colitis, HS0001 in 90 subjects with moderate to severe hidradenitis suppurativa, AS0008 in 
303 subjects with AS, PA0008 in 206 subjects with PsA, PS0008 in 478 subjects with moderate 
to severe chronic plaque PSO, PS0009 in 567 subjects with moderate to severe chronic plaque 
PSO and PS0013 in 435 subjects with moderate to severe chronic plaque PSO. 
Information on the clinical data for bimekizumab from completed studies is available in the 
current version of the IB. 
2.2.2.2 
Ongoing studies 
Several additional studies of bimekizumab in subjects with axSpA are ongoing:  
• AS0009 is an open-label extension study for AS0008. 
• AS0013 is a Phase 2a Investigator- and subject-blind parallel-group study to evaluate the 
efficacy and safety of bimekizumab and certolizumab pegol (CZP) in subjects with active 
AS.  
• AS0010 is a Phase 3, double-blind, randomized, placebo-controlled study to evaluate the 
efficacy and safety of bimekizumab in subjects with active nr-axSpA. 
• AS0014 is a Phase 3, open-label extension study for AS0010 and AS0011. 
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Bimekizumab is also being evaluated in the treatment of other indications (eg, PsA, PSO, 
hidradenitis suppurativa).  
Additional information on the ongoing studies for bimekizumab is available in the current 
version of the IB. 
3 
STUDY OBJECTIVE(S) 
3.1 
Primary objective 
The primary objective is to demonstrate the efficacy of bimekizumab administered sc Q4W 
compared to placebo in the treatment of subjects with active AS. 
3.2 
Secondary objectives 
The secondary objectives of the study are as follows: 
• To assess the efficacy of bimekizumab compared to placebo  
• To assess the safety and tolerability of bimekizumab 
• To assess the impact of bimekizumab on patient-reported quality of life  
• To assess the impact of bimekizumab on spinal mobility  
• To assess the impact of bimekizumab on enthesitis and on peripheral arthritis 
3.3 
Other objectives 
The other objectives are as follows: 
• To assess the immunogenicity of bimekizumab 
• To assess the pharmacokinetics of bimekizumab  
• To assess the maintenance of efficacy of bimekizumab 
• To assess the relationship between exploratory biomarkers, drug treatment, and AS disease 
biology 
• To assess the impact of bimekizumab on work productivity  
• To assess the impact of bimekizumab on inflammatory changes using MRI  
4 
STUDY VARIABLES 
4.1 
Primary variable 
4.1.1 
Primary efficacy variable 
The primary efficacy variable for this study is: 
• ASAS40 response at Week 16.  
4.2 
Secondary variables 
4.2.1 
Secondary efficacy variables 
The secondary efficacy variables for this study are as follows:  
• ASAS40 response at Week 16 in TNFα inhibitor-naïve subjects 
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• ASAS20 response at Week 16 
• Change from Baseline in BASDAI total score at Week 16  
• ASAS partial remission (ASAS-PR) at Week 16 
• Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI) at 
Week 16  
• ASAS5/6 response at Week 16 
• Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 16  
• Change from Baseline in nocturnal spinal pain score (NRS) at Week 16 
• Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) total score at 
Week 16  
• Change from Baseline in the Short Form 36-Item Health Survey (SF-36) physical component 
summary (PCS) score at Week 16  
• Change from Baseline in Bath Ankylosing Spondylitis Disease Metrology Index (BASMI) at 
Week 16 
• Change from Baseline in the Maastricht Ankylosing Spondylitis Enthesitis (MASES) Index 
in the subgroup of subjects with enthesitis at Baseline at Week 16 
• Enthesitis-free state based on the MASES Index in the subgroup of subjects with enthesitis at 
Baseline at Week 16 
4.2.2 
Secondary safety variables 
Assessment time points for safety variables are specified in Table 5-2. Variables are as follows: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of treatment-emergent serious adverse events (SAEs) 
• TEAEs leading to withdrawal from IMP 
4.3 
Other variables 
4.3.1 
Other efficacy variables 
Other efficacy variables will be assessed as specified in Table 5-2. All time points not specified 
in Section 4.1.1 or Section 4.2.1 are exploratory:  
• ASAS40 response  
• Time to ASAS40 response  
• ASAS20 response  
• Time to ASAS20 response 
• ASAS5/6 response  
• ASAS-PR  
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• Change from Baseline in Ankylosing Spondylitis Disease Activity Score C-reactive protein 
(ASDAS-CRP)  
• ASDAS status (eg, inactive disease [ID], low disease [LD], high disease [HD], and very high 
disease [vHD])  
• ASDAS-MI  
• Change from Baseline in BASDAI total score  
• BASDAI50 response 
• Change from Baseline in BASFI  
• Change from Baseline in the MASES Index in the subgroup of subjects with enthesitis at 
Baseline  
• Enthesitis-free state based on the MASES in the subgroup of subjects with enthesitis at 
Baseline 
• Change from Baseline in BASMI  
• Change from Baseline in Physician’s Global Assessment of Disease Activity (PhGADA)  
• Change from Baseline in Patient’s Global Assessment of Disease Activity (PGADA)  
• Change from Baseline in total and nocturnal spinal pain score (NRS)  
• Change from Baseline in the average score of Questions 5 and 6 of the BASDAI concerning 
morning stiffness  
• Change from Baseline in CRP  
• Responses to the European Qol-5 Dimensions 3-Level (EQ-5D-3L)  
• Change from Baseline in EQ-5D-3L visual analog scale (VAS) scores  
• Change from Baseline in the EQ-5D utility score  
• Change from Baseline in the SF-36 PCS score 
• Change from Baseline in the SF-36 mental component summary (MCS) score 
• Change from Baseline in sleep quality score (Medical Outcomes Study [MOS 12-item] scale)  
• Change from Baseline in Functional Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue subscale score 
• Change from Baseline in ASQoL total score  
• Change from Baseline in the Work Productivity and Activity Impairment 
Questionnaire- specific health problem (WPAI-SHP)  
• Change from Baseline in (44/44) tender joint count (TJC) and swollen joint count (SJC) 
• Change from Baseline in Ankylosing Spondylitis spine MRI-activity (ASspiMRI-a) in the 
Berlin modification score  
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• Change from Baseline in sacroiliac joint Spondyloarthritis Research Consortium of Canada 
(SPARCC) score  
4.3.2 
Other safety variables 
Other safety variables to be assessed as specified in Table 5-2 are as follows: 
• Change from Baseline in vital signs (blood pressure [BP], temperature, and pulse rate)  
• Standard 12-lead electrocardiogram (ECG) results  
• Change from Baseline in clinical laboratory values (hematology, biochemistry, and 
urinalysis) 
• Change from Baseline in Patient Health Questionnaire-9 (PHQ-9) 
Physical examination findings considered clinically significant changes since the physical 
examination at the Screening Visit will be recorded as adverse events (AEs). 
4.3.3 
Pharmacokinetic variable 
The PK variable is the plasma concentration of bimekizumab.  
4.3.4 
Pharmacogenomic variables 
Additional blood and stool samples will be collected from subjects who consent to participate in 
the substudy at specific time points specified in Table 5-2. 
Genomic, genetic, epigenetic, proteins, and metabolite biomarkers may be measured to evaluate 
the relationship with response to treatment with bimekizumab, axSpA disease biology, bone 
metabolism, and inflammatory and immune response processes. The nature and format of these 
tentative substudy analyses will be determined at a later time.  
Additional candidate serum exploratory variables may include, but are not limited to the blood 
concentrations of cytokines and chemokines of relevance to the IL-17A/F signaling pathway and 
axSpA biology, and serum complement concentrations. Stool samples will be collected from 
subjects who consent to participate in the pharmacogenomics substudy at specific time points 
specified in Table 5-2. These samples may be used to assess biomarkers of gut inflammation 
including but not limited to calprotectin and microbiome testing. 
4.3.5 
Immunological variables 
The immunological variables are the anti-bimekizumab antibody status and the 
treatment-emergent antibody positivity derived from anti-drug antibody assays. 
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5 
STUDY DESIGN 
5.1 
Study description 
This is a multicenter, Phase 3, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of bimekizumab in subjects with active AS. To be eligible to participate 
in this study, subjects must meet the following key inclusion criteria:  
• Adult subjects with active AS, determined by documented radiologic evidence (x-ray) 
fulfilling the Modified New York criteria for AS (1984) (Section 19.2), including at least 
3 months of symptoms.  
• Age at symptom onset <45 years  
• Subject must have moderate-to-severe active disease as defined by BOTH of the following at 
Screening AND Baseline.  
− BASDAI ≥4 AND spinal pain ≥4 on a 0 to 10 NRS (from BASDAI Item 2)  
Detailed eligibility criteria are presented in Section 6.1 and Section 6.2.  
The study will include the following 3 periods: a Screening Period (minimum of approximately 
14 days [unless a screenfailed subject from AS0010 will be screened in AS0011] to ≤35 days), a 
Treatment Period (52 weeks) consisting of a 16-week Double-Blind Treatment Period and a 
36-week Maintenance Period, and a SFU Period (20 weeks after the final dose of IMP). 
Eligible subjects will be randomized 2:1 to receive 1 of 2 treatments (bimekizumab 
160mg sc Q4W or placebo sc Q4W), and will remain on their allowable background medication. 
Details of the Treatment Period are provided in Section 5.1.2. At the end of the 16-week 
Double-Blind Treatment Period subjects receiving placebo will be re-allocated to bimekizumab 
treatment at Week 16 after all assessments have been completed. These subjects will receive 
bimekizumab 160mg sc at Week 16 and 160mg sc Q4W thereafter. Starting at Week 20, 
nonbiologic rescue therapy for axial SpA may be adjusted or added, while continuing 
bimekizumab as outlined in Table 7‒2. 
Subjects completing Week 52 who are not withdrawn from IMP, may be eligible for enrollment 
in an extension study with bimekizumab. Subjects who are ineligible for or elect not to 
participate in the extension study at Week 52 will undergo a SFU Visit. 
Interim analyses of all available data (including efficacy, safety, and PK) will be conducted after 
the planned number of randomized subjects have completed 24 weeks and 52 weeks of treatment 
or have withdrawn from IMP or the study. Details of the interim analyses are given in 
Section 15.8.1. The final analysis of all available data will be performed after all randomized 
subjects have completed the SFU Visit or have withdrawn from the IMP and/or study.  
A detailed schedule of study assessments is presented in Table 5-2 and a study schematic 
diagram is presented in Figure 5‒1.  
5.1.1 
Screening Period/Baseline 
Assessments of eligibility as described in Section 6 will be initiated during the Screening Period 
with a minimum duration of approximately 14 days (unless a screenfailed subject from AS0010 
will be screened in AS0011) and a maximum duration of up to 35 days. The Screening Period 
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will also enable the washout of medications not permitted for use during the study, allow 
initiation of latent TB treatment where necessary, and allow completion of imaging assessments 
required to determine eligibility including time for central reading.  
All subjects will have an anterior posterior (AP) pelvis or sacroiliac joint x-ray (read centrally) to 
determine eligibility as per mNY criteria. Subjects who are mNY-negative may be eligible for 
Screening in AS0010, a double-blind, randomized, placebo-controlled Phase 3 study in subjects 
with active nr-axSpA. It is recommended to perform the sacroiliac joint x-ray prior to any other 
screening assessment to avoid repetition of screening assessments (applicable at sites 
participating in both Phase 3 studies). 
5.1.1.1 
Within-study rescreening/retesting requirements 
Rules for rescreening or repetition of screening tests within the study are listed below: 
• Subjects who fail to meet the eligibility criteria for BASDAI, spinal pain, PHQ-9, eC-SSRS, 
or the TB questionnaire are not allowed to be rescreened. 
The Medical Monitor must be contacted for confirmation of rescreening/retesting in all other 
cases. 
• Subjects who initially fail to meet selected eligibility criteria (eg, documented completion of 
latent tuberculosis infection [LTBI] prophylactic therapy) may be rescreened. 
• Subjects for whom eligibility assessments could not be completed as planned (eg, for 
technical reasons) within the defined Screening Period of 35 days may be rescreened.  
• Subjects with individual laboratory screening tests for which the results are exclusionary, can 
be retested.  
Of note, repetition of laboratory screening tests within the Screening Period is permitted for 
technical reasons (eg, frozen sample, expired laboratory kit) without contacting the Medical 
Monitor. 
5.1.1.2 
Cross-study screening requirements 
Screening assessments for subjects previously screened for AS0010, who were not eligible for 
AS0010 based on mNY criteria and therefore entered AS0011 Screening for eligibility, must be 
repeated during the Screening Period unless defined in Table 5‒1. The Medical Monitor must be 
contacted for confirmation of the rescreening requirements in all cases. 
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Table 5‒1: 
Cross-study screening requirements 
Assessment  
Screening requirements 
Cross-study screening is not permitted in the following cases: 
BASDAI and 
spinal pain 
Screening of a subject not eligible for AS0010 who will be screened for AS0011, 
and who did not meet the related Inclusion Criteria in AS0010. 
PHQ-9, eC-SSRS, 
TB questionnaire 
(Q1) 
Screening of a subject not eligible for AS0010 who will be screened for AS0011, 
and who did meet the related Exclusion Criteria in AS0010. 
Cross-study screening is permitted in the following cases: 
CRP 
If a subject not eligible for AS0010 will be screened for AS0011, the Screening 
CRP testing must be repeated during Screening for AS0011 only if the result is 
older than 35 days at time of randomization at Baseline (Section 12.6). 
All safety 
laboratory 
assessments 
If a subject not eligible for AS0010 will be screened for AS0011, the Screening 
safety laboratory testing (hematology, biochemistry, urinalysis, urine drug 
screen, pregnancy testing as applicable, HIV, Hepatitis B and C, and IGRA TB 
testing), and HLA-B27 testing must be repeated during Screening for AS0011 
only if the results are older than 35 days at time of randomization at Baseline 
(Section 12.6). 
Anterior posterior 
pelvis x-ray 
The following will be accepted to qualify subjects with AS for this study: 
Anterior posterior pelvis x-ray centrally read for AS0010 and determined to be 
modified New York Criteria positive (+mNY); neither the x-ray nor the reading 
will be repeated (Section 9.20). The central imaging reader needs to be informed 
by the site about screening activities in order to transfer and confirm eligibility 
for the switch from AS0010 to AS0011. 
AS=ankylosing spondylitis; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; CRP=C-reactive 
protein; eC-SSRS=electronic Columbia-Suicide Severity Rating Scale; HIV=human immunodeficiency virus; 
HLA-B27=human leukocyte antigen B27; IGRA=Interferon-Gamma Release Assay; mNY=modified New 
York; PHQ-9=Patient Health Questionnaire 9; Q=question; TB=tuberculosis 
Assessments at the Screening Visit are presented in Table 5-2. 
5.1.2 
Treatment Period 
5.1.2.1 
Double-Blind Treatment Period 
During the Double-Blind Treatment Period, subjects will be randomized in a 2:1 fashion 
(stratified by region and prior TNFα inhibitor experience) to 1 of 2 treatment arms to receive 
blinded IMP regimens of bimekizumab 160mg sc Q4W or placebo sc Q4W. The enrollment of 
TNFα inhibitor-experienced subjects will be limited to 30% of the total study population.  
Investigational medicinal product treatment details are provided in Section 7.2.  
Visit windows of ±3 days are allowed from the first dose at all visits through Week 16. The visit 
window is relative to the Baseline Visit, not the previous study visit. The time between doses 
should be ≥25 days and ≤31 days. When applying the allowed visit windows, it must be ensured 
that the time between these 2 visits does not exceed the allowed time between doses. 
Bimekizumab or placebo will be administered sc by unblinded study personnel at the study site. 
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The Double-Blind Treatment Period ends after Week 16 assessments. At Week 16, subjects will 
transition from the double-blind, placebo-controlled treatment into the 36-week Maintenance 
Period with bimekizumab treatment, as discussed in Section 5.1.2.2. 
Subjects discontinuing IMP during the Double-Blind Treatment Period will be encouraged to 
return for all scheduled visits through Week 52 and the SFU Visit (20 weeks after the final dose 
of IMP), as applicable (Section 5.1.4). Subjects withdrawing from the study will have an 
ET Visit and a SFU Visit 20 weeks after the final dose of IMP, as applicable. 
5.1.2.2 
Maintenance Period 
The 36-week Maintenance Period starts with the Week 16 IMP administration. All subjects will 
receive bimekizumab 160mg sc Q4W during the Maintenance Period. 
• Subjects who received bimekizumab 160mg sc Q4W during the 16-week Double-Blind 
Treatment Period will continue to receive bimekizumab 160mg sc Q4W.  
• Subjects who received placebo during the 16-week Double-Blind Treatment Period will be 
re-allocated to bimekizumab treatment. After the Week 16 assessments are performed, all 
subjects will receive bimekizumab 160mg sc Q4W.  
Bimekizumab will be administered by the blinded or unblinded study personnel at the study site, 
according to the site-specific blinding plan.  
Visit windows of ±4 days are allowed for all visits after Week 16. The time between doses 
during the Maintenance Period should be ≥24 days and ≤32 days. When applying the allowed 
visit windows, it must be ensured that the time between these 2 visits does not exceed the 
allowed time between doses. 
All subjects will be eligible for nonbiologic rescue therapy from Week 20 onwards, as defined in 
Table 7‒2. 
Prior to completion of the Maintenance Period, Investigators should discuss treatment options 
with the subject. Subjects who complete AS0011 and meet the eligibility criteria may enroll in an 
extension study to continue to receive bimekizumab.  
Subjects discontinuing IMP during the Maintenance Period after Week 16 will be encouraged to 
return for all scheduled visits through Week 52 and the SFU Visit (20 weeks after the final dose 
of IMP), as applicable. The SFU Visit is not required if the Week 52 Visit is ≥20 weeks after the 
final dose of IMP (Section 5.1.4). Subjects withdrawing from the study will have an ET Visit and 
a SFU Visit 20 weeks after the final dose of IMP. 
5.1.3 
Early Termination Visit 
Subjects withdrawing consent and withdrawn early from the study will undergo the ET Visit 
assessments (see Section 8.5) and will enter the SFU Period. 
Subjects withdrawing from IMP who are not continuing for all scheduled visits through 
Week 52, will undergo the ET Visit, and will enter the SFU Period. 
5.1.4 
Safety Follow-Up Visit 
All subjects who complete the study and do not enter the extension study will undergo the 
SFU Visit 20 weeks after their final dose of IMP (see Section 8.6). 
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Subjects withdrawing from the IMP during the study, will be encouraged by the Investigator to 
return for all scheduled visits through Week 52 and the SFU Visit (unless the Week 52 Visit 
occurs ≥20 weeks after the final dose of IMP). 
Subjects withdrawing from IMP who are not continuing for all scheduled visits, will undergo the 
ET Visit and the SFU Visit 20 weeks after their final dose of IMP. 
Subjects withdrawing consent and withdrawn early from the study will undergo the ET Visit 
assessments and will enter the SFU Period. 
5.1.5 
Study duration per subject 
For each subject, the study will last up to 73 weeks, as follows: 
• Screening Period: minimum duration of approximately 14 days (unless a screenfailed subject 
from AS0010 will be screened in AS0011) to ≤35 days 
• 16-week Double-Blind Treatment Period 
• 36-week Maintenance Period 
• A SFU Visit for subjects who complete the study and who do not enter the extension study or 
who discontinue from the study early, including those withdrawn from IMP, will be 
conducted 20 weeks after the final dose of the IMP as applicable (ie, Week 48 for subjects 
who completed AS0011). 
The end of the study is defined as the date of the last visit of the last subject in the study. 
5.1.6 
Planned number of subjects and site(s) 
Approximately 300 subjects will be randomly assigned in a 2:1 ratio to the following treatment 
groups: bimekizumab 160mg sc Q4W (200 subjects) or placebo sc Q4W (100 subjects). The 
planned number of study sites is approximately 95.  
Enrollment requirements will be applied and controlled by the IXRS system. 
The minimum proportion of TNFα inhibitor-naïve subjects will be approximately 70% and the 
maximum proportion of subjects with prior use of TNFα inhibitor will be approximately 30%.  
5.1.7 
Anticipated regions and countries 
This will be a multicenter, international study conducted in approximately 14 countries in the 
US, Eastern and Western Europe, and Asia. Enrollment will be competitive among study sites 
and may be capped in regions or at sites.  
5.2 
Schedule of study assessments 
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Table 5-2: 
Schedule of study assessments 
Protocol activity 
SC 
BL (D1) 
Double-Blind Treatment 
Period (16 weeks) 
Maintenance Period (36 weeks) 
ET 
SFUb 
Weeka 
 
 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data including 
lifestyle and infection history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AS history including EAMs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Significant past medical history 
and concomitant diseases 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Incl./excl. criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
eC-SSRSd 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PHQ-9 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ASQoL 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
BASDAI 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
  
 
X 
X 
 
BASFI 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
SF-36 PCS and MCS 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
MOS Short Sleep Scale (12 items) 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
PGADA 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
Total and nocturnal spinal pain 
(NRS) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
Tuberculosis questionnaire 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
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Table 5-2: 
Schedule of study assessments 
Protocol activity 
SC 
BL (D1) 
Double-Blind Treatment 
Period (16 weeks) 
Maintenance Period (36 weeks) 
ET 
SFUb 
Weeka 
 
 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
 
FACIT-Fatigue subscale 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
EQ-5D-3L 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
WPAI-SHP 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
Vital signs (BP, pulse, 
temperature)e 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and body weightf 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Physical examinationg 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
TJC/SJC (44/44) 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
MASES 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
BASMI 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
PhGADA 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
ECGh 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
Hematology/ 
biochemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Pregnancy testingi 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B and C testingj,k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV testingj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA-B27 analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol 
Bimekizumab 
AS0011 
 
 
 
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Table 5-2: 
Schedule of study assessments 
Protocol activity 
SC 
BL (D1) 
Double-Blind Treatment 
Period (16 weeks) 
Maintenance Period (36 weeks) 
ET 
SFUb 
Weeka 
 
 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
 
BKZ plasma concentrationj 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
Anti-BKZ antibody detectionj 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
Serum and plasma samples for 
exploratory biomarkersj,l 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
RNA blood samples for 
exploratory biomarkersj,l 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Blood sample for genetic/ 
epigenetic analysisj,l 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Stool samplesl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
IGRA TB testj,m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Chest x-rayn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sacroiliac joint x-rayo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spine x-rayp 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sacroiliac and spine MRIq 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Enter IXRSr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP administrations 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AS=ankylosing spondylitis; ASQoL=Ankylosing Spondylitis Quality of Life; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASFI=Bath 
Ankylosing Spondylitis Functional Index; BASMI=Bath Ankylosing Spondylitis Metrology Index; BL=Baseline; BKZ=bimekizumab; BP=blood pressure; 
CRP=C-reactive protein; D=day; EAM=extra-articular manifestation; eC-SSRS=electronic Columbia-Suicide Severity Scale; ECG=electrocardiogram; EQ-
5D-3L=EuroQol 5 Dimensions 3 Level; ET=Early Termination; excl.=excluding; FACIT=Functional Assessment of Chronic Illness Therapy; HIV=human 
immunodeficiency virus; HLA-B27=human leukocyte antigen B27; IGRA=interferon gamma release assay; IMP=investigational medicinal product; 
incl.=including; IXRS=interactive voice or web response system; MASES=Maastricht Ankylosing Spondylitis Enthesitis; MCS=mental component score; 
MOS=Medical Outcomes Study; MRI=magnetic resonance imaging; NRS=numeric rating scale; mNY=modified New York; PCS=physical component score; 
PGADA=Patient’s Global Assessment of Disease Activity; PhGADA=Physician’s Global Assessment of Disease Activity; PHQ-9=Patient’s Health 
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Table 5-2: 
Schedule of study assessments 
Protocol activity 
SC 
BL (D1) 
Double-Blind Treatment 
Period (16 weeks) 
Maintenance Period (36 weeks) 
ET 
SFUb 
Weeka 
 
 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
 
Questionnaire 9; RNA=ribonucleic acid; SC=Screening; SF-36=Short Form-36 Health Survey; SFU=Safety Follow-Up; SJC=swollen joint count; 
TB=tuberculosis; TJC=tender joint count; WPAI-SHP=Work Productivity and Activity Impairment Questionnaire-specific health problem 
a Visit windows of ±3 days are allowed for all visits through Week 16. The visit window is relative to the Baseline Visit, not the previous week’s visit. During 
the Maintenance Period, visit windows of ±4 days are permitted for all visits after Week 16. 
b The SFU Visit occurs 20 weeks after the final dose for all subjects who complete the study and do not enter the extension study or who discontinue early, 
including those withdrawn from study treatment. The visit window for the SFU Visit is -3/+7 days. 
c Ensure there are no significant changes in medical history that would exclude the subject based on the exclusion criteria. 
d If an Unscheduled Visit is conducted due to safety or efficacy reasons, an eC-SSRS assessment will be performed with the subject during the visit. 
e Collect vital signs (pulse, BP, and temperature) prior to IMP administration and then at 30 minutes after administration and 1 hour after administration at 
Baseline and Week 16 only. At all other applicable visits, vital signs will be collected once prior to IMP administration. All other procedures are done prior 
to dosing. 
f The Investigator or designee will measure the height of the subject with shoes removed in meters once at Screening and the weight of the subject in 
kilograms. 
g Includes evaluation of signs and symptoms of active TB and risk for exposure to TB. 
h ECGs will be read centrally. 
i Pregnancy testing will consist of serum testing at Screening for all women of childbearing potential. A urine dipstick will be used for pregnancy testing at all 
other visits (Section 12.7.6). 
j At dosing visits, all blood samples are taken prior to dosing. Blood samples for bimekizumab and anti-bimekizumab antibody detection as well as 
pharmacogenetics/genomics will be processed as per instructions in the lab manual. 
k Subjects who have evidence of or test positive for hepatitis B or hepatitis C are excluded. Positive test criteria are defined in Section 6.2. 
l A separate Informed Consent Form will be required for subjects who decide to participate in the pharmacogenomic substudy. The Informed Consent Form 
must be signed prior to collecting any samples for the substudy. Blood and/or stool samples are collected for exploratory purposes and participation in either 
blood or stool sampling (or both) is optional.  
m An IGRA TB test will be performed at the central laboratory. Details will be specified in the Laboratory Manual.  
n If a subject has had a recent x-ray of the chest within 3 months prior to the Screening Visit, it may be used as the Screening chest x-ray. Any findings 
suggestive of active TB are exclusionary. 
o The following will be accepted to qualify AS subjects for this study: a) sacroiliac joint x-ray centrally read for the Phase 3 study AS0010 determined to be 
modified New York Criteria positive (+mNY); neither the reading nor the x-ray will be repeated; b) prior sacroiliac joint x-ray (performed at any time prior 
to the study) was submitted and centrally read for the purposes of this study and determined to be modified New York Criteria positive (+mNY). If the prior 
x-ray is not meeting central reading criteria for randomization, another x-ray may be performed if prior x-ray is more than 1 year old and if permitted by 
local guidelines, or c) if no prior x-ray is available, one must be performed at Screening. 
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Table 5-2: 
Schedule of study assessments 
Protocol activity 
SC 
BL (D1) 
Double-Blind Treatment 
Period (16 weeks) 
Maintenance Period (36 weeks) 
ET 
SFUb 
Weeka 
 
 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
 
p The spine x-ray at Baseline for subjects with confirmed eligibility can be performed prior to or after the Baseline Visit, and must be performed prior to or no 
later than on the day of the second administration of IMP. The spine x-ray will be centrally read and will be used to assess disease progression in the spine in 
the extension study, given the subject is willing to enter this subsequent study. If the subject has a spine x-ray available from the past 6 months prior to 
Screening, this x-ray may be used and submitted for central reading. 
q Sacroiliac joint and spine MRIs will be performed for subjects participating in the MRI substudy. Baseline sacroiliac joint and spine MRIs should be 
performed after confirmation of eligibility based on screening assessments for the study and before the first dose of IMP. The sacroiliac joint and spine MRIs 
can be performed at Baseline or prior to the actual Baseline Visit. Further sacroiliac joint and spine MRIs will be performed at Weeks 16 and 52, within a 
window of ±5 days for all subjects participating in the substudy.  
r The IXRS is used to register subjects at Screening, randomize subjects at Baseline/Day 1, rerandomize subjects at Week 16 and to register all visits. 
s At Week 16, the Maintenance Period dosing will start, as detailed Section 5.1.2.2. At Week 52, IMP administration will only occur for subjects entering the 
extension study. Dosing details at Week 52 will be provided in the protocol of the extension study. 
 
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5.3 
Schematic diagram 
Figure 5‒1: Schematic diagram: study overview 
 
 
ASAS40=Assessment of SpondyloArthritis International Society 40% response criteria; BKZ=bimekizumab; BL=Baseline; IMP=investigational medicinal 
product; Q4W=every 4 weeks; sc=subcutaneous; SFU=Safety Follow-Up; W=week 
a Subjects are eligible for nonbiologic rescue therapy starting at Week 20 with treatment at the discretion of the Investigator while continuing to receive BKZ. 
Treatment with non-BKZ biologics or prohibited treatment (see Section 7.8.2) will lead to BKZ discontinuation (Table 7‒2).  
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5.4 
Rationale for study design and selection of dose 
AS0011 will evaluate the efficacy and safety of bimekizumab at a dose level of bimekizumab 
160mg sc Q4W in adult subjects with AS. 
5.4.1 
Study design 
A randomized, double-blind, placebo-controlled study design has been selected to evaluate the 
efficacy and safety of bimekizumab. The study population will include adult subjects with active 
AS and allow subjects who have received previous biologic treatment (eg, a TNFα inhibitor) as 
well as those who are biologic treatment-naïve. The primary efficacy outcome measures 
(ASAS40 response) and other efficacy assessments included in this study are consistent with 
those used for other axSpA studies and are considered appropriate for establishing efficacy of 
bimekizumab. An initial double-blind treatment period of 16 weeks will be used to demonstrate 
the efficacy of bimekizumab over placebo. The study duration extends beyond the initial 
Double-Blind Treatment Period (ie, Maintenance Period up to 52 weeks) to collect data on the 
maintenance of efficacy of bimekizumab for exploratory analyses and to allow continued 
evaluation of safety data. 
5.4.2 
Dose selection 
A bimekizumab dose of 160mg sc Q4W has been selected for AS0011. 
Bimekizumab doses of 16mg to 320mg Q4W were evaluated in a multicenter, Phase 2b, 
double-blind, placebo-controlled, randomized, parallel-group study in subjects with active AS 
(AS0008). Results from the Week 12 interim analysis indicated bimekizumab doses up to and 
including 320mg have an acceptable safety profile and PK/PD modelling indicated a plateau in 
Week 12 ASAS40 response at doses of 160mg and above. This plateau at bimekizumab160mg 
was further confirmed based on the observed noncontrolled Week 48 data, which demonstrated a 
similar ASAS40 response between 160mg and 320mg Q4W at Week 48. 
There were no dose-related safety concerns or changes in laboratory values in the preliminary 
data review up to 48 weeks that preclude the use of any of the tested doses in AS0008 for the 
Phase 3 program in axSpA. 
The same dosing regimen was selected for a Phase 3 program evaluating bimekizumab in 
subjects with active PsA.  
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met:  
1a. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the subject. 
2a. Subject is considered reliable and capable of adhering to the protocol (eg, able to understand 
and complete diaries), visit schedule, or medication intake according to the judgment of the 
Investigator. 
3. Subject is male or female at least 18 years of age. 
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4. Subject has AS as per the Modified New York (mNY) criteria (1984) including documented 
radiologic evidence (x-ray) based on central reading and at least 3 months of symptoms 
(Table 19‒2) with age at symptom onset <45 years.  
5. Subject has moderate-to-severe active disease as defined by BOTH of the following at 
Screening AND Baseline: 
− BASDAI ≥4 AND spinal pain ≥4 on a 0 to 10 NRS (from BASDAI Item 2) 
6a. Subjects had to have either failed to respond to 2 different NSAIDs given at the maximum 
tolerated dose for a total of 4 weeks or have a history of intolerance to or a contraindication 
to NSAID therapy.  
7. Subjects who are regularly taking NSAIDs/COX-2 inhibitors or analgesics (including mild 
potency opioids) are required to be on a stable dose for at least 14 days before Baseline.  
8. Subjects taking corticosteroids must be on an average daily dose of ≤10mg/day prednisone or 
equivalent for at least 14 days before Baseline.  
9. Subjects taking MTX (≤25mg/week) or LEF (≤20mg/day or an average of 20mg/day if not 
dosed daily) are allowed to continue their medication if started at least 12 weeks prior to 
Baseline, with a stable dose and route of administration (MTX) for at least 8 weeks before 
randomization. It is strongly recommended that subjects taking MTX are also taking folic 
acid supplementation.  
10. Subjects taking SSZ up to 3g/day (or 4g/day if in accordance with local standard of care), 
HCQ up to 400mg/day (other anti-malarials may be used if in accordance with local standard 
of care), or apremilast (up to 60mg/day and dosed as per local label) are allowed to continue 
their medication if started at least 8 weeks prior to Baseline, with a stable dose for at least 
4 weeks before randomization.  
11. Subjects who have taken a TNFα inhibitor must have experienced an inadequate response to 
previous treatment given at an approved dose for at least 12 weeks or have been intolerant to 
treatment.  
12. Female subjects must be: 
− Postmenopausal. Menopause is defined as 12 consecutive months of amenorrhea, for 
which there is no other obvious pathological or physiological cause. 
− Permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy). 
− Or, if of childbearing potential (and engaged in sexual activity that could result in 
procreation), must be willing to use a highly effective method of contraception 
throughout the duration of the study until 20 weeks after last administration of IMP, and 
have a negative pregnancy test at Visit 1 (Screening) and immediately prior to first dose. 
The following methods are considered highly effective when used consistently and correctly: 
− Combined (estrogen and progestogen) hormonal contraception associated with inhibition 
of ovulation (oral, intravaginal or transdermal) 
− Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable) 
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− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system (IUS) 
− Vasectomized partner 
− Abstinence as a form of birth control is generally not allowed in the study unless 
abstinence is in accordance with a subject’s preferred and common lifestyle. Study 
personnel must confirm the continued use of abstinence is still in accordance with the 
subject’s lifestyle at regular intervals during the study 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria are met: 
1. Female subject who is breastfeeding, pregnant, or plans to become pregnant during the study 
or within 20 weeks following the final dose of IMP. 
2. Subject has previously participated in a bimekizumab clinical study who received at least 
1 dose of the IMP (including placebo). 
3a. Subject previously participated in another study of a medication (systemic) under 
investigation within the 12 weeks or at least 5 half-lifes prior to the Baseline Visit, whichever 
is greater, or is currently participating in another study of a medication (systemic) under 
investigation, with the exception of subjects who were screen failures in AS0010. 
4. Subject previously participated in another study of a medical device under investigation 
within the 4 weeks prior to the Screening Visit, or is currently participating in another study 
of a medical device under investigation.  
5. Subject has a known hypersensitivity to any excipients of bimekizumab. 
6. Subjects with a total ankylosis of the spine.  
7. Subjects with fibromyalgia or osteoarthritis symptoms that in the Investigator’s opinion 
would have potential to interfere with efficacy assessments. 
8. Subject had acute anterior uveitis within 6 weeks of the Baseline Visit. 
9. Subjects who have received more than 1 TNFα inhibitor and/or more than 2 additional 
non-TNFα biological response modifiers, or any IL-17 biological response modifier at any 
time are excluded (please refer to Table 7‒2).  
10. Subject is taking or has taken prohibited medications as outlined in Table 7‒2 without 
meeting the mandatory washout period(s) relative to the Baseline visit. 
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11. Subject has an active infection or history of infections as follows: 
− Any active infection (except common cold) within 14 days prior to Baseline. 
− A serious infection, defined as requiring hospitalization or iv anti-infectives within 
2 months prior to Baseline. 
− A history of opportunistic, recurrent or chronic infections that, in the opinion of the 
Investigator, might cause this study to be detrimental to the subject. Opportunistic 
infections are infections caused by uncommon pathogens (eg, Pneumocystis jirovicii, 
Cryptococcosis) or unusually severe infections caused by common pathogens (eg, 
cytomegalovirus [CMV], herpes zoster). 
12. Subject has concurrent acute or chronic viral hepatitis B or C or human immunodeficiency 
virus (HIV) infection. Subjects who have evidence of, or tested positive for hepatitis B or 
hepatitis C are excluded. 
A positive test for the hepatitis B virus (HBV) is defined as:  
− Positive for hepatitis B surface antigen (HBsAg+); or,  
− Positive for anti-hepatitis B core antibody (HBcAb+)  
A positive test for the hepatitis C virus (HCV) is defined as:  
− Positive for hepatitis C antibody (anti-HCV Ab), and  
− Positive via a confirmatory test for HCV (for example, HCV polymerase chain reaction). 
13. Subject has received any live (includes attenuated) vaccination within the 8 weeks prior to 
the Baseline Visit (eg, inactivated influenza and pneumococcal vaccines are allowed, but 
nasal influenza vaccination is not permitted) or has received Bacillus Calmette-Guerin 
vaccinations within 1 year prior to the Baseline Visit. 
14. Subject has known tuberculosis (TB) infection, at high risk of acquiring TB infection, or 
current or history of nontuberculous mycobacterium (NTMB) infection. A subject with latent 
tuberculosis (LTB) (a positive interferon-gammy release assay [IGRA] and diagnosis 
confirmed by TB specialist) may be rescreened once and enrolled after receiving at least 
4 weeks of appropriate LTB infection therapy and if no evidence of therapy-related 
hepatotoxicity has occurred prior to the first injection (alanine aminotransferase 
[ALT]/aspartate aminotransferase [AST] remain ≤3 times upper limit of normal [ULN]). 
Subject has a past history of active TB involving any organ system, unless adequately treated 
according to World Health Organization (WHO)/Center for Disease Control and Prevention 
(CDC) therapeutic guidance and proven to be fully recovered upon consult with a TB 
specialist. 
Refer to Section 12.7.5 for details on determining full TB exclusion criteria. 
15. Subject has a history of a lymphoproliferative disorder including lymphoma or current signs 
and symptoms suggestive of lymphoproliferative disease. 
16. Subject has any active malignancy or history of malignancy within 5 years prior to the 
Screening Visit EXCEPT treated and considered cured cutaneous squamous or basal cell 
carcinoma or in situ cervical cancer. 
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17a. Subject has a diagnosis of inflammatory conditions other than AS, including but not limited 
to psoriatic arthritis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, and 
reactive arthritis. Subjects with a diagnosis of Crohn’s disease, ulcerative colitis, or other 
IBD are allowed as long as they have no active symptomatic disease at Screening or 
Baseline. 
18. Subject has had major surgery (including joint surgery) within the 3 months prior to the 
Baseline, or has planned major surgery within 6 months after entering the study. 
19. Subject has any systemic disease (ie, cardiovascular, neurological, renal, hepatic, metabolic, 
gastrointestinal, hematological, immunological, etc) considered by the Investigator to be 
uncontrolled, unstable or likely to progress to a clinically significant degree during the course 
of the study. 
20. Subject has had myocardial infarction or stroke within the 6 months prior to the Screening 
Visit. 
21. Subject has laboratory abnormalities at Screening, including any of the following: 
a. ≥3.0 ULN of any of the following: ALT, AST, alkaline phosphatase (ALP); or >ULN 
total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome) 
b. White blood cell (WBC) count <3.00 x103/µL 
c. Absolute neutrophil count <1.5 x103/µL 
d. Absolute lymphocyte count <500 cells/µL  
e. Hemoglobin <8.5g/dL 
f. Creatinine >2mg/dL 
g. Any other laboratory abnormality, which, in the opinion of the Investigator, will 
prevent the subject from completing the study or will interfere with the interpretation 
of the study results 
Individual screening tests for which the results are in error, borderline, or indeterminate for 
inclusion in the study, can be repeated once for confirmation during the Screening Period. 
Upon retesting, subjects whose results remain outside this threshold should not be 
randomized. 
22. Subject has any other condition, including medical or psychiatric, which, in the Investigator's 
judgment, would make the subject unsuitable for inclusion in the study.  
23. Presence of active suicidal ideation, or positive suicide behavior using the “Screening” 
version of the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) with either of 
the following criteria: 
− History of a suicide attempt within the 5 years prior to the Screening Visit. Subjects with 
a history of a suicide attempt more than 5 years ago should be evaluated by a mental 
healthcare practitioner (HCP) before enrolling into the study. 
− Suicidal ideation in the past month prior to the Screening Visit as indicated by a positive 
response (“Yes”) to either Question 4 or Question 5 of the “Screening” version of the 
eC-SSRS  
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24. Subject has moderately severe major depression or severe major depression, indicated by a 
score ≥15 using the Screening PHQ-9. Medication used to treat depression should be stable 
for 8 weeks prior to Baseline. 
25. Subject has a history of chronic alcohol or drug abuse within 6 months prior to Screening as 
evaluated by the Investigator based on medical history, site interview, and/or results of the 
specified urine drug screen.  
26. Subject is a member of Investigator site personnel directly affiliated with this study and/or 
their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, 
whether biological or legally adopted. 
27. Subject is a UCB employee or employee of third-party organizations involved in the study. 
6.3 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.  
Subjects should be withdrawn from the study if the subject withdraws his/her consent. 
Subjects should be withdrawn from IMP and encouraged by the Investigator to return for all 
scheduled visits through Week 52, and the SFU Visit (if the Week 52 Visit is ≥20 weeks after the 
final dose of IMP, the SFU Visit is not required) if any of the following events occur: 
1. The Sponsor or a regulatory agency requests withdrawal of the subject.  
2. Subject develops an illness that in the opinion of the Investigator would interfere with his/her 
continued participation if the risk of continuing IMP outweighs the potential benefit. 
3. Subject is noncompliant with the study procedures or medications in the opinion of the 
Investigator.  
4. Subject uses prohibited concomitant medications as defined in this protocol (Section 7.8.2), 
that may present a risk to the safety of the subject or the integrity of the study data, in the 
opinion of the Investigator and/or the Medical Monitor. 
5. Subject has a clinical laboratory value meeting any of the following criteria: 
a. Hepatotoxicity as described in Section 6.3.1. 
b. A laboratory value meeting any of the following criteria:  
− Absolute neutrophil count <1.0 x103/µL  
− Absolute lymphocyte count <200 cells/µL 
Subjects may remain on IMP if the result is transient. A retest is required within 1 to 2 weeks 
at a scheduled or unscheduled visit. If the repeat absolute neutrophil count or absolute 
lymphocyte count is still below the allowable values, the subject must be withdrawn from the 
IMP. If the repeat absolute neutrophil count or absolute lymphocyte count is above the 
allowable values, the subject may continue to receive IMP. 
6. The subject experiences a severe AE, an SAE, or a clinically significant change in a 
laboratory value occurs that, in the opinion of the Investigator, merits the discontinuation of 
the IMP and appropriate measures being taken. 
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7. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test (see Section 12.2 for more information regarding pregnancies). 
8. A subject considered as having either a suspected new LTB infection or who develops active 
TB or NTMB infection during the study (including but not limited to, conversion 
demonstrated by IGRA or other diagnostic means) must be immediately discontinued from 
IMP, and an ET Visit must be scheduled as soon as possible, but not later than the next 
regular visit. 
The subject must be permanently withdrawn if further examinations result in a diagnosis of 
active TB, or if the subject is diagnosed with latent TB infection (LTBI) with no initiation of 
prophylactic treatment, prematurely discontinues prophylactic treatment, or, in the opinion of 
the Investigator or Sponsor, is noncompliant with prophylactic TB therapy. 
Confirmed active TB is an SAE and must be captured in the eCRF in the SAE Report Form 
section. As with all SAEs, periodic follow-up reports should be completed as per protocol 
requirements until such time as the TB infection resolves. 
Additional information on TB policies is provided in Section 12.7.5. 
9. Subjects with newly diagnosed IBD or with IBD flares during the study must: 
− Be referred, as appropriate, to a healthcare professional treating IBD, such as a 
gastroenterologist 
− Discontinue IMP and be followed-up until resolution of active IBD symptoms 
If IBD flares increase in severity or frequency during the study, the Investigator should use 
clinical judgement in deciding whether the subject should continue on IMP and contact the 
Medical Monitor and UCB Study Physician to confirm the subject’s suitability for continued 
participation in the study. 
10. Subjects must be referred immediately to a mental healthcare professional and may be 
withdrawn from the study based upon the Investigator’s judgment of benefit/risk for: 
− Active suicidal ideation as indicated by a positive response (“Yes”) to Question 4 of the 
“Since Last Visit” version of the eC-SSRS  
− Moderately severe major depression as indicated by a PHQ-9 score of 15 to 19 if this 
represents an increase of 3 points compared to the last visit  
The mental health consultation must be recorded in the subject’s source documentation. 
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11. Subjects must be referred immediately to a mental healthcare professional and must be 
withdrawn from the study in case of: 
− Active suicidal ideation as indicated by a positive response ("Yes") to Question 5 of the 
"Since Last Visit" version of the eC-SSRS. 
− Any suicidal behavior since last visit. 
− Severe major depression as indicated by a PHQ-9 score ≥20. 
The mental health consultation must be recorded in the subject’s source documentation. 
12. Any subject who develops a clinically important infection or recurrent infections not 
responsive to standard therapy during the study must discontinue IMP until resolution of the 
infection. The Investigator should use clinical judgement in deciding whether the subject 
should restart IMP and contact the Medical Monitor and UCB study physician to confirm the 
subject’s suitability for continued participation in the study. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject from IMP or from the study in advance. 
Subjects withdrawing from the study who are not continuing for all scheduled visits, will 
undergo the ET Visit and the SFU Visit 20 weeks after their final dose of IMP, as applicable. 
For subjects considered as lost to follow-up, the Investigator should make an effort (at least 
1 phone call and 1 written message to the subject), and document his/her effort (date and 
summary of the phone call and copy of the written message in the source documents), to 
complete the final evaluation. All results of these evaluations and observations, together with a 
narrative description of the reason(s) for removing the subject, must be recorded in the source 
documents. The electronic Case Report Form (eCRF) must document the primary reason for 
withdrawal or discontinuation. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance. 
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6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued.  
The PDILI criteria below require immediate discontinuation of IMP for subjects with either of 
the following:  
• ALT or AST ≥8x ULN  
• ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN  
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%).  
If a nondrug-related cause for the symptoms can be confirmed, these subjects may resume 
IMP administration after discussion with the responsible UCB physician, but only when the 
requirements for rechallenge with IMP as provided in (Section 12.6.1.2.1) are followed.  
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
Investigator.  
• Subjects with ALT or AST ≥5xULN and <8xULN, total bilirubin <2xULN, and no 
eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness).  
Evaluation of PDILI must be initiated as described in Section 12.6.1 with repeat tests performed 
in 2 weeks. Upon re-test, if ALT or AST values have reduced to <5xULN, the subject can 
continue with the study. However, if ALT or AST remains ≥5xULN and <8xULN after re-test, 
IMP should be temporarily withheld and subject should undergo a repeat test in 2 weeks. If ALT 
or AST values remain ≥5xULN even after the second re-test, then the subject should be 
immediately discontinued from IMP and should be followed for possible PDILI.  
If subjects are unable to comply with the applicable monitoring schedule, IMP must be 
discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
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7 
STUDY TREATMENTS 
7.1 
Description of investigational medicinal products 
The IMPs used in this study are bimekizumab and placebo. 
• 
 
 
 
• Placebo will be supplied as 0.9% sodium chloride aqueous solution (physiological saline, 
preservative free) of pharmacopoeia (US Pharmacopoeia/European Pharmacopoeia) quality 
in a 1mL PFS for sc injection. 
Details of the IMPs and their specification will be provided in the IMP Handling Manual.  
7.2 
Treatment(s) to be administered 
Unblinded study personnel will be responsible for recording the administration information on 
source documents, and administration of the IMP as sc injections. The unblinded personnel will 
not be involved in any other aspect of the study. During the Maintenance Period, bimekizumab 
will be administered by unblinded study personnel, unless the site-specific blinding plan allows 
for the administration by blinded study personnel.  
Suitable areas for sc injections are the lateral abdominal wall, upper arm, and upper outer thigh. 
Injection sites should be rotated and injections should not be given in areas where the skin is 
tender, bruised, red, or hard.  
An IMP Handling Manual will be provided to each site containing instructions regarding drug 
preparation and dosing. 
7.2.1 
Double-Blind Treatment Period 
Subjects will be randomized 2:1 to receive 1 of 2 blinded treatment regimens during the 
Double-Blind Treatment Period. To keep the blinding, all subjects will receive administrations as 
per the dosing scheme shown in Table 7‒1.  
The IMP (bimekizumab and placebo) will be administered at the time points indicated in 
Table 5-2. The Double-Blind Treatment Period ends with Week 16 assessments and the final 
dose in the Double-Blind Period will be administered at Week 12. 
During the Double-Blind Treatment Period, bimekizumab or placebo will be administered by 
unblinded study personnel at the study site. 
Table 7‒1: 
Overview on dosing during the Double-Blind Treatment Period 
Treatment arm 
Dosing 
BKZ 160mg sc Q4W  
Subjects will receive 1 BKZ 160mg injection sc at Week 0 
(Baseline) followed by BKZ 160mg sc Q4W at Weeks 4, 8, and 12.  
PBO sc Q4W 
Subjects will receive 1 PBO injection sc at Week 0 (Baseline) 
followed by PBO sc Q4W at Weeks 4, 8, and 12. 
BKZ=bimekizumab; PBO=placebo; Q4W=every 4 weeks, sc=subcutaneous 
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7.2.2 
Maintenance Period 
The 36-week Maintenance Period starts with the Week 16 IMP administration. All subjects will 
receive bimekizumab 160mg sc Q4W during the Maintenance Period and will receive treatments 
as follows: 
• Subjects who received bimekizumab 160mg sc Q4W during the 16-week Double-Blind 
Treatment Period will continue to receive bimekizumab 160mg sc Q4W.  
• Subjects who received placebo during the 16-week Double-Blind Treatment Period will be 
re-allocated to bimekizumab treatment. After the Week 16 assessments are performed, all 
subjects will receive bimekizumab 160mg sc at the Week 16 Visit.  
During the Maintenance Period, all subjects will receive bimekizumab, and the responsibility for 
recording the administration information and the administration of the IMP can be switched to 
the blinded team only if the site-specific blinding plan defines a process of maintaining the blind 
of the documentation of IMP administration of the Double-Blind Treatment Period.  
7.3 
Packaging 
The IMPs are manufactured, packaged, and labeled according to Good Manufacturing Practice 
(GMP) guidelines and applicable laws or regulations. Investigational medicinal products will be 
suitably packaged in such a way as to protect the IMPs from deterioration during transport and 
storage.  
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language. 
7.5 
Handling and storage requirements 
Investigational Medicinal Product must be stored under refrigerated conditions (2ºC to 8ºC) 
protected from light. The IMP must not be frozen. 
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the Investigator is to be kept in a secured area with 
limited access according to the storage conditions mentioned on the label. 
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room, 
refrigeration unit) or by completion of a temperature log in accordance with local requirements 
on a regular basis, showing actual and minimum/maximum temperatures reached over the time 
interval. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
7.6 
Drug accountability 
A Drug Accountability Form will be used to record IMP dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any IMP lost, damaged (due to breakage or wastage), not used, partially used, disposed of at the 
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study site, or returned to the Sponsor or designee must also be recorded on the appropriate forms. 
All supplies and pharmacy documentation must be made available throughout the study for UCB 
(or designee) to review. 
The packaging identifies each kit by a unique number and by the content. Unblinded study staff 
will be responsible for preparation (eg, breaking tamper proof sticker on kit) of the clinical trial 
material, including recording the administration information in the source document during the 
Double-Blind Treatment Period. During the Maintenance Period, bimekizumab will be 
administered by unblinded study personnel unless the site-specific blinding plan allows the 
administration by blinded study personnel (Section 7.2.2). 
All IMP documentation of the Double-Blind Treatment Period (eg, shipping receipts, drug 
accountability logs, IXRS randomization materials) must be maintained and accessed by 
unblinded, trained site personnel only. Designated, unblinded site personnel must be 
appropriately trained and licensed (per country guidelines) to administer injections. Each site 
will be required to have a written site-specific blinding plan in place signed by the Investigator, 
which will detail the site’s steps for ensuring that the double-blind nature of the study is 
maintained from Week 0 to Week 16/ET, and for defining site-specific responsibilities of the 
blinded and unblinded team during the course of the study. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The Investigator must ensure that the IMP is used only in accordance with the protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired IMP must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB SOPs or returned to UCB (or 
designee). Investigational medicinal product intended for the study cannot be used for any other 
purpose than that described in this protocol. 
7.7 
Procedures for monitoring subject compliance 
During the Double-Blind Treatment Period and the Maintenance Period, bimekizumab and 
placebo will be administered in the clinic and compliance will be determined at the visit by study 
personnel. Drug accountability must be recorded on the Drug Accountability Form. 
7.8 
Concomitant medications/treatments 
All concomitant medications, including over-the-counter products, herbal, traditional remedies, 
vitamin or mineral supplements, other dietary supplements, “nutraceuticals,” and hormones must 
be recorded in the subject’s source documentation (eg, clinical chart) and 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. 
Medications listed in Table 7‒2 are prohibited, restricted, or used as nonbiologic rescue therapy. 
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Table 7‒2: 
Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
Analgesics 
• 
Acetaminophen/ 
paracetamol 
Any change in dose/dose 
regimen within 14 days 
prior to BL 
Stable dose/regimen permitted  
Ad hoc/PRN/“as needed use” 
permitted, but: 
No ad hoc/PRN/“as needed use” 
in the 24h prior to any study visit 
Ad hoc/PRN/“as needed use” permitted, but: 
No ad hoc/PRN/“as needed use” in the 24h prior to 
any study visit 
 
NSAID/COX-2 inhibitors  
Any change in dose/dose 
regimen within 14 days 
prior to BL 
Stable dose/ regimen permitted 
No change until Week 20 Visit 
Nonbiologic rescue therapy will be at the 
Investigator’s discretion with the following options for 
symptoms: 
• 
For subjects taking an NSAID/COX-2 inhibitor 
dosing can be optimized; a change can be made to 
a different NSAID/COX-2 inhibitor; changes 
from an NSAID to a COX-2 inhibitor or from a 
COX-2 inhibitor to an NSAID are also permitted 
up to the maximum approved or tolerated dose, 
whichever is lower. Only 1 NSAID/COX-2 
inhibitor may be taken at a given time. 
• 
For subjects not taking NSAID/COX-2 inhibitors 
either 1 NSAID, or 1 COX-2 inhibitor can be 
initiated, up to the maximum approved or 
tolerated dose, whichever is lower. Only 
1 NSAID/COX-2 inhibitor may be taken at a 
given time. 
• 
For subjects who cannot take NSAIDs/COX-2 
inhibitors, topical NSAIDs are also a potential 
nonbiologic rescue therapy in regions where they 
are approved, up to the maximum approved or 
tolerated dose, whichever is lower.  
Mild potency opioids permitted 
only eg,: 
• 
Tramadol/any dose up to 
maximum approved dose 
• 
Codeine/only <90mg of 
codeine per dosage unit 
Any change in dose/dose 
regimen within 14 days 
prior to BL 
Dosing/ schedule should remain 
stable for the first 20 weeks of 
the study 
Prohibited for rescue therapy 
 
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Table 7‒2: 
Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
Oral corticosteroids/average daily 
dose of ≤10mg/day prednisone or 
equivalent 
Any change in dose/dose 
regimen within 14 days 
prior to BL 
Permitted, but: 
• 
No steroid bursts/tapers 
• 
No increase in steroid 
dosing 
• 
No initiation of steroids 
until the Week 20 Visit 
Prohibited for rescue therapy 
Topical corticosteroids 
None 
Permitted 
Not applicable 
Corticosteroids: 
• 
Intramuscular 
• 
Intravenous 
• 
Intra-articular  
• 
Bursal 
 
Use within 28 days prior to 
BL 
Prohibited unless used as rescue 
therapy from Week 20 or later 
Nonbiologic rescue therapy will be at the 
Investigator’s discretion with the following options for 
symptoms: 
• 
Sacroiliac joint steroid injection(s), either 
unilateral or bilateral. 
For non-axial symptoms: 
• 
One peripheral joint (or bursa) may be injected 
with a steroid at or after any visit where 
nonbiologic rescue therapy eligibility is assessed; 
however, the same joint may not be injected more 
than once during the study and should not be 
injected within 4 weeks of a sacroiliac joint 
injection(s). 
Intra-articular hyaluronic acid 
Use within 8 weeks prior 
to the BL Visit or during 
the study 
Prohibited 
Not applicable 
Any established antidepressant 
regimen 
Any change in dose/dose 
regimen within 8 weeks 
prior to BL 
Permitted 
Not applicable 
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Table 7‒2: 
Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
csARDs/formerly known as 
DMARDs 
 
 
 
• 
Azathioprine 
• 
Cyclosporine 
• 
Cyclophosphamide 
• 
Mycophenolic acid 
• 
Mycophenylate mofetil 
• 
Any other small molecule 
DMARDs 
Use within 8 weeks prior 
to BL 
Prohibited 
Prohibited for rescue  
• 
Methotrexate (MTX) 
 
Use within 12 weeks prior 
to BL unless Inclusion 
Criterion #9 is met 
Permitted 
MTX (≤25mg/week) 
For non-axial symptoms: 
• 
MTX may be added or increased to a maximum 
dose of 25mg/week, or the maximum tolerated 
dose, whichever is lower, in accordance with local 
standard of care. The route of administration may 
be changed from oral to sc or from sc to oral, at 
any visit at Week 20 or later. It is strongly 
recommended that subjects taking MTX are also 
taking folic acid supplementation. 
• 
Leflunomide (LEF) 
Use in the 6 months prior 
to the BL Visit (unless a 
cholestyramine washout 
has been performed; in 
which case, use up to 
28 days prior to the BL 
Visit is acceptable) unless 
Inclusion Criterion #9 is 
met 
Permitted 
LEF (≤20mg/day or an average 
of 20mg/day if not dosed daily) 
For non-axial symptoms: 
• 
Leflunomide may be given at a maximum dose of 
20mg/day (or an average of 20mg/day if not 
dosed daily), or the maximum tolerated dose, 
whichever is lower.  
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Table 7‒2: 
Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
• 
Hydroxychloroquine (HCQ) 
(and other anti-malarials) 
• 
Sulfasalazine (SSZ) 
• 
Apremilast 
 
Use within 8 weeks prior 
to BL unless Inclusion 
Criterion #10 is met 
Permitted 
For non-axial symptoms: 
• 
HCQ may be added or increased to a maximum 
dose of 400mg/day or the maximum tolerated 
dose, whichever is lower. Other anti-malarials 
may be used in accordance with local standard of 
care. 
• 
SSZ may be added or increased up to a maximum 
dose of 3g/day (up to 4g/day if in accordance with 
local standard of care), or the maximum tolerated 
dose, whichever is lower.  
• 
Apremilast may be given at a maximum dose of 
60mg/day and dosed as per Investigator’s 
discretion or local label. 
Combination DMARDs are allowed except that LEF 
and MTX may not be given together. 
JAK inhibitors 
 
 
 
• 
Eg, tofacitinib 
• 
Upadacitinib 
Use within 8 weeks prior 
to BL 
Prohibited 
Not applicable 
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Table 7‒2: 
Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
Biologic DMARDs 
 
 
 
TNFα inhibitors: 
• 
Infliximab (IFX) 
• 
Golimumab (GOL) 
• 
Certolizumab pegol (CZP) 
• 
Adalimumab (ADA) 
• 
Etanercept (ETN) 
• 
Biosimilar versions of any 
TNFα inhibitor 
For IFX, ADA, GOL, and 
CZP, any use within the 
12 weeks prior to the BL 
Visit 
For ETN, use within the 
28 days prior to the BL 
Visit 
Any use of >1 TNFα in the 
history 
Subjects not meeting 
Inclusion Criterion #11. 
Prohibited 
Not applicable 
Other biologics: 
• 
Abatacept 
Any use within 12 weeks 
prior to BL 
Prohibited 
Not applicable 
• 
Alefacept 
 
 
• 
Efalizumab 
 
 
• 
Guselkumab 
 
 
• 
Sarilumab 
 
 
• 
Sirukumab 
 
 
• 
Tocilizumab 
 
 
• 
Others in development 
targeting IL-6 or IL-6R 
 
 
• 
Ustekinumab 
 
Any use within 24 weeks 
prior to BL 
Prohibited 
Not applicable 
• 
Tildrakizumab 
Any use within 4 months 
prior to BL 
Prohibited 
Not applicable 
• 
Risankizumab 
Any use within 5 months 
prior to BL 
Prohibited 
Not applicable 
• 
Briakinumab 
 
Any use within 6 months 
prior to BL 
Prohibited 
Not applicable 
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Table 7‒2: 
Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
• 
Rituximab (incl. biosimilars), 
ocrelizumab 
Any use within 12 months 
prior to BL 
Prohibited 
Not applicable 
Anti-IL-17 therapy: 
• 
Bimekizumab 
• 
Secukinumab 
• 
Ixekizumab 
• 
Brodalumab 
• 
Others in development 
Any exposure history 
Prohibited 
Not applicable 
BL=Baseline; ADA=adalimumab; COX-2=cyclooxygenase 2; csARD=conventional synthetic antirheumatic drug; CZP=certolizumab pegol; 
DMARD=disease-modifying antirheumatic drug; ETN=etanercept; GOL=golimumab; h=hour; HCQ=hydroxychloroquine; IFX=infliximab; JAK=Janus 
kinase; LEF=leflunomide; IL=interleukin; MTX=methotrexate; NSAID=nonsteroidal anti-inflammatory drug; PRN=as needed; sc=subcutaneous; 
SSZ=sulfasalazine; TNFα=tumor necrosis factor alpha 
a 
Note: any medication not listed here for rescue therapy must be approved by the Medical Monitor prior to starting that medication. 
 
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7.8.1 
Permitted concomitant treatments (medications and therapies) 
No medication increases or additions for AS are permitted until after the Week 20 Visit 
assessments. However, a decrease in dose or dosing frequency of any agent is permitted for 
reasons of intolerance/AEs/side-effects at any time. Permitted nonbiologic rescue therapy is 
described in Table 7‒2. 
Whenever possible, physical therapy/physiotherapy/non-medication/complementary and 
alternative treatment(s) (including traditional Chinese medications) of AS should remain stable 
through the Week 20 Visit.  
Subjects are allowed to use any other medications, including biologics, after at least 28 days of 
their final dose of the IMP. This is applicable for subjects who discontinue from the study early, 
including those permanently withdrawn from IMP, or subjects who have completed the study 
treatment without entering the extension study and are in the SFU Period. 
7.8.2 
Prohibited concomitant treatments (medications and therapies) 
Prohibited concomitant treatments are described in Table 7‒2. 
7.8.3 
Nonbiologic rescue therapy 
Nonbiologic rescue therapy will be at the Investigator’s discretion as add-on therapy to 
bimekizumab at any time from Week 20 or later as described in Table 7‒2. 
7.8.4 
Vaccines 
Administration of live (including attenuated) vaccines is not allowed during the conduct of the 
study and for 20 weeks after the final dose of IMP. Administration of inactivated vaccines is 
allowed during the study at the discretion of the Investigator. 
7.9 
Blinding 
Due to differences in presentation between bimekizumab and placebo treatments in the 
Double-Blind Treatment Period up to Week 16, special precautions will be taken to ensure study 
blinding and study sites will have blinded and unblinded personnel. 
Bimekizumab and placebo injections will be administered at the investigational sites by 
unblinded, dedicated study personnel according to the site-specific blinding plan (Section 7.2). 
The unblinded personnel will not be involved in the study in any way other than assuring the 
medication is taken from the correct kit and prepared according to the pharmacy manual 
instructions, and administering the drug to the subjects.  
A full blinding plan for the Week 24 interim statistical analysis will be written as described in 
Section 15.8.1.  
7.9.1 
Procedures for maintaining and breaking the treatment blind 
7.9.1.1 
Maintenance of study treatment blind 
All subject treatment details will be allocated and maintained by the interactive response 
technology (IXRS) system.  
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7.9.1.2 
Breaking the treatment blind in an emergency situation 
The integrity of this clinical study must be maintained by observing the treatment blind. In the 
event of an emergency for which the appropriate treatment for a subject cannot be made without 
knowing the treatment assignment, it will be possible to determine to which treatment arm and 
dose the subject has been allocated by contacting the IXRS. All sites will be provided with 
details of how to contact the system for code breaking at the start of the study. The Medical 
Monitor or equivalent should be consulted prior to unblinding, whenever possible. 
The Clinical Project Manager (CPM) will be informed immediately via the IXRS when a code is 
broken, but will remain blinded to specific treatment information. Any unblinding of the IMP 
performed by the Investigator must be recorded in the source documents and on the Study 
Termination eCRF page. 
7.10 
Randomization and numbering of subjects 
An IXRS will be used for assigning eligible subjects to a treatment regimen based on a 
predetermined production randomization and/or packaging schedule provided by the UCB (or 
designee). The randomization schedule will be produced by the IXRS vendor. The IXRS will 
generate individual assignments for subject kits of IMP, as appropriate, according to the visit 
schedule. Subjects treatment assignment will be stratified by region and prior TNFα inhibitor 
exposure (yes/no). Enrollment of TNFα inhibitor-experienced subjects will be limited to 30% of 
the total study population.  
At Screening, each subject will be assigned a 5-digit number that serves as the subject identifier 
throughout the study. The subject number will be required in all communication between the 
Investigator or designee and the IXRS regarding a particular subject. Subjects who were screen 
failures in AS0010 and who are rescreened in AS0011, will be assigned a new subject number 
and will be registered in IXRS. 
Eligible subjects will be randomized to treatment groups at the Baseline Visit (Day 1). To 
randomize a subject, unblinded study personnel will contact the IXRS and provide brief details 
about the subject to be randomized. The IXRS will automatically inform the unblinded study 
personnel of the subject’s randomization number and the treatment arm assigned. At the end of 
the 16-week Double-Blind Treatment Period subjects receiving placebo will be re-allocated to 
the bimekizumab treatment group. The IXRS will allocate kit numbers to the subject based on 
the subject number during the course of the study. Subject numbers and kit numbers will be 
tracked via the IXRS. 
8 
STUDY PROCEDURES BY VISIT  
The Schedule of Assessments (Table 5-2) provides a general overview of study assessments. A 
list of procedures to be completed at each visit is described below.  
Visit windows are ±3 days from Baseline (Day 1, first dose of IMP) at all visits through the 
Week 16 Visit and ±4 days from all visits thereafter. For the SFU Visit (20 weeks after the final 
dose), the visit should occur no more than 3 days prior to the scheduled visit date and within 
7 days after the scheduled visit date (-3 days/+7 days). The minimum amount of time between 
bimekizumab doses should be no less than 25 days and no more than 31 days from Baseline to 
Week 16 and 24 to 32 days thereafter. When applying the allowed visit windows, it must be 
ensured that the time between these 2 visits does not exceed the allowed time between doses. 
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Changes to the dosing schedule outside of the allowed windows should be discussed with the 
Medical Monitor and may result in subject withdrawal. 
8.1 
Screening (Visit 1) 
The Screening Period will last for a minimum of approximately 14 days (unless a screenfailed 
subject from AS0010 will be screened in AS0011) and up to a maximum of 35 days. 
Prior to any study specific activities, subjects will be asked to read, sign, and date an Informed 
Consent Form (ICF) that has been approved by the Sponsor and an IEC/IRB, and that complies 
with regulatory requirements. Subjects will be given adequate time to consider any information 
concerning the study given to them by the Investigator (or designee). As part of the informed 
consent procedure, subjects will be given the opportunity to ask the Investigator any questions 
regarding potential risks and benefits of participation in the study. 
Subjects will also be given the option to participate in the pharmacogenomic and/or MRI 
substudies. Subjects who decide to participate in the substudies will need to complete a separate 
ICF following the same procedure and given the same considerations as the main ICF. Their 
willingness to participate in the substudies will be independent from their consent to participate 
in the main study. 
Subjects who initially fail to meet selected eligibility criteria (including but not limited to 
documented completion of LTBI prophylactic therapy) or for whom eligibility assessments could 
not be completed as planned may be rescreened once after discussion with the Medical Monitor. 
An overview on rescreening/retesting requirements is provided in Section 5.1.1.1 and 
Section 5.1.1.2. 
The following procedures or assessments will be performed at the Screening Visit: 
• Obtain written informed consent for the main study and for the MRI and/or the 
pharmacogenomic substudies for participating subjects. 
• Collect demographic data including the lifestyle and infection history. 
• Collect AS history including extra-articular manifestations (EAMs). 
• Collect significant past medical history and concomitant diseases. 
• Assess that all inclusion and no exclusion criteria are met. 
• Record prior medications. 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the BASDAI. 
• Administer the TB questionnaire. 
• Measure BP, pulse, and temperature. 
• Measure height and body weight. 
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• Perform a physical examination, including an evaluation for signs and symptoms of active 
TB, and risk for exposure to TB.  
• Perform an ECG. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Serum pregnancy test if the subject is a woman of childbearing potential.  
− Hepatitis B and C tests. 
− HIV test. 
− HLA-B27 status. 
− IGRA TB test. 
• Collect urine samples for: 
− Urinalysis. 
− Urine drug screen. 
• Obtain a chest x-ray, unless one has been obtained within 3 months prior to the Screening 
Visit. Any findings suggestive of active TB are exclusionary. 
• Obtain an x-ray of the sacroiliac joint unless one has been obtained up to 6 months prior to 
Screening or as part of screening for AS0010 (see Section 9.20.1 for details). 
• Register the subject using the interactive voice or web response system (IXRS). 
8.2 
Baseline (Visit 2, Day 1, first dose of IMP) 
The following procedures of assessments will be completed prior to administration of IMP: 
• Review significant past medical history and concomitant diseases to ensure there are no 
significant changes in medical history that would exclude the subject based on the exclusion 
criteria. 
• Confirm that the subject meets all inclusion and no exclusion criteria. 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the ASQoL. 
• Administer the BASDAI. 
• Administer the BASFI. 
• Administer the SF-36 questionnaire. 
• Administer the MOS Short Sleep Scale (12 items). 
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• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Administer the TB questionnaire. 
• Administer the FACIT-Fatigue subscale. 
• Administer the EQ-5D-3L. 
• Administer the WPAI-SHP. 
• Measure BP, pulse, and temperature. 
• Measure body weight. 
• Perform a physical examination, including an evaluation for signs and symptoms of active 
TB, and risk for exposure to TB.  
• Perform the TJC and SJC assessment. 
• Determine the MASES. 
• Determine the BASMI. 
• Administer the PhGADA. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• For subjects consenting on a separate ICF for participation in the pharmacogenomic 
substudy: 
− Collect serum and plasma samples for exploratory biomarkers. 
− Collect ribonucleic acid (RNA) blood samples for exploratory biomarkers. 
− Collect blood samples for genetic/epigenetic analysis. 
− Collect stool samples. 
• Obtain an x-ray of the spine unless one has been obtained up to 6 months prior to Screening 
(see Section 9.20.2 for details). The spine x-ray must be performed prior to or no later than 
on the day of the second administration of IMP. 
• Obtain MRIs of the sacroiliac joint and the spine for subjects consenting on a separate ICF 
for participation in the MRI substudy prior to the first IMP administration (see Section 9.20.3 
for details). 
• Randomize the subject using the IXRS. 
• Administer IMP. 
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The following procedures of assessments will be completed following administration of IMP: 
• Measure vital signs approximately 30 minutes and 1 hour after dosing. 
8.3 
Double-Blind Treatment Period 
8.3.1 
Week 1 (±3 days) (Visit 3)  
• Record concomitant medications. 
• Record AEs. 
• Administer the BASDAI. 
• Administer the BASFI. 
• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Record the visit in the IXRS. 
8.3.2 
Week 2 (±3 days) (Visit 4) 
• Record concomitant medications. 
• Record AEs. 
• Administer the BASDAI. 
• Administer the BASFI. 
• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Measure BP, pulse, and temperature. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations. 
• Record the visit in the IXRS. 
8.3.3 
Week 4 (±3 days) (Visit 5) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the ASQoL. 
• Administer the BASDAI. 
• Administer the BASFI. 
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• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Administer the FACIT-Fatigue subscale. 
• Administer the EQ-5D-3L. 
• Measure BP, pulse, and temperature. 
• Determine the MASES. 
• Administer the PhGADA. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
8.3.4 
Week 8 (±3 days) (Visit 6) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the ASQoL. 
• Administer the BASDAI. 
• Administer the BASFI. 
• Administer the SF-36 questionnaire. 
• Administer the MOS Short Sleep Scale (12 items). 
• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Measure BP, pulse, and temperature. 
• Measure body weight. 
• Perform a physical examination, including an evaluation for signs and symptoms of active 
TB, and risk for exposure to TB. 
• Perform the TJC and SJC assessment. 
• Determine the MASES. 
• Determine the BASMI. 
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• Administer the PhGADA. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
8.3.5 
Week 12 (±3 days) (Visit 7) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the ASQoL. 
• Administer the BASDAI. 
• Administer the BASFI. 
• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Administer the TB questionnaire. 
• Measure BP, pulse, and temperature. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
8.3.6 
Week 16 (±3 days) (Visit 8) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the ASQoL. 
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• Administer the BASDAI. 
• Administer the BASFI. 
• Administer the SF-36 questionnaire. 
• Administer the MOS Short Sleep Scale (12 items). 
• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Administer the FACIT-Fatigue subscale. 
• Administer the EQ-5D-3L. 
• Administer the WPAI-SHP. 
• Measure BP, pulse, and temperature. 
• Measure body weight. 
• Perform a physical examination, including an evaluation for signs and symptoms of active 
TB, and risk for exposure to TB. 
• Perform the TJC and SJC assessment. 
• Determine the MASES. 
• Determine the BASMI. 
• Administer the PhGADA. 
• Perform an ECG. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Collect urine samples for: 
− Urinalysis. 
− Urine pregnancy test if the subject is a woman of childbearing potential.  
• For subjects consenting on a separate ICF for participation in the pharmacogenomic 
substudy: 
− Collect serum and plasma samples for exploratory biomarkers. 
− Collect RNA blood samples for exploratory biomarkers. 
− Collect blood samples for genetic/epigenetic analysis. 
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• Obtain MRIs of the sacroiliac joint and the spine for subjects consenting on a separate ICF 
for participation in the MRI substudy. Magnetic resonance imaging at Week 16 should be 
performed within ±5 days (see Section 9.20.3 for details). 
• Record the visit in the IXRS. 
• Administer IMP. 
The following procedures of assessments will be completed following administration of IMP: 
• Measure vital signs approximately 30 minutes and 1 hour after dosing. 
8.4 
Maintenance Period  
8.4.1 
Week 20 (±4 days) (Visit 9) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Measure BP, pulse, and temperature. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
8.4.2 
Week 24 (±4 days) (Visit 10) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the ASQoL. 
• Administer the BASDAI. 
• Administer the BASFI. 
• Administer the SF-36 questionnaire. 
• Administer the MOS Short Sleep Scale (12 items). 
• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Administer the TB questionnaire. 
• Administer the FACIT-Fatigue subscale. 
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• Administer the EQ-5D-3L. 
• Administer the WPAI-SHP. 
• Measure BP, pulse, and temperature. 
• Measure body weight. 
• Perform a physical examination, including an evaluation for signs and symptoms of active 
TB, and risk for exposure to TB. 
• Perform the TJC and SJC assessment. 
• Determine the MASES. 
• Determine the BASMI. 
• Administer the PhGADA. 
• Perform an ECG. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
8.4.3 
Week 28 (±4 days) (Visit 11) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Measure BP, pulse, and temperature. 
• Collect blood samples for hematology and biochemistry. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
8.4.4 
Week 32 (±4 days) (Visit 12) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Measure BP, pulse, and temperature. 
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• Collect blood samples for hematology and biochemistry. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
8.4.5 
Week 36 (±4 days) (Visit 13) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the ASQoL. 
• Administer the BASDAI. 
• Administer the BASFI. 
• Administer the SF-36 questionnaire. 
• Administer the MOS Short Sleep Scale (12 items). 
• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Administer the TB questionnaire. 
• Administer the FACIT-Fatigue subscale. 
• Administer the EQ-5D-3L. 
• Administer the WPAI-SHP. 
• Measure BP, pulse, and temperature. 
• Measure body weight. 
• Perform a physical examination, including an evaluation for signs and symptoms of active 
TB, and risk for exposure to TB. 
• Administer the PhGADA. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Collect urine samples for: 
− Urinalysis. 
− Urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
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• Administer IMP. 
8.4.6 
Week 40 (±4 days) (Visit 14)  
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Measure BP, pulse, and temperature. 
• Collect blood samples for hematology and biochemistry. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
8.4.7 
Week 44 (±4 days) (Visit 15) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Measure BP, pulse, and temperature. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− IGRA TB test. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
8.4.8 
Week 48 (±4 days) (Visit 16) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the TB questionnaire. 
• Measure BP, pulse, and temperature. 
• Collect blood samples for hematology and biochemistry. 
• Perform a urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
• Administer IMP. 
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8.4.9 
Week 52 (±4 days) (Visit 17) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the ASQoL. 
• Administer the BASDAI. 
• Administer the BASFI. 
• Administer the SF-36 questionnaire. 
• Administer the MOS Short Sleep Scale (12 items). 
• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Administer the FACIT-Fatigue subscale. 
• Administer the EQ-5D-3L. 
• Administer the WPAI-SHP. 
• Measure BP, pulse, and temperature. 
• Measure body weight. 
• Perform a physical examination, including an evaluation for signs and symptoms of active 
TB, and risk for exposure to TB. 
• Perform the TJC and SJC assessment. 
• Determine the MASES. 
• Determine the BASMI. 
• Administer the PhGADA. 
• Perform an ECG. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Collect urine samples for: 
− Urinalysis. 
− Urine pregnancy test if the subject is a woman of childbearing potential.  
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• For subjects consenting on a separate ICF for participation in the pharmacogenomic 
substudy: 
− Collect serum and plasma samples for exploratory biomarkers. 
− Collect RNA blood samples for exploratory biomarkers. 
− Collect blood samples for genetic/epigenetic analysis. 
− Collect stool samples 
• Obtain MRIs of the sacroiliac joint and the spine for subjects consenting on a separate ICF 
for participation in the MRI substudy. Magnetic resonance imaging should be performed 
within ±5 days of the Week 52 Visit (see Section 9.20.3 for details). 
• Record the visit in the IXRS. 
8.5 
Early Termination Visit (if applicable) 
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the ASQoL. 
• Administer the BASDAI. 
• Administer the BASFI. 
• Administer the SF-36 questionnaire. 
• Administer the MOS Short Sleep Scale (12 items). 
• Perform the PGADA. 
• Administer the total and nocturnal spinal pain NRS. 
• Administer the TB questionnaire. 
• Administer the FACIT-Fatigue subscale. 
• Administer the EQ-5D-3L. 
• Administer the WPAI-SHP. 
• Measure BP, pulse, and temperature. 
• Measure body weight. 
• Perform a physical examination, including an evaluation for signs and symptoms of active 
TB, and risk for exposure to TB. 
• Determine the MASES. 
• Determine the BASMI. 
• Administer the PhGADA. 
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• Perform an ECG. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Collect urine samples for: 
− Urinalysis. 
− Urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
8.6 
Safety Follow-Up Visit (-3 days/+7 days)  
• Record concomitant medications. 
• Record AEs. 
• Administer the eC-SSRS and the PHQ-9. 
• Administer the TB questionnaire. 
• Measure BP, pulse, and temperature. 
• Measure body weight. 
• Perform a physical examination, including an evaluation for signs and symptoms of active 
TB, and risk for exposure to TB. 
• Perform an ECG. 
• Collect blood samples for: 
− Hematology and biochemistry. 
− CRP. 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
• Collect samples for: 
− Urinalysis. 
− Urine pregnancy test if the subject is a woman of childbearing potential.  
• Record the visit in the IXRS. 
8.7 
Unscheduled Visit 
At the Investigator’s discretion, an Unscheduled Visit may be completed at any time during the 
study but prior to the SFU Visit, if deemed necessary for the subject’s safety and well-being.  
If an Unscheduled Visit is conducted due to safety or efficacy reasons, an eC-SSRS assessment 
will be performed with the subject during the visit. If an Unscheduled Visit is conducted for 
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reasons other than safety or efficacy concerns (eg, repeated collection of a laboratory specimen 
due to collection or analysis issues) an eC-SSRS will not be required at these visits.  
At this visit, assessments including, but not limited to the following may be performed, 
depending on the reason for the visit: 
• Record concomitant medication. 
• Record AEs. 
• Administer the eC-SSRS. 
• Measure BP, pulse, and temperature.  
• Physical examination. 
• Record 12-lead ECG. 
• If indicated, obtain blood sample(s) for: 
− Standard safety laboratory tests (hematology, serum chemistry). 
− Bimekizumab plasma concentrations and anti-bimekizumab antibody detection. 
− An IGRA TB test. 
• Obtain urine sample for: 
− Urine pregnancy test. 
− Urinalysis. 
9 
ASSESSMENT OF EFFICACY 
9.1 
ASAS20, 40, ASAS 5/6 response, and ASAS-PR 
The ASAS20 response is defined as an improvement of at least 20% and absolute improvement 
of at least 1 unit on a 0 to 10 NRS in at least 3 of the 4 following domains: 
• PGADA (see Section 9.8) 
• Pain assessment (the total spinal pain NRS score; see Section 9.9) 
• Physical function (measured by BASFI, Section 9.5) 
• Inflammation (the mean of the BASDAI Questions 5 and 6, [see Section 9.3] concerning 
morning stiffness intensity and duration)  
and absence of deterioration in the potential remaining domain (deterioration is defined as a 
relative worsening of at least 20% and an absolute worsening of at least 1 unit). 
The ASAS criteria for 40% improvement are defined as relative improvements of at least 40%, 
and absolute improvement of at least 2 units on a 0 to 10 NRS in at least 3 of the 4 domains and 
no worsening at all in the remaining domain. 
The ASAS 5/6 response is defined as at least 20% improvement in 5 of 6 domains, including 
spinal mobility (lateral spinal flexion) and CRP as more objective measures (Brandt et al, 2004). 
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The ASAS-PR is defined as a score of ≤2 units on a 0 to 10 unit scale in all 4 domains listed 
above for ASAS20. 
The ASAS20, 40, ASAS 5/6 response, and ASAS-PR will be derived from assessments at the 
visits specified in Table 5-2.  
9.2 
ASQoL 
The ASQoL, a validated disease-specific 18-item questionnaire, has been developed specifically 
for measuring health-related quality of life (HRQoL) in subjects with AS (Doward et al, 2003). 
The ASQoL has been used and has shown to be responsive in axSpA (Barkham et al, 2009; 
Haibel et al, 2008). Each statement on the ASQoL is given a score of 1 = Yes or 0 = No. A score 
of "1" is given where the item is affirmed, indicating adverse quality of life. All item scores are 
summed to total score ranging from 0 to 18 with a higher score indicating worse HRQoL.  
The ASQoL will be assessed by the subject at the visits specified in Table 5-2. 
9.3 
Inflammation – BASDAI (mean of Questions 5 and 6) 
Question 5 of the BASDAI (described completely in Section 9.4) measures intensity of morning 
stiffness. The subject considers the previous week and responds to the question, “How would 
you describe the overall level of morning stiffness you have had from the time you wake up?” 
The response is indicated on a 10-point NRS in which 0=None and 10=Very severe. Question 6 
of the BASDAI measures duration of morning stiffness. The subject considers the previous week 
and responds to the question, “How long does your morning stiffness last from the time you 
wake up? The response is indicated on a 10-point NRS in which 0=0 hours, 5=1 hour, and 
10=2 or more hours. The ratings for each question are summed and divided by 2 to provide the 
mean of questions 5 and 6.  
The BASDAI Questions 5 and 6 will be assessed by the subject at the visits specified  
in Table 5-2. 
9.4 
BASDAI 
The most common instrument used to measure the disease activity of AS from the subject’s 
perspective is the BASDAI (Garrett et al, 1994). The BASDAI is a validated self-reported 
instrument which consists of six 10-unit horizontal NRSs to measure severity of fatigue, spinal 
and peripheral joint pain and swelling, enthesitis, and morning stiffness (both severity and 
duration, respectively) over the last week (van Tubergen et al, 2015). The final BASDAI score 
ranges from 0 to 10, with lower scores indicating lower disease activity. 
 
 
and the score is used as the “total back pain” factor in the calculation of ASDAS-CRP. 
 
 and the score is used as the “peripheral 
pain/swelling” factor in the calculation of ASDAS-CRP. Question 6 of the BASDAI asks the 
subject to describe his/her overall stiffness from the time of awakening in the past week, and the 
score is used as the “duration of morning stiffness” factor in the calculation of ASDAS-CRP. 
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The BASDAI total score is calculated as follows:  
𝐵𝐴𝑆𝐷𝐴𝐼=
Q1+Q2+Q3+Q4+(𝑄5+𝑄6
2
)
5
  
 
 
 
 
Fatigue item of the BASDAI 
Fatigue, as a major symptom of AS, can effectively be measured with single-item questions such 
as the BASDAI item (van Tubergen et al, 2002b). This item has shown moderate to good 
reliability and responsiveness (van Tubergen et al, 2002b). The same minimal clinically 
important difference (MCID) will be used for the fatigue item of the BASDAI as for the total 
BASDAI score, ie, a change of 1 unit on the NRS. 
The BASDAI will be assessed at the visits specified in Table 5-2.  
9.5 
Physical function – BASFI 
The BASFI is a validated disease-specific instrument for assessing physical function (van der 
Heijde et al, 2005; Calin et al, 1994). The BASFI comprises 10 items relating to the past week. 
The NRS version will be used for the answering options of each item on a scale of 0 (“Easy”) 
to 10 (“Impossible”) (van Tubergen et al, 2015; van Tubergen et al, 2002a). The BASFI is the 
mean of the 10 scores such that the total score ranges from 0 to 10, with lower scores indicating 
better physical function. The MCID used to interpret scores is 7mm on a 0 to 100mm VAS or 
17.5% of the Baseline score (Pavy et al, 2005); an MCID of 1 unit will be used for the NRS 
version.  
The BASFI will be assessed by the subject at the visits specified in Table 5-2. 
9.6 
SF-36 
The SF-36 (Version 2, standard recall) is a 36-item generic HRQoL instrument that uses a recall 
period of 4 weeks. Items are grouped into 8 domains as follows: Physical Functioning (10 items), 
Role Physical (4 items), Bodily Pain (2 items), General Health (5 items), Vitality (4 items), 
Social Functioning (2 items), Role Emotional (3 items), Mental Health (5 items). One additional 
item asks respondents about health change (Health Transition) over the past year. The concepts 
represented by these domains contribute to physical, mental, and social aspects of HRQoL. 
In addition to domain scores, the Physical Component Summary and Mental Component 
Summary scores are calculated from the 8 domains (excluding the Health Transition item). 
Component scores appreciate the impact of each domain on physical and mental health status 
(Maruish, 2011). The norm-based T-scores for the 2 SF-36 component summary (PCS and MCS) 
and the 8 domain scores are standardized with a mean of 50 and a standard deviation (SD) of 10 
in the general US population (Maruish, 2011). An individual respondent’s score that falls outside 
the T-score range of 45 to 55 should be considered outside the average range for the US general 
population. When considering group-level data, a score below 47 should be considered indicative 
of impaired functioning within that health domain or dimension. Similar to individual respondent 
data, group mean scores of 47 or greater should be considered average or above average as 
compared to the general US population. Higher scores indicate a better health status. 
The SF-36 will be assessed by the subject at the visits specified in Table 5-2. 
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9.7 
MOS-12 
The MOS Sleep Scale is a validated generic self-administered scale measuring specific aspects 
of sleep. The frequency with which each problem has been experienced during the previous 
4 weeks is rated on a 5-point scale ranging from “none of the time” to “all of the time,” except 
sleep quantity, which is reported in hours. All scores are transformed linearly to range from 
0 to 100, again with the exception of the sleep quantity subscale, which is scored in hours. 
Higher scores indicate more of the attribute implied by the scale name (eg, more sleep 
disturbance, more adequate sleep, and greater sleep quantity). The psychometric properties of the 
MOS Sleep Scale have been found to be satisfactory by Hays and colleagues (Hays et al, 2005). 
The domains of interest for this study are the Sleep Disturbance and the Sleep Problems Index II 
domains.  
The MOS-12 Sleep Scale will be assessed by the subject at the visits specified in Table 5-2. 
9.8 
PGADA 
Subjects will score the global assessment of their disease activity in response to the question 
“How active was your spondylitis on average during the last week?” using a NRS where 0 is 
“not active” and 10 is “very active” (van Tubergen et al, 2015).  
The PGADA will be assessed by the subject at the visits specified in Table 5-2.  
9.9 
Total and nocturnal spinal pain 
The pain experienced by AS subjects is adequately measured by 2 separate questions: 1) total 
pain in the spine due to AS (ie, “How much pain of your spine due to spondylitis do you have?”); 
and 2) pain in the spine at night due to AS (ie, “How much pain of your spine due to spondylitis 
do you have at night?”) (Sieper et al, 2009; van der Heijde et al, 2005; Committee for Proprietary 
Medicinal Product [CPMP]/EWP/556/95, 2004). When responding to each question, the subject 
is to consider the average amount of pain in the preceding week.  
Total and nocturnal spinal pain will be assessed by the subject at the visits specified in 
Table 5-2. 
9.10 
FACIT-Fatigue subscale 
The FACIT-F is a 40-item measure that assesses self-reported fatigue and its impact upon daily 
activities and function over the past 7 days (FACIT.org). The scale consists of 5 subscales 
(physical well-being, social/family well-being, emotional well-being, functional well-being, and 
fatigue). The fatigue subscale is the only one used in this study. It is composed of 13 items, all 
scored from 0 (Not at all) to 4 (Very much). The FACIT-Fatigue subscale score ranges from 0 to 
52 with 0 being the worst possible score and 52 being the best possible score. To obtain a score 
from 0 to 52, all negatively worded questions have to be recoded, so that responses range from 
worst (0) to the best (4) outcome.   
The FACIT-Fatigue subscale will be completed by the subject at the visits specified in Table 5-2. 
9.11 
EQ-5D-3L 
The EQ-5D-3L is comprised of a 5-item health status dimension and a VAS. The response to 
each of the 5 health status dimensions is divided into 3 levels (no problem, some or moderate 
problems, or extreme problems) and is scored as 1, 2, and 3, respectively. The EQ-5D-3L VAS 
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records the respondent’s self-rated health status on a vertical 20cm scale, 0 to 100 graduated 
(0=worst imaginable health status, 100=best imaginable health status). 
The EQ-5D-3L will be assessed by the subject at the visits specified in Table 5-2. 
9.12 
TJC and SJC (44/44) 
The following 44 joints are to be examined for tenderness and swelling by the Investigator, 
another delegated physician, or an appropriately qualified medical professional (based on local 
requirements) who has had documented training on how to perform these assessments correctly. 
Preferably the same assessor should evaluate the subject at each arthritis assessment. 
• Upper body (4) – bilateral sternoclavicular, and acromioclavicular joints. 
• Upper extremity (26) – bilateral shoulders, elbows, wrists (includes radiocarpal, carpal and 
carpometacarpal bones considered as a single unit), metacarpophalangeals (MCPs) I, II, III, 
IV, and V, and thumb interphalangeals (IPs), and proximal IPs (PIPs) II, III, IV, and V. 
• Lower extremity (14) – bilateral knees, ankles, and metatarsophalangeals (I, II, III, IV, 
and V). 
The assessment for tenderness and swelling is made on 44 joints from the above list. Artificial 
and ankylosed joints are excluded from swelling and tenderness assessments. The assessments 
per visit are described in the schedule of study assessments Table 5-2. 
Table 9‒1 summarizes the swelling and tenderness grading criteria. 
Table 9‒1: 
Tenderness and swelling grading 
Grade 
Tenderness response (44) 
Swelling response (44) 
0 
Not tender  
None 
1 
Tenderness present  
Detectable synovial thickening 
9.13 
WPAI-SHP v2.0 
The WPAI-SHP v2.0 is a patient-reported questionnaire that assesses subject’s employment 
status, work absenteeism, work impairment while working (presenteeism), overall work, and 
daily activity impairment attributable to a specific health problem (WPAI-SHP) (Reilly et al, 
1993). It has been used in several clinical studies of biologic therapy in subjects with plaque PSO 
(Kimball et al, 2012; Vender et al, 2012). 
Five out of 6 items of the WPAI-SHP are regrouped into the 4 dimensions, with scores expressed 
as percentage, where higher numbers indicate greater impairment and less productivity, ie, worse 
outcomes, as described in the WPAI-SHP scoring rules. 
The WPAI-SHP v2.0 will be assessed by the subject at the visits specified in Table 5-2. 
9.14 
CRP 
Blood will be collected for measurement of CRP (ie, determination of hs-CRP). After Baseline, 
the CRP data will not be sent to the Investigator to protect the blinded nature of the treatment 
assignments and response. 
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9.15 
ASDAS 
The ASDAS is comprised of a number of assessments which are scored by the subject and 
Investigator and multiplied by a validated formula (van der Heijde et al, 2009) as listed: 
• 0.121 x Total back pain (BASDAI Q2 result, Section 9.4) 
• 0.058 x Duration of morning stiffness (BASDAI Q6 result, Section 9.4) 
• 0.110 x PGADA (Section 9.8) 
• 0.073 x Peripheral pain/swelling (BASDAI Q3 result, Section 9.4) 
• 0.579 x (natural logarithm of the CRP [mg/L] + 1)  
Back pain, PGADA, duration of morning stiffness, peripheral pain/swelling, and fatigue are all 
assessed on a numerical scale (0 to 10 units) (Lukas et al, 2009). The results of these calculations 
are summed to calculate the ASDAS.  
The variables related to ASDAS disease activity are defined as follows: 
• ASDAS-Inactive Disease (ASDAS-ID): ASDAS <1.3 
• ASDAS-Low Disease activity (ASDAS-LD): ASDAS ≥1.3, <2.1 
• ASDAS-High Disease activity (ASDAS-HD): ASDAS ≥2.1, ≤3.5 
• ASDAS-very High Disease activity (ASDAS-vHD): ASDAS >3.5 
The variable related to ASDAS improvement is defined as follows: 
• ASDAS-MI: ASDAS reduction (improvement) of ≥2.0 relative to Baseline 
The ASDAS variables will be derived from assessments at the visits specified in Table 5-2. 
9.16 
MASES 
Enthesitis is assessed with the MASES. The MASES is an index that measures the severity (ie, 
intensity and extent) of enthesitis through the assessment of 13 entheses (bilateral 
costochondral 1, costochondral 7, anterior superior iliac spine, posterior iliac spine, iliac crest 
and proximal insertion of the Achilles tendon sites, and the fifth lumbar vertebral body spinous 
process) (Heuft-Dorenbosch et al, 2003) each scored as 0 or 1 and then summed for a possible 
score of 0 to 13. 
The MASES will be assessed at the visits specified Table 5-2. 
9.17 
BASMI 
The BASMI characterizes the spinal mobility of subjects with AS. The BASMI is a 
disease-specific measure consisting of 5 clinical measures to reflect subject axial status: cervical 
rotation; tragus to wall distance; lateral spinal flexion; modified Schober test; intermalleolar 
distance. Each of the 5 movements is scored according to the linear BASMI definition. The mean 
of the 5 scores provides the BASMI score. The higher the BASMI score the more severe the 
subject’s limitation of movement due to their AS. 
The BASMI will be assessed at the visits specified in Table 5-2. 
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9.18 
PhGADA 
The Investigator will assess the overall status of the subject with respect to their AS signs and 
symptoms and functional capacity using an NRS in which 0=very good, asymptomatic and no 
limitations of normal activities and 10=very poor, very severe symptoms which are intolerable 
and inability to carry out normal activities.  
This assessment by the Investigator should be made blind to the PGADA. 
The PhGADA will be assessed at the visits specified in Table 5-2. 
9.19 
Occurrence of extra-articular manifestations 
Information regarding dactylitis, PSO, uveitis, and IBD events during the study will be captured 
as AEs. Enthesitis will be assessed regularly via the MASES performed at site visits as specified 
in Table 5-2.  
9.20 
Imaging evaluation 
Screening imaging evaluations need to be completed during the Screening Period.  
Radiographs and MRIs are read by 2 independent, highly trained expert rheumatology imaging 
specialist physicians. A third person will serve as an adjudicator. 
Details for standardized performance and processing of the x-rays and MRIs will be provided in 
an Imaging Manual.  
The MRIs and x-rays in Section 9.20 will be read centrally by readers who are blinded to 
treatment assignment and chronological order of the imaging according to a charter for 
independent imaging assessment.  
Chest x-rays are discussed in Section 12.7.5.2. 
In addition to the analyses mentioned below, x-rays and MRI images may be evaluated using 
other reading criteria or methods. 
9.20.1 
Sacroiliac joint x-ray (AP Pelvis Joint Film for modified New York 
Criteria) 
The sacroiliac joint is assessed by radiography with an AP pelvis or sacroiliac joint x-ray that 
will be assessed by a central reading review during the Screening Period to evaluate for modified 
New York Criteria status (Table 19‒2) as described in Section 6.1. Sacroiliac joint changes will 
be scored according to the imaging specifications. 
The following will be accepted to qualify subjects with AS for this study: 
• Anterior posterior pelvis x-ray centrally read for one of the Phase 3 studies AS0010 or 
AS0011 and determined to be modified New York Criteria positive (+mNY); neither the 
x-ray nor the reading will be repeated.  
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• Prior sacroiliac joint or AP pelvis x-ray (performed at any time prior to the study) was 
submitted and centrally read for the purposes of this study and determined to be modified 
New York Criteria positive (+mNY). If the prior x-ray does not meet central reading criteria 
for randomization, another x-ray may be performed if the prior x-ray is more than 1 year old 
and if permitted by local guidelines.  
• If no recent x-ray is available, one must be performed at Screening. 
9.20.2 
Spine x-ray 
Subjects with confirmed eligibility based on screening assessments will have a spine x-ray 
performed at Baseline. The x-ray can be performed prior to or after the Baseline Visit, and must 
be performed prior to or no later than on the day of the second administration of IMP. 
If the subject has a spine x-ray available from the past 6 months prior to Screening, this x-ray 
may be used and submitted for central reading. The spine x-ray will be centrally read and will be 
used to assess disease progression in the spine after 1 year in the extension study, given the 
subject is willing to enter this subsequent study. 
9.20.3 
Sacroiliac joint and spine MRI assessment substudy 
While radiography can detect chronic bony changes (eg, sclerosis, erosions, bridging, and 
ankyloses), structural changes generally occur slowly and x-rays are insensitive; therefore, 
changes are difficult to detect in the relatively short duration of a randomized clinical study. 
Unlike radiography, MRI can be used to visualize active inflammation in the sacroiliac joints and 
spine in addition to structural lesions. Inflammation of the sacroiliac joints and spine is a key 
feature of axSpA that is potentially amenable to treatment with bimekizumab. If bimekizumab is 
effective, it is expected that reduction in inflammation in the sacroiliac joints and spine can be 
detected using MRI within the 52-week Treatment Period of this study. Recently, a Danish study 
demonstrated significant changes in ASspiMRI-a (Berlin modification) and 
SPARCC MRI-assessed inflammation scores and in MRI-assessed erosion scores within 
12 weeks after initiation of adalimumab (see below for further description of these MRI scoring 
methods). The researchers concluded that MRI-assessed structural lesions change rapidly and 
may have value for assessing the effects of disease-modifying treatment in clinical trials 
(Pedersen et al, 2016). In this study, MRI changes will be evaluated in the sacroiliac joint and 
spine to evaluate the effect of bimekizumab on objective signs of inflammation through the 
SPARCC and ASspiMRI scores as outlined below. In addition, exploratory evaluation of other 
chronic MRI features, such as erosions and fatty lesions, will be performed as indicators of 
disease modification associated with structural disease progression (Baraliakos et al, 2014). 
Magnetic resonance imaging of the spine and sacroiliac joints will be performed for consenting 
subjects in the MRI substudy after confirmation of eligibility based on screening assessments 
and before the first dose of IMP. If needed, the sacroiliac joint and spine MRIs can be performed 
at Baseline or prior to the actual Baseline Visit after confirmation of eligibility based on 
Screening assessments. 
A central reader will assess the Baseline MRIs to identify MRI-positive subjects as per the 
OMERACT criteria. Further MRIs of the spine and sacroiliac joint for MRI-positive and 
MRI-negative subjects will be performed at Week 16 and Week 52 within a window of ±5 days 
for subjects participating in the MRI substudy. All MRIs will be centrally read. 
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Refusal to participate in the substudy will not affect a subject’s opportunity to participate in the 
main study. 
The following 2 different scoring systems will be utilized to determine changes from Screening 
(Lukas et al, 2007): 
SPARCC Sacroiliac Joint score 
This method is a scoring system for assessing the sacroiliac joint based on short-tau-inversion 
recovery (STIR) sequences. An abnormal increased signal on the STIR sequence represents bone 
marrow edema. The sacroiliac joint is divided into 4 quadrants (upper iliac, lower iliac, upper 
sacral, and lower sacral). The presence of increased signal on STIR in each of these 4 quadrants 
is scored as either 0=normal signal or 1=increased signal. The maximum score for abnormal 
signal in the 2 sacroiliac joints of 1 coronal slice is therefore 8. Joints that include a lesion 
exhibiting intense signal are each given an additional score of 1 per slice (that demonstrate this 
feature). Each sacroiliac joint that includes a lesion demonstrating continuous increase signal of 
depth ≥1cm from the articular surface is also given an additional score of 1. The maximum score 
for a single coronal slice is 12. Scoring is repeated in each of 6 consecutive coronal slices, so that 
the total sacroiliac joint SPARCC MRI score can range from 0 to 72. 
ASspiMRI-a (Berlin modification) score (spine) 
This method is a scoring system with a concentration on STIR sequences which quantifies 
changes in 23 disco-vertebral units (DVU) of the spine. A DVU is defined as the region between 
2 virtual lines through the middle of each vertebra. Active inflammation is scored by grading the 
degree of bone marrow edema from 0 to 3 in 1 dimension on 1 or more consecutive slices that 
represent the highest level of inflammation in a particular DVU. There is no grading for erosion 
in the Berlin modification. The total spine ASspiMRI-a score in the Berlin modification can 
range from 0 to 69.  
Additional scoring systems of inflammation may be used as appropriate methodology becomes 
accepted. 
10 
ASSESSMENT OF PHARMACOKINETIC AND 
PHARMACOGENOMIC VARIABLES 
10.1 
Pharmacokinetic variables 
The PK variable is the plasma concentrations of bimekizumab. The Investigator or designee will 
obtain blood samples for these measurements at the time points specified in Table 5-2. When 
these samples are required at a visit during which the subject is dosed with IMP, the blood 
samples will be drawn prior to dosing. Samples should be drawn at the same time of the 
sampling for clinical laboratory tests. The time and date of collection will be recorded in the 
eCRF. Instructions pertaining to sample collection, processing, storage, labeling, and shipping 
are provided in the laboratory manual for this study. Detailed information on sample analysis 
will be provided in a bioanalytical report. The relationship between PK concentrations and 
efficacy, PD and safety endpoints may also be assessed. The data from this study may be 
combined with data from other studies as part of this assessment. 
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10.2 
Pharmacogenomic variables 
A separate ICF will be required for those subjects who agree to participate in the genomics, 
genetics, and proteomics substudy, and must be signed prior to collection of any samples for the 
substudy. The substudy will only be conducted where ethically accepted and authorized by the 
regulatory agencies. Refusal to participate in the substudy will not affect a subject’s ability to 
participate in the main study. 
These analyses will enable evaluation of biomarkers relative to disease biology and progression, 
drug treatment and bone metabolism, and inflammatory and immune response processes. The 
nature and format of these tentative analyses will be determined at a later date. 
For individuals consenting to the genomics, genetics, and proteomics substudy, blood samples 
will be drawn for exploratory genetic/epigenetic, genomic, proteomic, metabolomics analysis, 
and for candidate biomarker analyses. Candidate biomarker evaluations may include, but are not 
limited to, IL-17A/IL-17F pathway signaling and axSpA biology (eg, IL-17A, IL-17F, IL-23, IL-
6, tumor necrosis factor, dendritic cell-specific transmembrane protein, and circulating osteoclast 
precursors). These plasma samples may be used for additional analyses of other exploratory 
biomarkers. 
Collection of these samples will occur at the time points specified in the schedule of study 
assessments (Table 5-2). At dosing visits, blood samples will be drawn prior to dosing, and will 
be drawn at the same time of the sampling for clinical laboratory tests. The time and date of 
collection will be recorded in the eCRF. The samples will be stored at -80°C at the central 
biorepository for up to 20 years to allow for future exploratory research. 
Stool samples will be collected at time points specified in Table 5-2. These samples may be used 
to assess biomarkers of gut inflammation including but not limited to calprotectin and 
microbiome testing. 
Blood and/or stool samples for pharmacogenomic and biomarker assessments are collected for 
exploratory purposes and participation in either blood or stool sampling (or both) is optional.  
Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the laboratory manual for this study. Detailed information on sample analysis will be 
provided in a bioanalytical report. 
11 
ASSESSMENT OF IMMUNOLOGICAL VARIABLES 
Immunological variables are the anti-bimekizumab antibody status, and the treatment-emergent 
antibody positivity derived from anti-drug antibody assays.  
The Investigator or designee will obtain blood samples for these measurements at the time points 
specified in Table 5-2. When these samples are required at a visit during which the subject is 
dosed with IMP, the blood samples will be drawn prior to dosing. Samples should be drawn at 
the same time of the sampling for clinical laboratory tests. The time and date of collection will be 
recorded in the eCRF. Instructions pertaining to sample collection, processing, storage, labeling, 
and shipping are provided in the laboratory manual for this study. The presence of antibodies to 
bimekizumab will be determined using a validated bioanalytical method. Detailed information on 
sample analysis will be provided in a bioanalytical report. 
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The presence of anti-bimekizumab antibodies will be determined using a tiered approach of 
screening, confirmatory, and titer assays. Where applicable, a neutralizing-antibody assay will be 
performed. 
12 
ASSESSMENT OF SAFETY 
12.1 
Adverse events 
12.1.1 
Definitions 
12.1.1.1 
Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and post-treatment periods required by the 
protocol, must be reported in the eCRF even if no IMP was taken but specific study procedures 
were conducted. This includes all AEs not present prior to the initial visit and all AEs that 
recurred or worsened after the initial visit. 
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
Investigator from the subject’s history or the Baseline Period.  
12.1.1.2 
Serious adverse event 
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria: 
• Death 
• Life-threatening 
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.) 
• Significant or persistent disability/incapacity 
• Congenital anomaly/birth defect (including that occurring in a fetus) 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious 
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 12.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.) 
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• Initial inpatient hospitalization or prolongation of hospitalization 
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.) 
12.1.1.2.1 
Anticipated serious adverse events 
The following Anticipated SAEs are anticipated to occur in the population studied in this 
protocol at some frequency that is independent of drug exposure.  
This list does not change the Investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 12.1.2.3. 
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Table 12‒1: Anticipated serious adverse events for the population of subjects 
with AS 
MedDRA system organ class  
MedDRA preferred term 
Skin and subcutaneous tissue disorders 
Psoriasis 
Eye disorders  
Uveitis 
Musculoskeletal and connective tissue disorders  
Dactylitis 
Tendonitis 
Atlantoaxial instability 
Gastrointestinal disorders  
Colitis ulcerative  
Crohn's disease 
Cardiac disorders  
Aortic valve incompetence 
Atrial tachycardia 
Atrioventricular block 
Bundle branch block 
Cardiomyopathy 
Vascular disorders 
Aortitis 
Respiratory, thoracic and mediastinal disorders  
Pulmonary fibrosis 
Nervous system disorders 
Cauda equina syndrome 
Injury, poisoning and procedural complications  
Spinal cord injury 
Spinal fracture 
Cervical vertebral fracture 
Lumbar vertebral fracture 
Thoracic vertebral fracture 
Immune system disorders  
Amyloidosis 
Psychiatric disorders  
Depression 
AS=ankylosing spondylitis; MedDRA=Medical Dictionary for Regulatory Activities; SAE=serious adverse event 
Note: Exception: Listed events will not be regarded as anticipated SAEs if they are life threatening or if they 
result in the death of the study subject. 
12.1.1.3 
Adverse events of special interest 
An AE of special interest (AESI) 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. 
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AESI (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 subject. 
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12.1.1.4 
Other safety topics of interest 
Pre-specified safety topics of interest for the study are: infections (serious, opportunistic, fungal, 
and TB), neutropenia, hypersensitivity, suicidal ideation and behavior, major cardiovascular 
events, liver function test changes/enzyme elevations, malignancies, and inflammatory bowel 
diseases (with gastroenterology referral, as appropriate).  
This is based on findings from the IMP clinical program to date, potential risks generally 
associated with biologic immunomodulators, or findings from other medicines with a related 
mechanism of action. There are no specific AE reporting requirements for these topics, however 
special monitoring, additional data collection activities, and/or enhanced signal detection 
activities (within UCB) are in place. 
12.1.2 
Procedures for reporting and recording adverse events 
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the Investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study. 
12.1.2.1 
Description of adverse events 
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation. 
Details for completion of the Adverse Event eCRF (including judgment of relationship to IMP) 
are described in the eCRF Completion Guidelines. 
12.1.2.2 
Rule for repetition of an adverse event 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
• The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening” 
• The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one 
12.1.2.3 
Additional procedures for reporting serious adverse events 
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site. The Investigator must enter the information regarding the SAE into the appropriate 
eCRFs and transmit to UCB via the clinical database, even if the data are incomplete, or if it is 
obvious that more data will be needed in order to draw any conclusions. This information will be 
received by UCB and entered into the global safety database. Any ancillary documentation (eg, 
autopsy or other documentation) that is valid for the SAE can be sent to UCB using the contact 
information (fax/email) for SAE reporting listed in the Serious Adverse Event Reporting section 
at the front of the protocol. 
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It is important for the Investigator, when entering the SAE data into the eCRF, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the Investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner. 
Additional information received by the Investigator must be provided within 24 hours. All 
documents in the local language must be accompanied by a translation in English, or the relevant 
information included in the same document must be summarized in the eCRF and transmitted to 
UCB via the clinical database. 
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the IMP), up to 
30 days from the end of the study for each subject, and to also inform participating subjects of 
the need to inform the Investigator of any SAE within this period. Serious AEs that the 
Investigator thinks may be associated with the IMP must be reported to UCB regardless of the 
time between the event and the end of the study. 
Upon receipt of the electronic transmission of the SAE, UCB will perform an assessment of 
expectedness of the reported SAE. The assessment of the expectedness of the SAE is based on 
the Investigator’s Brochure. 
12.1.3 
Follow up of adverse events 
An AE should be followed until it has resolved, has stable sequelae, the Investigator determines 
that it is no longer clinically significant, or the subject is lost to follow up. This follow-up 
requirement applies to AEs, SAEs, and AEs of special interest; further details regarding follow 
up of PDILI events is provided in Section 12.6.1.4.  
If an AE is ongoing at the end of the study for a subject, follow-up should be provided until 
resolution/stable level of sequelae is achieved, or until the Investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
Investigator must provide a justification. The follow up will usually be continued for 20 weeks 
after the subject has discontinued his/her IMP. 
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time. 
12.2 
Pregnancy 
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the Investigator must immediately (within 24 hours) notify UCB’s PS department by entering all 
pregnancy information into the eCRF. An automatic notification will be sent to UCB’s PS 
department. The subject should be permanently withdrawn from IMP as soon as pregnancy is 
known (by positive pregnancy test), and the following should be completed: 
• The subject should immediately stop the intake of the IMP.  
• The subject should return for an early ad-hoc study visit. 
• A Safety Follow-Up Visit should be scheduled 20 weeks after the final dose of IMP. 
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The Investigator should discuss with the subject the possibility to continue the study by attending 
the scheduled visits for assessments without IMP administration. The tests or assessments, which 
are considered contraindicated during the pregnancy should not be performed. The early ad-hoc 
study visit will be considered as the ET Visit if the subject does not wish to pursue the study 
investigations. 
The Investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives. 
The pregnancy will be documented in the eCRF. The progression of the pregnancy and the 
eventual birth (if applicable) must be followed up using the eCRF. The Investigator must inform 
the subject of information currently known about potential risks and about available treatment 
alternatives. 
The pregnancy will be documented on the Pregnancy Report and Outcome Form provided to the 
Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome Form in which the Investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the Investigator and filed at the site. 
UCB’s PS department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up. 
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the 
Investigator or designee is asked to contact the subject to request consent of the partner via the 
Partner Pregnancy Consent Form that has been approved by the responsible IRB/IEC and should 
be available in the Investigator site file. In case of questions about the consent process, the 
Investigator may contact the UCB/contract research organization (CRO) contract monitor for the 
study. The Investigator will complete the information in the eCRF only after the partner has 
agreed that additional information can be captured and has provided the signed Partner 
Pregnancy Consent Form. UCB’s PS department is also the primary contact for any questions 
related to the data collection for the partner pregnancy, eventual birth, and follow up. 
A pregnancy becomes an SAE in the following circumstances: miscarriage, elective abortion, 
medically indicated abortion (eg, when the pregnancy is endangering life or health of the woman, 
or when the fetus will be born with severe abnormalities), unintended pregnancy after hormonal 
contraceptive failure (if the hormonal contraceptive was correctly used), ectopic pregnancy, fetal 
demise, or any congenital anomaly/birth defect of the baby. Those SAEs must be additionally 
reported using the eCRF.  
12.3 
Suspected transmission of an infectious agent 
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
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12.4 
Overdose of investigational medicinal product 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt). 
12.5 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that Investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study. 
In addition, an independent Data Monitoring Committee (DMC) will periodically review and 
monitor safety data from this study and advise UCB. Details are provided in the DMC Charter. 
Cardiovascular and Neuropsychiatric Adjudication Committees will also periodically review and 
monitor safety data from this study and advise UCB. Details are provided in the Adjudication 
Committee Charters. 
12.6 
Laboratory measurements 
Clinical laboratory assessments consist of biochemistry, hematology, urinalysis, and pregnancy 
tests (serum or urine) (Table 12‒2). A centralized laboratory will be used to supply all laboratory 
test supplies and analyze all blood and urine samples (except the urine pregnancy test). Any 
unscheduled laboratory testing should also be collected using the central laboratory (with the 
exception of urgent safety laboratory measurements which should be performed locally and 
centrally simultaneously). Testing to exclude hepatitis B, hepatitis C, and HIV (see Exclusion 
Criterion #12, Section 6.2) will be performed at Screening in addition to those measurements 
listed in Table 12‒2. A urine dipstick will be used for pregnancy testing. 
Rescreening and retesting rules are provided in Section 5.1.1.1 and Section 5.1.1.2. 
Specific details regarding the handling and processing of biochemistry and hematology samples 
are provided in the study laboratory manuals. 
For subjects consenting to the pharmacogenomic substudy, blood and/or stool samples will be 
collected at defined timepoints (Table 5-2) and shipped and stored according to the laboratory 
manual. 
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The following laboratory parameters will be measured: 
Table 12‒2: Laboratory measurements 
Hematology 
Biochemistry 
Urinalysis 
Basophils 
Calcium 
pH 
Eosinophils 
Chloride 
Albumin (protein) 
Lymphocytes 
Magnesium 
Glucose 
Monocytes 
Potassium 
Blood 
Neutrophils 
Sodium 
Leukocyte esterase 
Hematocrit 
Glucose 
Nitrite 
Hemoglobin 
BUN 
Urine dipstick for pregnancy 
testinga 
MCH 
Creatinine 
Urine drug screenc 
MCHC 
AST 
 
MCV 
ALT 
 
Platelet count 
ALP 
 
RBC count  
GGT 
 
WBC count  
Total bilirubin 
 
 
LDH 
 
 
Total cholesterol 
 
 
Serum pregnancy testinga 
 
 
CRPb 
 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; CRP=C-reactive protein; ET=Early Termination; GGT=gamma-glutamyltransferase; 
IMP=investigational medicinal product; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; RBC=red blood cell; 
SFU=Safety Follow-Up; WBC=white blood cell 
a A serum pregnancy test will be performed at Screening for all women of childbearing potential. A urine 
pregnancy test (urine dipstick analyzed locally) is also required at the Baseline Visit, Q4W from Week 4 to 
Week 52, ET, and at SFU visits. Pregnancy test results must be negative prior to administering IMP. 
b CRP will be tested at specified visits (Table 5-2). 
c Urine drug screen will be performed at the Screening Visit. 
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12.6.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and PDILI events meeting SAE criteria should be reported to the 
Sponsor within 24 hours of learning of their occurrence. Any PDILI event that meets the 
criterion for potential Hy’s Law must be reported within 24 hours of learning of their occurrence 
as an AE of special interest (see Section 12.1.1.3), and, if applicable, also reported as an SAE 
(see Section 12.1.1.2).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 12‒3) specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 12.6.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 12.6.1.4).  
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and Sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the Investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be discontinued 
unless a subsequent alternative diagnosis fully explains the hepatic findings. If a subsequent 
alternative diagnosis fully explains the hepatic findings, and the requirements provided in 
Section 12.6.1.2.1 are met, rechallenge with IMP may be appropriate. 
The approach to investigate PDILI is summarized in Table 12‒3. 
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Table 12‒3: Required investigations and follow-up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULN
b 
NA 
Hepatology consultc 
Medical Monitor must 
be notified within 
24 hours (eg, by 
laboratory alert) and 
subject discussed with 
Medical Monitor ASAP. 
Immediate IMP 
discontinuationd. 
 
Essential: Must have 
repeat liver 
chemistry values and 
additional testing 
completed ASAP 
(see 
Section 12.6.1.3); 
recommended to 
occur at the site with 
HCP. 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
values.e 
≥3xULN 
NA 
Yes 
≥8xULN 
NA 
NA 
 
 
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Table 12‒3: Required investigations and follow-up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥5xULN 
(and ≥2x 
baseline) 
and 
<8xULN  
<2xULN 
No 
Discussion with Medical 
Monitor required. 
Consider need for 
hepatology consult if 
there is no evidence of 
resolution (see Follow 
up requirements).c 
Further investigation 
– immediate IMP 
discontinuation not 
required (see 
Section 12.6.1.2). 
 
IMP discontinuation 
required if any of the 
following occur: 
• 
Subject cannot 
comply with 
monitoring 
schedule. 
• 
Liver chemistry 
values continue 
to increase 
• 
Liver chemistry 
values remain 
≥5xULN (and 
≥2x baseline) 
after 4 weeks of 
monitoring 
without 
evidence of 
resolution 
Essential: Every 
attempt must be 
made to have repeat 
liver chemistry 
values and 
additional testing 
completed within 
48 hours at the site 
with HCP (see 
Section 12.6.1.3). 
Monitoring of liver chemistry 
values at least twice per week for 
2 weeks.e 
• 
Immediate IMP 
discontinuation required if 
liver chemistry values 
continue to increase. 
After 2 weeks of monitoring 
liver chemistry values: 
• 
ALT or AST remains 
≥5xULN <8xULN, IMP 
should be temporarily 
withheld and subject should 
undergo repeat test in 2 
weeks. 
Continue IMP if ALT or 
AST values <5xULN; 
continue to monitor at least 
twice per week until values 
normalize, stabilize, or 
return to within baseline 
values. 
If ALT or AST remains 
≥5xULN after second re-
test, immediate IMP 
discontinuation required. 
Continue to monitor until values 
normalize, stabilize, or return to 
within baseline values.e 
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Table 12‒3: Required investigations and follow-up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug induced liver injury; ULN=upper limit of normal 
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia 
(>5%), rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
c Details provided in Section 12.6.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d Details are provided in Section 12.6.1.2. 
e Unless an alternative monitoring schedule is agreed by the Investigator and UCB responsible physician. Determination of stabilization is at the discretion 
of the Investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
 
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12.6.1.1 
Consultation with Medical Monitor and local hepatologist  
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also be discussed with the local hepatologist. The 
local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this discussion should be followed by a full 
hepatology assessment (see Section 12.6.1.3) and SAE report (if applicable). 
12.6.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring.  
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate discontinuation (see Section 6.3.1 and Table 12‒3 for details). 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The Investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative. 
12.6.1.2.1 
IMP restart/rechallenge  
Subjects who are immediately discontinued from IMP due to having met certain criteria for 
PDILI (as described in Section 6.3.1 and Table 12‒3), but for whom an alternative diagnosis is 
confirmed, ie, drug-induced liver injury is excluded, can rarely restart IMP. Rechallenge with 
IMP can occur only if ALL of the following requirements are met at the time of the rechallenge: 
• The results of additional testing and monitoring described in Section 12.6.1.3 and 
Section 12.6.1.4 confirm a nondrug-related cause for the abnormal hepatic laboratory 
parameters and any associated symptoms (ie, a subsequent alternative diagnosis fully 
explains the hepatic findings).  
• No alternative treatment options are available to the subject. 
• The subject has shown clear therapeutic benefit from the IMP. 
• Subject’s ALT or AST elevations do not exceed ≥3xULN. 
• Subject’s total bilirubin is <1.5xULN. 
• Subject has no signs or symptoms of hypersensitivity.  
• The rechallenge is approved by the UCB responsible physician and a hepatologist. The 
hepatologist must be external to UCB. It is recommended that the hepatologist be a local 
hepatology expert or the hepatologist treating the subject. 
• Subject agrees to the investigator-recommended monitoring plan and understands their 
individual benefit risk for restarting IMP and this is adequately documented.  
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12.6.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 12‒4 (laboratory measurements) and Table 12‒5 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the Sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory. 
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The following measurements are to be assessed: 
Table 12‒4: PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain heterophile 
antibody or monospot testing) 
Immunology 
Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Urine drug screena 
Chemistry 
Amylase 
 
Sodium, potassium, chloride, glucose, BUN, creatinine 
 
Total bilirubin, ALP, AST, ALT, GGT, total cholesterol, albumin 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation  
Additional 
Prothrombin time/INRb 
Serum pregnancy testc 
PK sample 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; CPK=creatine phosphokinase; GGT=gamma-glutamyltransferase; HBcAb-IgM=hepatitis B core 
antibody-IgM; HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; 
LDH=lactate dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RNA=ribonucleic 
acid; ULN=upper limit of normal 
a Tests in addition to the specified analytes may be performed based on the Investigator’s medical judgment and 
subject history. 
b Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause). 
c For women of childbearing potential. 
Additional information to be collected is presented in Table 12‒5. 
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Table 12‒5: PDILI information to be collected 
New or updated information 
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included. 
Pertinent medical history, including the following: 
• 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”) 
• 
Adverse reactions to drugs 
• 
Allergies 
• 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency) 
• 
Recent travel  
• 
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash) 
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Alcohol and illicit drug use 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Any postmortem/pathology reports 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury 
12.6.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 12‒3. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to Baseline. Determination of stabilization is at the discretion of the Investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
12.7 
Other safety measurements 
12.7.1 
Vital signs 
The Investigator or designee should measure all vital signs (systolic and diastolic BP, 
temperature [oral, axillary, or otic], pulse rate) prior to dosing after the subject has been sitting 
for at least 5 minutes, and the subject should remain seated during the measurements. At 
Baseline/Day 1 and Week 16, collect vital signs prior to drug administration and then at 
approximately 30 minutes and 1 hour after dosing.  
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12.7.2 
Body weight and height 
Height is collected at Screening only. The Investigator or designee will measure the height of the 
subject with shoes removed in meters and the weight of the subject in kilograms at the time 
points listed in Table 5-2. The same scale should be utilized throughout the study where possible. 
12.7.3 
Physical examination 
The physical examination should be conducted by the Investigator or designee at the time points 
listed in Table 5-2 and will include general appearance; ear, nose, and throat; eyes, hair, and 
skin; respiratory; cardiovascular; GI; musculoskeletal; hepatic; neurological (including limb 
reflexes); and mental status. Findings considered clinically significant changes since the physical 
examination at the Screening Visit will be recorded as AEs. 
12.7.4 
12-lead electrocardiogram 
The Investigator or designee will perform the ECG which will be read centrally at the time points 
listed in Table 5-2. Full details of ECG recording will be provided in the ECG Manual. 
12.7.5 
Assessment and management of TB and TB risk factors 
All subjects will be assessed for TB at Screening and at the time points specified in the schedule 
of assessments (Table 5-2) through physical examination for signs and symptoms of TB, chest 
x-ray (Section 12.7.5.2), laboratory testing (Section 12.7.5.1), and TB questionnaire 
(Section 12.7.5.3). 
At Screening, all subjects will have an IGRA test (QuantiFERON TB test is recommended), a 
chest x-ray (unless already performed within 3 months of Screening) and examination for signs 
and symptoms of TB. In addition, each subject will complete a TB questionnaire directed at 
potential exposure to TB and symptoms of TB.  
For the purposes of this study, TB definitions are as follows: 
a. Known TB infection: 
− Active TB infection or clinical signs and symptoms suspicious for TB (pulmonary or 
extra-pulmonary). 
− History of active TB infection involving any organ system or findings in other organ 
systems consistent with TB infection, unless adequately treated and proven to be fully 
recovered upon consult with a TB specialist. 
− Any evidence by radiography or other imaging modalities consistent with previously 
active TB infection that is not reported in the subject’s medical history. 
b. High risk of acquiring TB infection: 
− Known close exposure to another person with active TB infection within the 3 months 
prior to Screening. 
− Time spent in a healthcare delivery setting or institution where individuals infected with 
TB are housed and where the risk of transmission of infection is high. 
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c. Latent TB infection (unless appropriate prophylaxis is initiated at least 4 weeks prior to IMP 
dosing and continued to completion of prophylaxis): 
− The absence of signs, symptoms, or physical findings suggestive of TB infection with a 
positive IGRA test (or 2 indeterminate IGRA test results) and a chest x-ray (or other 
imaging) without evidence of TB infection. If the result of the IGRA test is 
indeterminate, the particular IGRA test previously performed may be repeated once; if 
positive or indeterminate on retest, the subject may not be randomized to IMP without 
further evaluation by a TB specialist and discussion with the Study Physician, if LTB 
infection is identified. The retest must be done during the protocol-defined Screening 
window. 
− Note: If available, respiratory or other specimens must also be smear and culture negative 
for TB (CDC diagnosis of LTB infection) http://www.cdc.gov/TB/topic 
/testing/default.htm). 
d. NTMB infection is defined as a clinical infection caused by mycobacterial species other than 
those belonging to the Mycobacterium tuberculosis complex. 
e. Tuberculosis test conversion: 
− A positive IGRA result for the current test when previous IGRA test results were 
negative. All subjects with TB test conversion must immediately stop IMP administration 
and be referred to a TB specialist for further evaluation. Confirmed TB test conversions 
should be classified as due to LTBI, active TB infection, or NTMB, and reported to the 
UCB PS function. 
Subject eligibility, retesting requirements, and treatment requirements are shown in Figure 12‒1. 
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Figure 12‒1: Schematic diagram of TB test results and study eligibility 
 
CDC=Center for Disease Control; IGRA=interferon-gamma release assay; LTBI=latent tuberculosis infection; 
TB=tuberculosis; WHO=World Health Organization 
a IGRA retest must be done during the protocol-defined Screening window. 
b Subject has a past history of active TB involving any organ system unless adequately treated according to 
WHO/CDC therapeutic guidance and proven to be fully recovered upon consult with a TB specialist. Subjects who 
have recently (no more than 12 months prior to Screening) completed the full treatment course of prophylaxis for 
LTBI are allowed. Prophylaxis should be in accordance with WHO or CDC guidelines and TB specialist judgment 
based on the origin of infection.  
c Subjects with LTBI may enter the study only after they have completed at least 4 weeks of appropriate 
prophylactic therapy and thereafter, will continue and complete the entire regimen. 
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Figure 12‒2: Schematic diagram of TB test results during the study 
 
ASAP=as soon as possible; IGRA=interferon-gamma release assay; IMP=investigational medicinal product; 
LTBI=latent tuberculosis infection; TB=tuberculosis 
a IGRA retest must be done ASAP and prior to the next IMP dose 
b Subjects with LTBI may continue the study only after they have completed at least 4 weeks of appropriate 
prophylactic therapy and thereafter, will continue and complete the entire regimen.  
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12.7.5.1 
Tuberculosis assessment by IGRA 
During conduct of the study, the TB assessment by IGRA (QuantiFERON TB test is 
recommended) will be performed as described in Table 5-2 for all subjects. The test results will 
be reported as positive, negative, or indeterminate. Positive and indeterminate TB test results that 
occur during the course of the study must be reported as an AE and appropriately updated once 
the final diagnosis is known (eg, active TB, latent TB, or false positive TB test). UCB also 
recommends that a TB specialist be consulted where TB (latent or active) is suspected or if there 
are doubts regarding test results. If latent or active TB is identified, subject must undergo 
appropriate study-specified withdrawal procedures. For indeterminate test results, the retest 
during Screening must be done during the protocol-defined Screening window. 
12.7.5.2 
Chest x-ray for tuberculosis 
A plain posteroanterior chest x-ray must be performed in the Screening Period unless one has 
been performed within 3 months prior to the Screening Visit. The chest x-ray (or, if done, 
Computed Axial Tomography [CAT] of the chest) must be clear of signs of TB infection 
(previous or current) before first IMP administration. All chest imaging (particularly x-rays) 
should be available for review by the Investigator before randomization of the subject. The chest 
x-ray reading should be repeated if the TB test was confirmed positive. If the second read of the 
pretreatment chest x-ray is confirmed to be clear, the subject may be included in the study 
4 weeks after the start of the TB prophylactic treatment. If the pretreatment chest x-ray is not 
available for a re-read, it should be repeated after notification to the radiologist that this subject 
is IGRA positive, and confirmed to be clear for signs of TB. 
The chest imaging must be negative for any old or recent TB infection as determined by a 
qualified radiologist and/or pulmonary physician. Any new clinically significant findings post 
Baseline on chest x-ray must be documented in the source documents and the eCRF as an AE. 
12.7.5.3 
Tuberculosis questionnaire 
The questionnaire “Evaluation of signs and symptoms of tuberculosis” should be used as a 
source document. The questionnaire will be completed as described in Table 5-2. The 
questionnaire will assist with the identification of subjects who may require therapy for TB. A 
subject who answers “Yes” to the question 
 
 Screening 
is excluded. A “Yes” response to any of the other questions within the questionnaire at Screening 
should trigger further careful assessment to determine if subject has LTB or active TB (see 
Exclusion Criterion #14 in Section 6.2). A “Yes” response to any of the questions during the 
study should trigger further assessments to determine if the subject has either LTB or active TB 
infection.  
12.7.5.4 
Tuberculosis management 
During the study, subjects who develop evidence of LTB infection or active TB must 
immediately stop further administration of IMP and will be referred to an appropriate TB 
specialist (pulmonologist or infectious disease specialist) for further evaluation. Evidence of 
LTB infection is defined as subject’s IGRA test converts to positive or indeterminate (and 
confirmed indeterminate on repeat), or the subject’s questionnaire or history and physical 
indicates that TB infection or exposure may have occurred. Evidence of active TB includes, in 
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addition to the aforementioned tests, signs and symptoms of organ involvement. In either 
situation, the subject should be carefully assessed by a TB specialist for active TB. Subjects 
diagnosed with active TB should be withdrawn from the study and receive appropriate TB or 
prophylaxis therapy.  
If a TB specialist excludes an active TB infection the subject can proceed with the IMP no earlier 
than 4 weeks after the start of an appropriate prophylactic therapy. 
Any presumptive diagnosis or diagnosis of a TB infection is a reportable event. Confirmed active 
TB must be reported as an SAE. The Investigator is to complete and submit the TB follow-up 
Form provided. 
The subject should be transferred to the care of his/her physician and managed according to the 
best available standard of care. Subjects identified as having converted to active TB during the 
study must be withdrawn and scheduled to return for the ET Visit as soon as possible but no later 
than the next scheduled study visit and complete all ET Visit assessments.  
The subject should be encouraged to complete a SFU Visit (20 weeks after the final dose of 
IMP). 
If infection with NTMB is identified during the study, the same procedure as for active TB 
acquired during the study must be followed. 
12.7.6 
Pregnancy testing 
Pregnancy testing will consist of serum testing at Screening for all women of childbearing 
potential. A urine dipstick will be used for pregnancy testing at all other visits. 
The Screening Visit serum pregnancy test results must be negative, and received and reviewed 
prior to randomization. A negative urine pregnancy test result should be obtained immediately 
prior to each administration of IMP and at all visits specified in Table 5-2. Pregnancy tests 
should be administered to all female subjects of childbearing potential, regardless of their use of 
birth control. 
12.7.7 
PHQ-9 
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring, and measuring 
the severity of depression. The PHQ-9 scores for depression range from 0 to 27 with higher 
scores indicating worse state. A score of 5 to 9 is considered to be minimal symptoms of 
depression. A score of 10 to 14 is considered minor depression, dysthymia, or mild major 
depression. A score of 15 to 19 is considered to indicate moderately severe major depression, 
and a score ≥20 is considered to be severe major depression.  
The PHQ-9 will be completed by the subject at the visits specified in Table 5-2.  
Refer to Section 6.3 for PHQ-9-related withdrawal criteria. 
12.7.8 
Assessment of suicidal ideation and behavior 
Suicidal ideation and behavior will be assessed by using the eC-SSRS; the questionnaire will be 
completed by the subject. This scale will be used to assess suicidal ideation and behavior that 
may occur during the study. The visits at which the eC-SSRS assessments will be performed are 
specified in the schedule of study assessments (Table 5-2). 
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The eC-SSRS is a standardized and validated instrument developed for the assessment of the 
severity and frequency of suicidal ideation and behavior (Posner et al, 2011; Mundt et al, 2010). 
Subjects respond to standardized clinical questions that are presented in a uniform fashion. The 
eC-SSRS defines 5 subtypes of suicidal ideation and behavior in addition to self-injurious 
behavior with no suicidal intent. The eC-SSRS takes approximately 3 to 10 minutes to complete. 
Refer to Section 6.3 for eC-SSRS-related withdrawal criteria.  
13 
OTHER STUDY MEASUREMENTS 
13.1 
Demography 
The Investigator or designee will collect demographic information for all subjects according to 
local rules and regulations. This will include age, gender, race and ethnicity. Demographic 
information will be recorded in the eCRF. 
The Investigator or designee will obtain a complete history of lifestyle (alcohol or drug 
consumption within 6 months prior to Screening, nicotine consumption at the time of screening) 
and infections (fungal skin infections within 12 months prior to Screening) as part of the 
screening assessment. Lifestyle and infection history will be recorded in the eCRF. 
13.2 
Medical and ankylosing spondylitis history 
The Investigator or designee will obtain a complete medical history and a medical history related 
to AS (including EAMs, the date of diagnosis, and past treatments for AS, and ASAS 
classification criteria as referenced in Section 19.1) as part of the Screening assessment and 
include all clinically relevant past or coexisting medical conditions, responses to AS treatment as 
available, Baseline GI-related symptoms, and surgeries. Findings will be recorded in the eCRF. 
13.3 
Prior and concomitant medications 
As part of the medical history, the Investigator or designee will determine prior and concomitant 
medications and record these in the eCRF. 
14 
STUDY MANAGEMENT AND ADMINISTRATION  
14.1 
Adherence to protocol 
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
Sponsor.  
After implementation of such measure, the Investigator must notify the CPM of the Sponsor 
within 24 hours and follow any local regulatory requirements. 
14.2 
Monitoring 
UCB (or designee) will monitor the study to meet the CRO’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, and to ensure 
that study initiation, conduct, and closure are adequate. Monitoring of the study may be 
delegated by UCB to a CRO or a contract monitor. 
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The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The Investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The Investigator will allow UCB (or designee) to periodically review all CRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of CRFs, ensure that all protocol 
requirements, applicable authorities’ regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records. 
14.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents. Source documents are original records in which raw data are first 
recorded. These may include hospital/clinic/general practitioner records, charts, diaries, x-rays, 
laboratory results, printouts, pharmacy records, care records, ECG or other printouts, completed 
scales, quality of life questionnaires, or video, for example. Source documents should be kept in 
a secure, limited access area. 
Electronic Patient-Reported Outcome (ePRO) measures (eg, ASQoL; BASDAI, BASFI, SF-36, 
MOS-12, PGADA, total and nocturnal spinal pain, FACIT-Fatigue, EQ-5D-3L, WPAI-SHP) will 
be completed by each subject and will be collected electronically.  
The data collection and database management system will be supplied by a vendor and will be 
compliant with the relevant regulations. The data collected on the ePROs will be uploaded to a 
central server database and will be sent electronically to UCB (or a designated CRO). 
Sponsor or designee will review to ensure that computerized source documents produced by the 
site are compliant with Food and Drug Administration (FDA) Part 11 requirements and 
document appropriately. Source documents that are computer generated and stored electronically 
must be printed for review by the monitor (eg, ECG reports). Once printed, these copies should 
be signed and dated by the Investigator and become a permanent part of the subject’s source 
documents. The Investigator will 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 must be saved and stored as instructed by UCB (or designee).  
14.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 14.2.1. 
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14.3 
Data handling 
14.3.1 
Case Report Form completion 
This study will use electronic data capture (EDC); the Investigator is responsible for prompt 
reporting of accurate, complete, and legible data in the eCRF and in all required reports. 
This study will also use an electronic device (Site Tablet) to capture patient reported outcomes. 
Serious AE reporting will be done using the eCRF in the appropriate SAE Report Form section 
and transmitted to Patient Safety (see Section 12.1.2.3). The safety database and the clinical 
database will be reconciled during the study and discrepancies will be corrected as needed. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Access to the EDC will be given after training has been received. A training certificate will be 
provided and filed. 
Detailed instructions on the use of the EDC will be provided in the eCRF Completion 
Guidelines. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be re-approved by the Investigator. Any change or correction 
to the eCRF after saving must be accompanied by a reason for the change. 
14.3.2 
Database entry and reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. Case Report Form data are entered into the clinical database using independent, 
double-data entry, with the exception of comment fields, which are verified by a second person. 
The data are entered into the eCRFs once and are subsequently verified if the study is performed 
using electronic data capture. 
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed. 
14.3.3 
Subject Screening and Enrollment log/Subject Identification Code list 
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment 
Log. 
The Investigator will keep a Subject Identification Code list. This list remains with the 
Investigator and is used for unambiguous identification of each subject. 
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation. 
14.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
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safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the Sponsor or by the Investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused IMP and other material in accordance with UCB procedures for the study. 
14.5 
Archiving and data retention 
The Investigator will maintain adequate records for the study, including CRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
All essential documents are to be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (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. 
14.6 
Audit and inspection 
The Investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities. 
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of the 
IMP have been processed and reported in compliance with the planned arrangements, the 
protocol, investigational site, and IRB/IEC SOPs, ICH GCP, and applicable regulatory 
requirements. 
The Investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the Investigator will immediately 
inform UCB (or designee). 
14.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the Sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
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15 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
15.1 
Definition of analysis sets 
The following analysis sets were defined: 
• The Enrolled Set (ES) will consist of all subjects who have given informed consent. 
• The Randomized Set (RS) will consist of all randomized subjects. 
• The Safety Set (SS) will consist of all randomized subjects who received at least 1 dose of 
the IMP. 
• The Full Analysis Set (FAS) will consist of all randomized subjects who received at least 
1 dose of the IMP and have a valid measurement of all components of the primary efficacy 
variable at Baseline. 
• The Per-Protocol Set (PPS) will consist of all subjects in the RS who had no important 
protocol deviation affecting the primary efficacy variable. Important protocol deviations will 
be predefined and subjects with important protocol deviations will be evaluated during a data 
evaluation meeting prior to unblinding of the data. Exclusions from the FAS will be 
considered important protocol deviations that also result in exclusion from the PPS. 
• The Pharmacokinetics Per-Protocol Set (PK-PPS) consists of all randomized subjects who 
received at least 1 dose of the IMP and provided at least 1 quantifiable plasma concentration 
post-dose without important protocol deviations that would affect the concentration.  
• The coronavirus disease 2019 (COVID-19) free set will consist of all subjects in the RS who 
had no COVID-19 impact up to the primary efficacy endpoint. Further details will be defined 
as part of the SAP. 
15.2 
General statistical considerations 
Summary statistics will consist of frequency tables for categorical variables. For continuous 
variables, summary statistics will consist of number of available observations, arithmetic mean, 
SD, median, minimum, and maximum unless stated otherwise. 
All statistical tests will be performed 2-sided at a 5% level of significance unless stated 
otherwise. 
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15.3 
Planned efficacy analyses 
15.3.1 
Analysis of the primary and secondary efficacy variables 
A fixed sequence testing procedure will be applied for each of the primary and selected 
secondary variables. The testing procedure will control the family-wise type-I-error and will 
account for multiplicity. The family-wise error will be set to α=0.05 (2-sided).  
For the testing procedure, the hypotheses are mapped into a set ranging from H1 to H12.  
For each test based on a binary efficacy variable, the null hypothesis is that the conditional odds 
ratio is equal to 1. 
H0: ORT1/T2 = 1 
The alternative hypothesis is that the conditional odds ratio is not equal to 1. 
HA: ORT1/T2 ≠ 1  
For each test on a continuous efficacy variable, the null hypothesis is that there is no difference 
between treatment groups. 
H0: T1 – T2 = 0 
The alternative hypothesis is that there is a difference between treatment groups. 
HA: T1 – T2 ≠ 0 
The treatment comparison for each of these hypotheses is between bimekizumab 160mg sc Q4W 
and placebo. Point estimates and 95% confidence intervals (CI) will be calculated. 
The testing starts with H1. If H1 can be rejected at α=0.05 (2-sided), the corresponding α will be 
passed on to the next test in the sequence (ie, H2) and testing will continue. The hierarchical 
testing will be stopped if a hypothesis cannot be rejected at α=0.05 (2-sided). 
The sequential testing procedure of primary and secondary efficacy endpoints is shown in 
Figure 15‒1. 
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Figure 15‒1: Sequential testing procedure of primary/secondary efficacy 
endpoints  
 
ASAS40 (20)=Assessment of SpondyloArthritis International Society 40% (20%) response criteria; 
ASAS5/6=Assessment of SpondyloArthritis International Society 5 out of 6 response criteria; 
ASAS-PR=Assessment of SpondyloArthritis International Society partial remission; ASDAS-MI=Ankylosing 
Spondylitis Disease Activity Score major improvement; ASQoL=Ankylosing Spondylitis Quality of Life; 
BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASFI=Bath Ankylosing Spondylitis Functional 
Index; BASMI=Bath Ankylosing Spondylitis Metrology Index; BKZ=bimekizumab; CfB=change from Baseline; 
H=hypothesis; PCS=physical component summary; SF-36=Short Form 36-item Health Survey; TNFα=tumor 
necrosis factor alpha; W=Week 
15.3.1.1 
Analysis of the primary efficacy variable 
The primary efficacy analysis will be performed based on the RS.  
The primary endpoint is the ASAS40 response at Week 16. The primary efficacy analysis will 
evaluate the composite estimand in the RS. The composite estimand combines the clinically 
meaningful improvement from Baseline based on the ASAS40 response and not discontinuing 
treatment early. In practice, this composite estimand is similar to non-responder imputation 
(NRI), referred to here as modified NRI. 
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The following 4 attributes describe the estimand that will be used to define the treatment effect 
of interest for the primary efficacy analysis: 
1. Population = Subjects enrolled according to the protocol-specified inclusion/exclusion 
criteria and randomized to IMP. 
2. Subject-level outcome = ASAS40 at Week 16. 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment prior to Week 16. A composite strategy will be implemented in which a positive 
clinical outcome is defined as achieving ASAS40 at Week 16 and not discontinuing study 
treatment through Week 16. 
4. Population-level summary measure = Conditional odds ratio comparing bimekizumab to 
placebo. 
Missing data at Week 16 that are not preceded by an intercurrent event, and any data after an 
intercurrent event will be imputed as non-responders. 
Any use of prohibited or rescue therapy through Week 16 would constitute an important protocol 
deviation which would be accounted for when the supportive analysis based on the PPS is 
performed (see Section 15.3.1.1.1). 
The statistical hypothesis for the ASAS40 response at Week 16 is that the conditional odds ratio 
for the ASAS40 response in the bimekizumab treatment group relative to the placebo group is 
equal to 1.  
A logistic regression model will be used to assess the effect of bimekizumab vs placebo on 
ASAS40 response. The model will include fixed effects for treatment. The suitability of 
including the stratification variables of prior TNFα inhibitor exposure (yes/no) and region will be 
assessed, and will be added to the model if appropriate. Comparisons will be made for 
bimekizumab vs placebo using the 2-sided Wald test at a significance level of α=0.05 (ie, H1 in 
Figure 15‒1). The odds ratio versus placebo, p-value, and the 95% CI will be calculated. 
15.3.1.1.1 
Supportive analyses 
Supportive analyses for the primary efficacy variable will be conducted. The analyses will be 
repeated: 
1. Based on the PPS to evaluate the effect of important protocol deviations on the analysis.  
2. For all subjects in the FAS to evaluate the consistency between the RS and the more 
restrictive FAS. This analysis will only be performed if the number of subjects in RS and 
FAS are different. 
3. For all individual components of the ASAS40 response to explore the effect of the signs and 
symptoms of the individual components on the composite endpoint. Since all ASAS 
components are continuous variables (eg, change from Baseline in total spinal pain), an 
analysis of covariance (ANCOVA) with treatment, region, and prior TNFα inhibitor 
exposure as fixed effects and the Baseline values as covariate will be used for the analysis. 
4. Using a modified composite estimand where intercurrent events are defined only as 
discontinuation due to adverse event or lack of efficacy. 
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5. Using a treatment policy imputation. 
6. Using a tipping point analysis. 
7. Using observed cases only (OC). 
8. Using the COVID-19-free set. 
Further specification of additional supportive analyses to evaluate varying assumptions related to 
the handling of missing data will also be performed and are described in Section 15.7. 
15.3.1.2 
Analyses of the secondary efficacy variables 
The secondary efficacy variables will be analyzed for all subjects in the RS.  
Binary variables will be analyzed to evaluate the composite estimand in the RS, as done for the 
primary efficacy variable. The composite estimand combines (1) achieving the given binary 
response and (2) not discontinuing treatment prior to Week 16. The statistical hypothesis for the 
binary variables at Week 16 is that the conditional odds ratio for binary variables in the 
bimekizumab treatment group compared with the placebo treatment group is equal to 1. 
Continuous variables will be analyzed for treatment effects using a similar estimand approach as 
for the primary efficacy variable, except for the following: 
• Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment prior to Week 16. A hypothetical strategy for addressing intercurrent events will be 
implemented. This estimand targets the treatment difference in a scenario where withdrawal 
from study treatment does not occur, such that outcomes for subjects without an intercurrent 
event are as observed, and outcomes for subjects with an intercurrent event are treated as 
though they had completed the randomized study treatment through Week 16. A multiple 
imputation strategy will be used to impute data following an intercurrent event. 
• Population-level summary measure = The difference in adjusted means between 
bimekizumab and placebo. 
Any missing data at Week 16 that is not preceded by an intercurrent event (ie, discontinuation of 
study medication) will be imputed based on a predefined multiple imputation (MI) model. The 
missing value will be replaced by a set of plausible values, where each value is a Bayesian draw 
from the conditional distribution of the missing data given the observed data. Intermittent 
missing data will be imputed using the Markov-Chain Monte Carlo (MCMC) method, followed 
by monotone regression for monotone missing data. The statistical model for the comparison of 
bimekizumab and placebo will be an ANCOVA with treatment, region, and prior TNFα inhibitor 
exposure as fixed effects and the Baseline value as covariate. The statistical hypothesis for the 
continuous variables at Week 16 is that the treatment difference between the bimekizumab 
treatment group and placebo is equal to 0. 
All secondary efficacy variables will also be summarized based on observed case data. Binary 
outcomes will also be summarized using the modified composite estimand. 
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15.3.2 
Analyses of other efficacy variables 
All other efficacy variables will be analyzed based on the RS.  
Binary variables will be summarized using frequency tables by each visit. Generally, the 
estimand structure for binary other efficacy variables is as described below. Note that further 
details will be provided in the SAP. 
1. Population = Subjects meeting the protocol-specified inclusion/exclusion criteria. 
2. Subject-level outcome = The given variable and time point being summarized (eg, ASAS-PR 
at Week 24). 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment prior to the time point being summarized. A composite strategy will be 
implemented in which a positive clinical outcome is defined as achieving the given variable 
at the specified time point and not discontinuing study treatment through that time point. 
4. Population-level summary measure = Unadjusted proportion of responders. 
Any missing data that are not preceded by an intercurrent event as described above will be 
imputed based on a NRI as described for the primary and secondary efficacy variables. 
Continuous variables will be summarized using descriptive statistics by each visit. Generally, the 
estimand structure for continuous other efficacy variables is as described below. Note that further 
details will be provided in the SAP. 
1. Population = Subjects meeting the protocol-specified inclusion/exclusion criteria. 
2. Subject-level outcome = The given variable and time point being summarized (eg, Change 
from Baseline in BASFI at Week 36). 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment prior to the time point being summarized. A hypothetical strategy will be 
implemented in which outcomes for subjects without an intercurrent event are as observed at 
the given time point, and outcomes for subjects with an intercurrent event are treated as 
though they had completed the randomized study treatment through the time point being 
summarized. A multiple imputation strategy will be used to impute data following an 
intercurrent event.  
4. Population-level summary measure = Unadjusted mean. 
Any missing data that are not preceded by an intercurrent event as described above will be 
imputed based on a predefined multiple imputation model as described for continuous secondary 
efficacy variables. 
In some cases, other efficacy variables may also be summarized based on observed case data (ie, 
subjects with missing data or who have prematurely discontinued study treatment are treated as 
missing). 
Time to ASAS20/40 response will be estimated and presented using the Kaplan-Meier 
product-limit method for each treatment. Time to a given response will be defined as the length 
in days from Baseline until the first date when the response is achieved. Subjects who 
discontinue study treatment prior to achieving a response will be censored at the date of study 
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treatment discontinuation. The median time to response, including the 2-sided 95% CI, will be 
calculated for each treatment. Between-group differences will be analyzed with the log-rank 
statistic. 
15.3.3 
Subgroup analyses 
Subgroup analyses using descriptive statistics will be performed on the primary efficacy 
variable. The following variables for subgroup analyses will be defined:  
• Age at Baseline (<45 years of age; ≥45 years of age) 
• Gender (male; female) 
• Disease duration (<5 years; ≥5 years) 
• Region (eg, Asia, Eastern Europe, North America, Western Europe) 
• Body mass index at Baseline (<18.5kg/m2; 18.5kg/m2 to <25kg/m2; 25kg/m2 to <30kg/m2; 
≥30kg/m2) 
• Prior TNFα inhibitor exposure (yes; no) 
• CRP at Baseline (≤ULN; >ULN) 
• ASDAS status at Baseline (<1.3 [inactive disease]; 1.3 to ≤2.1 [low disease activity]; 
>2.1 to ≤3.5 [high disease activity]; >3.5 [very high disease activity]) 
• HLA-B27 positivity (yes; no) 
• Anti-bimekizumab antibody status (positive, negative) 
15.4 
Planned safety analyses 
15.4.1 
Safety analyses 
Safety variables will be analyzed for all subjects in the SS. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA® 19.0). Adverse events with an onset date on or after the date of first IMP 
administration and up to 20 weeks after the last (most recent) dose of IMP will be defined as 
TEAEs. Treatment-emergent AEs will be summarized descriptively by treatment group, primary 
system organ class, high level term, and preferred term. Additional tables will summarize TEAEs 
leading to withdrawal from IMP, TEAEs by intensity and relationship to IMP. Treatment 
emergent AEs leading to withdrawal from both IMP or the study, serious TEAEs, TEAEs of 
special interest, TEAE of special monitoring, and deaths will be also be tabulated and listed. 
When analyzing categorical data, the number and percentage of subjects in each category will be 
presented by treatment group. In addition, shift tables may be used to evaluate the number and 
percentage of subjects having a different post-Baseline status when compared to their Baseline 
status. 
Laboratory values (including markedly abnormal values), urinary values, vital signs, ECGs, 
eC-SSRS, and extent of exposure will be presented descriptively by treatment group. Definitions 
for markedly abnormal laboratory values will be provided in the SAP. 
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15.5 
Planned other analyses 
15.5.1 
Pharmacokinetic analyses 
Pharmacokinetic variables will be analyzed for all subjects in the PK-PPS.  
Pharmacokinetic analyses will be detailed in a separate data analysis plan and reported in a 
separate document.  
Bimekizumab plasma concentrations will be summarized by treatment arm for subjects who 
received at least 1 dose of bimekizumab at applicable time points scheduled in Table 5-2. 
15.5.2 
Immunological analyses 
Anti-bimekizumab antibody levels will be determined using a tiered approach applying 
Screening, Confirmatory, and Titration assays. The details of this approach will be described in a 
separate Analytical Plan. Anti-bimekizumab antibody levels will be summarized by treatment 
arm for subjects who received at least 1 dose of bimekizumab at applicable time points 
scheduled in Table 5-2. 
15.6 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary efficacy, key safety, or PK outcomes for 
an individual subject. The criteria for identifying important protocol deviations will be defined 
within the appropriate protocol-specific document. Important protocol deviations will be 
reviewed as part of the ongoing data cleaning process and all important deviations will be 
identified and documented prior to unblinding to confirm exclusion from analysis sets. 
15.7 
Handling of dropouts or missing data 
The primary analysis for the primary variable will use a conservative approach to handling 
missing data that is similar to non-responder imputation. The sensitivity of results to the 
approach for handling missing data will be evaluated via supportive analyses using different 
missing data mechanisms. 
In instances where MI is used, the missing value is replaced by a set of plausible values, where 
each value is a Bayesian draw from the conditional distribution of the missing data given the 
observed data. Intermittent missing data will be imputed using the MCMC method, followed by 
regression for monotone missing data. The planned multiple imputation procedures are based on 
an assumption of data missing at random (MAR).  
The following supportive analyses for the primary efficacy variable will be conducted: 
1. Multiple imputation as described above will be performed using the modified composite 
estimand as specified for the use with the secondary variables. The definition of an 
intercurrent event is changed from all treatment discontinuation, to discontinuation of 
treatment due to AE or lack of efficacy.  
2. Tipping point analyses will be performed to evaluate missingness assumptions. These tipping 
point analyses will be performed on the monotone missing data and only if the primary 
analysis is significant at α=0.05. Various delta adjustments will be made to the assumed 
responses on the monotone missing data in each treatment group independently with various 
degrees of plausibility. It will include scenarios where subjects who have missing data and 
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are randomized to bimekizumab have a lower probability of response compared to subjects 
who have missing data and were randomized to placebo. For binary variables, this includes 
the worst case scenario where subjects who have missing data and are randomized to 
bimekizumab are considered nonresponders, while subjects who have missing data and were 
randomized to placebo are considered responders. The goal of the tipping point analysis is to 
systematically vary assumptions until there is no evidence of a treatment effect (if possible). 
The plausibility of such required delta adjustment will then be assessed. Details will be 
provided in the Statistical Analysis Plan (SAP).  
3. The treatment policy strategy for addressing intercurrent events will be considered. This will 
be based on an analysis of all available data at Week 16 regardless of the occurrence of 
intercurrent events. This analysis will use the same models specified for the primary and 
secondary analyses, where subjects are analyzed according to their randomized treatment, 
even if they discontinued study treatment for any reason prior to Week 16. Even though 
efforts will be made to collect the primary outcome data for all subjects at Week 16, there 
may still be some subjects for whom Week 16 efficacy data cannot be obtained. In this case, 
missing data will be imputed using MI under the assumption of MAR. Results will be 
combined into a single inference using Rubin's rule. It should be noted that this measures 
something different from the primary analysis and could be confounded by placebo subjects 
who withdraw and are subsequently on another active medication at the time of the Week 16 
assessment. Therefore, the results of this analysis should be interpreted in the appropriate 
context.  
4. An additional supportive analysis will be based on observed data only for subjects who are 
still on the initially randomized treatment at Week 16. Subjects with missing data or who 
have prematurely discontinued study treatment will be treated as missing. 
For the secondary and other efficacy variables, the binary endpoints will be analyzed using 
modified NRI, MI, and OC, and the continuous endpoints will be analyzed using MI and OC. 
Additional details on these supportive analyses will be provided in the SAP. 
15.8 
Planned interim analysis and data monitoring 
15.8.1 
Interim analyses 
Two interim analyses will be performed: one after the planned number of randomized subjects 
have completed the Double-Blind Treatment Period and the Week 24 assessments, and one after 
the planned number of subjects have completed Week 52.  
The purpose of the Week 24 interim analysis is to perform a comprehensive evaluation of all 
available double-blind data for the 2 treatment arms and to prepare a regulatory submission for a 
Marketing Authorization Application based on this analysis. 
For the Week 24 interim analysis, the database will be locked and the treatment codes will be 
made available to UCB personnel with exception of operational staff working on the study. An 
interim report will be written. The Investigators and subjects will remain blind to the original 
randomized IMP dosing regimen until the subject completes the Maintenance Period at Week 52. 
The Week 24 interim analysis will evaluate the primary and secondary efficacy variables, as well 
as all other efficacy, safety, and PK variables up to Week 24 according to the statistical methods 
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specified in the SAP. No formal alterations to the further study conduct (eg, stopping rules, 
sample size re-estimation, or changes to eligibility criteria) are planned for this interim analysis. 
To ensure blinding of Investigators and subjects, a statistical blinding plan will be written to 
evaluate the potential bias of the Maintenance Period, define blinded and unblinded teams, and 
describe the process of interim results generation and dissemination. The plan will be finalized 
prior to the lock of the database at the Week 24 interim analysis. 
The purpose of the Week 52 interim analysis is to perform a comprehensive evaluation of all 
available data for the study and to supplement the regulatory submission based on the Week 24 
interim analysis. 
The Week 52 interim analysis will evaluate all efficacy, safety, and PK variables up to Week 52 
according to the statistical methods specified in the SAP. Only data from the SFU visits for 
subjects who discontinued and did not enter the extension study will not be included. 
Additional interim analyses and data cuts may be performed for regulatory purposes. 
15.8.2 
Data monitoring and Adjudication Committees 
A DMC will be reviewing safety data on an ongoing basis. The DMC membership includes 
experienced clinicians and a statistician, all of whom have expertise in clinical studies. Further 
details are specified in the DMC Charter. 
Cardiovascular and Neuropsychiatric Adjudication Committees will also periodically review 
data from this study. Details are provided in the Cardiovascular Adjudication Committee and 
Neuropsychiatric Adjudication Committee charters.  
Other adjudication committees may be added as necessary. 
Both Data Monitoring and Adjudication Committee members may not participate in the study as 
principal or co-Investigators, or as study subject care physicians and must not be members of the 
study team at UCB or the conducting CRO. The duration of membership for the committees will 
be inclusive of planned analyses for AS0011.  
15.9 
Determination of sample size 
Approximately 300 subjects will be randomly assigned in a 2:1 ratio to the following treatment 
groups: bimekizumab 160mg sc Q4W (200 subjects) or placebo sc Q4W (100 subjects).  
The primary efficacy analysis is based on the bimekizumab dose versus placebo for 
ASAS40 response at Week 16.  
All sample size and power calculations were done at a significance level of 0.05. 
All sample size and power calculations were performed using the software nQuery Advisor® 7.0. 
15.9.1 
Power calculation for primary endpoint 
The sample size assumptions for bimekizumab versus placebo are based on the ASAS40 
response data from the Phase 2b bimekizumab study in subjects with active AS (AS0008). 
An ASAS40 response at Week 16 of 40% can be assumed for the bimekizumab treatment group. 
This assumed treatment response is based on the bimekizumab 160mg dose results of AS0008 at 
Week 12 (46.7%). It was also assumed that the treatment response at Week 12 and Week 16 
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would be the same (ie, conservative assumption). In addition, the observed ASAS40 response 
rates were adjusted to account for a higher number of subjects with prior TNFα inhibitor 
exposure and for a higher number of subjects with early withdrawal. Placebo ASAS40 response 
at Week 16 was assumed to be 15% and is more conservative than that of AS0008 at Week 12 
(ie, ASAS40 response=13.3%).  
The sample size for showing statistical superiority of bimekizumab versus placebo was 
calculated using a 2-sided 2-sample Chi square test with continuity correction (Fleiss et al, 
1980). With 200 subjects in the bimekizumab treatment group and 100 subjects in the placebo 
group, the test for detecting statistical superiority of bimekizumab versus placebo based on 
ASAS40 response at Week 16 is powered with >99%. 
15.9.2 
Power calculations for secondary endpoints in the hierarchical 
testing 
The assumptions for power calculations of the secondary endpoints are based on the Week 12 
results of AS0008, unless indicated otherwise. It was assumed that the treatment response at 
Week 12 and Week 16 would be the same (ie, conservative assumption). In addition, the 
observed data were adjusted in the same way as the primary endpoint to account for a higher 
number of subjects with prior TNFα inhibitor exposure and for a higher number of subjects with 
early withdrawal.  
All power calculations for binary endpoints were performed using a 2-sided 2-sample Chi-square 
test with continuity correction (Fleiss et al, 1980). All power calculations for continuous 
endpoints were performed using a 2-sided 2-group Satterthwaite t-test (Moser et al, 1989) The 
power calculations provided below represent independent evaluations for each endpoint and do 
not account for multiplicity. 
For ASAS40 response of the TNFα inhibitor-naïve population at Week 16, an ASAS40 response 
of 48% for the bimekizumab group was assumed. Placebo ASAS40 response at Week 16 is 18%. 
It is also assumed that 70% of the subjects in each treatment group are TNFα inhibitor-naïve. 
With those assumptions, the endpoint is powered with >99% at the planned sample size (ie, 
140 and 70 subjects in the bimekizumab and placebo group, respectively). 
For ASAS20 response at Week 16, an ASAS20 response of 70% for the bimekizumab group was 
assumed. Placebo ASAS20 response at Week 16 is 30%. With those assumptions, the endpoint is 
powered with 99% at the planned sample size. 
For change from Baseline in BASDAI total score at Week 16, an adjusted between-treatment 
difference of - 1.38 with an SD=1.8 for bimekizumab and SD=1.4 for placebo was used. With 
those assumptions, the endpoint is powered with >99% at the planned sample size. 
For ASAS-PR at Week 16, an ASAS-PR of 17% for the bimekizumab group was assumed. 
Placebo ASAS-PR at Week 16 was assumed to be 3.3%. With those assumptions, the endpoint is 
powered with 94% at the planned sample size. 
For ASDAS-MI at Week 16, the ASDAS-MI data of AS0008 at Week 12 and Week 16 were 
used and the placebo response was extrapolated to Week 16. The assumed ASDAS-MI are 
36.0% and 13.8% at Week 16 for the bimekizumab and placebo group, respectively. With those 
assumptions, the endpoint is powered with 98% at the planned sample size. 
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For ASAS5/6 response at Week 16, an ASAS5/6 response of 44% for the bimekizumab group 
was assumed. Placebo ASAS-PR at Week 16 was assumed to be 5%. With those assumptions, 
the endpoint is powered with >99% at the planned sample size. 
For change from Baseline in BASFI at Week 16, an adjusted between-treatment difference 
of - 2.35 with an SD=1.9 for bimekizumab and placebo was used. With those assumptions, the 
endpoint is powered with >99% at the planned sample size. 
For change from Baseline in nocturnal spinal pain score at Week 16, the AS data from the 
certolizumab pegol study AS001 were used. An adjusted between-treatment difference of -1.88 
with an SD=2.9 for bimekizumab and SD=2.4 for placebo was used. With those assumptions, the 
endpoint is powered with >99% at the planned sample size. 
For change from Baseline in ASQoL total score at Week 16, an adjusted between-treatment 
difference of - 2.39 with an SD=4.5 for bimekizumab and placebo was used. With those 
assumptions, the endpoint is powered with >99% at the planned sample size. 
For change from Baseline in SF-36 PCS score at Week 16, an adjusted between-treatment 
difference of 4.56 with an SD=8.1 for bimekizumab and SD=5.8 for placebo was used. With 
those assumptions, the endpoint is powered with >99% at the planned sample size. 
For change from Baseline in BASMI at Week 16, an adjusted between treatment difference 
of - 0.55 with an SD=0.8 for bimekizumab and SD=0.7 for placebo was used. With those 
assumptions, the endpoint is powered with >99% at the planned sample size. 
16 
ETHICS AND REGULATORY REQUIREMENTS 
16.1 
Informed consent 
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the Investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the Investigator. 
Prior to participation in the study, the Informed Consent Form should be signed and personally 
dated by the subject and by the person who conducted the informed consent discussion 
(Investigator or designee). The subject must receive a copy of the signed and dated Informed 
Consent Form. As part of the consent process, each subject must consent to direct access to 
his/her medical records for study-related monitoring, auditing, IRB/IEC review, and regulatory 
inspection. 
If the Informed Consent Form is amended during the study, the Investigator (or the Sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of the 
amended Informed Consent Form by the IRB/IEC and use of the amended form. 
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization Form. 
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The subject may withdraw his/her consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she has signed the Informed Consent Form. A eCRF 
must not be started, nor may any study specific procedure be performed for a given subject, 
without having obtained his/her written consent to participate in the study. 
16.2 
Subject identification cards 
Upon signing the Informed Consent Form, the subject will be provided with a subject 
identification card in the language of the subject. The Investigator will fill in the subject 
identifying information and medical emergency contact information. The Investigator will 
instruct the subject to keep the card with him/her at all times. 
16.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed 
Consent Form, Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other subject-related documents to be used for the study to 
the IRB/IEC for its review and approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects. 
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
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Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
16.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study). 
16.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
17 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable. 
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18 
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Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and 
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19 
APPENDICES 
19.1 
ASAS classification criteria for axial SpA 
Table 19‒1: ASAS classification criteria for axial SpA (for subjects with 
chronic back pain of at least 3 months and age at onset <45 years) 
Imaging criteria 
ASAS clinical criteria for axial SpA 
Sacroiliitis (MRI or radiographsa) plus ≥1 SpA feature 
HLA-B27 plus ≥2 other SpA features 
SpA featuresb 
 
Inflammatory back painc  
Psoriasis 
Arthritis 
Crohn’s disease/ulcerative colitis 
Enthesitis (heel)  
HLA-B27 
Uveitis  
Elevated CRP 
Dactylitis 
 
ASAS=Assessment of SpondyloArthritis International Society; axSpA=axial spondyloarthritis; CRP=C-reactive 
protein; HLA-B27=human leukocyte antigen B27; MRI=magnetic resonance imaging; NSAID=nonsteroidal 
anti-inflammatory drug; SpA=spondyloarthritis 
a Active inflammatory lesions of sacroiliac joints with definite bone marrow oedema/osteitis suggestive of 
sacroiliitis associated with spondyloarthritis in MRI or radiographic sacroiliitis Grade 2 to 4 bilaterally or 
Grade 3 to 4 unilaterally according to modified NY criteria. For this study, only MRI will be permitted for 
study entry for the imaging criterion. 
b “Family history for SpA” and “Good response to NSAIDs” are excluded as SpA feature criteria. 
c Inflammatory back pain according to ASAS criteria for axSpA defined as the presence of 4 out of 5 of the 
following parameters: 
1. age at onset <45 years 
2. insidious onset 
3. improvement with exercise 
4. no improvement with rest 
5. pain at night (with improvement upon getting up) 
 
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19.2 
Modified New York (mNY) Classification Criteria for AS 
Table 19‒2: Modified New York (mNY) Classification Criteria for AS  
Diagnosis 
Clinical criteria: 
a. Low back pain and stiffness for more than 3 months which improves with exercise, but is 
not relieved by rest  
b. Limitation of motion of the lumbar spine in both the sagittal and frontal planes. 
c. Limitation of chest expansion relative to normal values corrected for age and sex. 
Radiologic criterion: 
Sacroiliitis grade ≥2 bilaterally or grade 3 to 4 unilaterally 
Grading 
Definite ankylosing spondylitis if the radiologic criterion is associated with at least 1 clinical 
criterion 
AS=ankylosing spondylitis; mNY=modified New York Criteria 
Note: A second grading of “probable ankylosing spondylitis” is part of the modified NY criteria, but it is not 
applicable for this study.  
 
 
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19.3 
Protocol Amendment 1 
Rationale for the amendment 
The major purpose of this protocol amendment was to implement changes in response to 
scientific discussions and feedback provided at meetings with Investigators and advisors or for 
clarifications. Mainly, imaging assessments were amended with sacroiliac joint and spine MRIs 
performed at Weeks 16 and 52 for all consenting subjects participating in the MRI substudy 
regardless of MRI positivity at Baseline. These additional MRIs will allow an exploratory 
evaluation of any changes in the sacroiliac joint or spine after 16 or 52 weeks in subjects who 
were MRI-negative at Baseline and on early signals such as the impact on erosions and fatty 
lesions at Week 16. Additionally, including MRI-positive and MRI-negative subjects in the 
substudy was considered a more holistic strategy comparable to the approach used for other 
compounds. At the same time, the number of participating subjects will be expanded to include 
subjects in the substudy without restriction. 
Further key changes are summarized below. The amendment: 
• Clarifies that the minimum duration of the Screening Period of 14 days does not apply to 
screenfailed subjects from AS0010 who are screened for AS0011.  
• Changes the categorization of PHQ-9 from an other efficacy variable to an other safety 
variable for consistency within the program. 
• Clarifies that protected adults will not be enrolled in the study.  
• Clarifies that subjects with a diagnosis of PsA will be excluded from the study as per the 
revised Exclusion Criterion 17.  
• Adds new sections summarizing all within-study rescreening/retesting and cross-study 
screening rules in one place and updates corresponding protocol sections. 
• Updates the IMP description for consistency within the program. 
• Updates for clarification and adds more detail to sections presenting exclusionary, 
concomitant, or rescue medication. 
− To clarify that permitted acetaminophen/paracetamol serve as examples for the larger 
group of analgesics and are permitted as rescue therapy except for 24 hours prior to any 
study visit. 
− To add that topical steroids are permitted. 
− To clarify that any change in dose/dose regimen of oral corticosteroids within 14 days 
prior to Baseline is exclusionary. 
− To clarify that apremilast used as a rescue medication can be dosed as per Investigator’s 
discretion or local label. 
− To clarify that the use of more than 1 TNFα inhibitor and the inclusion of any subject not 
meeting the related Inclusion criterion is exclusionary. 
• Restructures sections related to exclusionary, concomitant medication, or rescue medication 
to allow a side by side presentation in one table. 
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• Clarifies that the 12-item MOS Sleep Scale is rated using the 5-point scale. 
• Removes the option for enrollment in a separate observational pregnancy follow-up study 
sponsored by UCB. 
• Updates statistical terminology and replaces “sensitivity analyses” with “supportive 
analyses”. 
• Increases the threshold for subgroup analyses by disease duration from 2 to 5 years. 
• Updates the section detailing the status of bimekizumab studies. 
• Updates the list of references. 
• Updates instances of “AS” in the summary and introduction to clarify that “AS” is also 
known as “radiographic axSpA”. 
• Updates instances of “ASAS criteria” to “ASAS classification criteria” for consistency where 
applicable. 
In addition, a few minor updates including consistency changes for PDILI-related text, contact 
details, the list of abbreviations, and minor formatting changes for the purpose of clarity have 
been made. 
Modifications and changes 
Global changes 
The following changes were made throughout the protocol: 
• All instances that referred to “legal representatives” were updated to remove this terminology 
from the entire protocol. Protected adults will not be enrolled in the study. 
• All instances that referred to a minimum of 14 days for the Screening Period have been 
updated to clarify that this requirement does not apply to screenfailed subjects from AS0010 
who are screened for AS0011. The minimum requirement is still applicable to all other 
subjects. 
• All instances of “sensitivity analysis” were replaced with “supportive analysis”. The revision 
corresponds to the structure of study estimands described in the ICH E9 (R1) Addendum. 
 
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Specific changes 
Change #1 
Study contact details 
Sponsor study physician 
 
UCB BIOSCIENCES Ltd. 
208 Bath Road 
Slough SL1 3WE 
UNITED KINGDOM 
 
Has been changed to: 
 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim am Rhein 
GERMANY 
 
Clinical Trial Biostatistician 
 
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
 
Has been changed to: 
 
UCB BIOSCIENCES Ltd. 
208 Bath Road 
Slough SL1 3WE 
UNITED KINGDOM 
 
 
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Change #2 
Section 1, Summary, paragraph 1 sentence 1 and paragraph 7  
This is a multicenter, Phase 3, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of bimekizumab in subjects with active ankylosing spondylitis (AS), a 
subtype of axial spondyloarthritis (axSpA) with radiographic evidence of disease. 
... 
The overall study design consists of a Screening Period (≥14 days to ≤35 days), a 16-week 
Double-Blind Treatment Period, a 36-week Maintenance Period, and a Safety Follow-Up (SFU) 
Visit 20 weeks after the final dose of the investigational medicinal product (IMP) .... 
Has been changed to: 
This is a multicenter, Phase 3, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of bimekizumab in subjects with active ankylosing spondylitis (AS), a 
subtype of axial spondyloarthritis (axSpA) with radiographic evidence of disease (also known as 
radiographic axSpA [r-axSpA]). 
... 
The overall study design consists of a Screening Period (minimum of approximately 14 days 
[unless a screenfailed subject from AS0010 will be screened in AS0011] to ≤35 days), a 
52-week Treatment Period consisting of a 16-week Double-Blind Treatment Period, a 36-week 
Maintenance Period, and a Safety Follow-Up (SFU) Visit 20 weeks after the final dose of the 
investigational medicinal product (IMP) ... 
 
Change #3 
Section 2.1, Axial spondyloarthritis, paragraph 2, sentence 3 
Therefore, peripheral SpA includes diseases affecting mainly peripheral joints, such as reactive 
arthritis and PsA, whereas axSpA comprises those diseases with mainly axial involvement 
(sacroiliac joints and spine), including AS diagnosed with definite radiographic changes of the 
sacroiliac joint and nr-axSpA.  
Has been changed to: 
Therefore, peripheral SpA includes diseases affecting mainly peripheral joints, such as reactive 
arthritis and PsA, whereas axSpA comprises those diseases with mainly axial involvement 
(sacroiliac joints and spine), including AS (also known as r-axSpA) diagnosed with definite 
radiographic changes of the sacroiliac joint and nr-axSpA.  
 
Change #4 
Section 2.2.2.1, Completed studies, paragraph 1 
Nine clinical studies of bimekizumab have been completed: UP0008 in 39 subjects with 
mild-to-moderate plaque PSO, RA0124 in 30 healthy volunteers, PA0007 in 53 subjects with 
PsA, UP0031 in 12 healthy volunteers, UP0042 in 48 Japanese and Caucasian healthy 
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volunteers, RA0123 in 159 subjects with moderate-to-severe RA, PS0010 in 250 subjects with 
moderate-to-severe chronic plaque PSO, PS0016 in 49 subjects with moderate-to-severe chronic 
plaque PSO, and UC0011 in 23 subjects with moderate-to-severe active ulcerative colitis. 
Has been changed to: 
Nine Thirteen clinical studies of bimekizumab have been completed: UP0008 in 39 subjects 
with mild-to-moderate plaque PSO, RA0124 in 30 healthy volunteers, PA0007 in 53 subjects 
with PsA, UP0031 in 12 healthy volunteers, UP0042 in 48 Japanese and Caucasian healthy 
volunteers, RA0123 in 159 subjects with moderate-to-severe RA, PS0010 in 250 subjects with 
moderate-to-severe chronic plaque PSO and the corresponding extension study (PS0011), 
PS0016 in 49 subjects with moderate-to-severe chronic plaque PSO and the corresponding 
extension study (PS0018), UC0011 in 23 subjects with moderate-to-severe active ulcerative 
colitis, AS0008 in 303 subjects with AS, and PA0008 in 206 subjects with PsA. 
 
Change #5 
Section 2.2.2.2, Ongoing studies 
The following bullet has been deleted: 
• AS0008 is a Phase 2b, double-blind, randomized, placebo-controlled, multiple-dose study to 
evaluate the efficacy and safety of bimekizumab in subjects with active AS.  
 
The following bullet has been added: 
• AS0010 is a Phase 3, double-blind, randomized, placebo-controlled study to evaluate 
the efficacy and safety of bimekizumab in subjects with active nr-axSpA. 
 
Change #6 
Section 4.3.1, Other efficacy variables 
The following variable has been removed: 
• Change from Baseline in Patient Health Questionnaire-9 (PHQ-9) 
 
Change #7 
Section 4.3.2, Other safety variables 
The following variable has been added: 
• Change from Baseline in Patient Health Questionnaire-9 (PHQ-9) 
 
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Change #8 
Section 5.1, Study description, paragraph 3 
The study will include the following 3 periods: a Screening Period (≥14 days to ≤35 days), a 
Treatment Period (52 weeks) consisting of a 16-week Double-Blind Treatment Period and a 36-
week Maintenance Period, and a SFU Period (20 weeks after the final dose of IMP). 
Has been changed to: 
The study will include the following 3 periods: a Screening Period (minimum of approximately 
14 days [unless a screenfailed subject from AS0010 will be screened in AS0011] to 
≤35 days), a Treatment Period (52 weeks) consisting of a 16-week Double-Blind Treatment 
Period and a 36-week Maintenance Period, and a SFU Period (20 weeks after the final dose of 
IMP). 
 
Change #9 
Section 5.1.1, Screening Period/Baseline, paragraph 1 first sentence 
Assessments of eligibility as described in Section 6 will be initiated during the Screening Period 
with a minimum duration of 14 days and a maximum duration of up to 35 days. 
Has been changed to: 
Assessments of eligibility as described in Section 6 will be initiated during the Screening Period 
with a minimum duration of approximately 14 days (unless a screenfailed subject from 
AS0010 will be screened in AS0011) and a maximum duration of up to 35 days. 
The following paragraph was added: 
All subjects will have an anterior posterior (AP) pelvis or sacroiliac joint x-ray (read 
centrally) to determine eligibility as per mNY criteria. Subjects who are mNY-negative 
may be eligible for Screening in AS0010, a double-blind, randomized, placebo-controlled 
Phase 3 study in subjects with active nr-axSpA. It is recommended to perform the 
sacroiliac joint x-ray prior to any other screening assessment to avoid repetition of 
screening assessments (applicable at sites participating in both Phase 3 studies). 
 
Change #10 
Section 5.1.1, Screening Period/Baseline, last paragraph  
Screening assessments for subjects previously screened for AS0010, who were not eligible for 
AS0010 and therefore entered Screening again for eligibility during the Screening Period of 
AS0011, must be repeated unless defined otherwise. These cross-study rescreening rules 
pertaining to laboratory testing are provided in Section 12.6 and imaging is described in 
Section 9.21. 
Has been deleted. 
 
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Change #11 
Section 5.1.1, Screening Period/Baseline 
The following sections have been added. 
5.1.1.1 Within-study rescreening/retesting requirements 
Rules for rescreening or repetition of screening tests within the study are listed below: 
• Subjects who fail to meet the eligibility criteria for BASDAI, spinal pain, PHQ-9, eC-SSRS, 
or the TB questionnaire are not allowed to be rescreened. 
The Medical Monitor must be contacted for confirmation of rescreening/retesting in all other 
cases. 
• Subjects who initially fail to meet selected eligibility criteria (eg, documented completion of 
latent tuberculosis infection [LTBI] prophylactic therapy) may be rescreened. 
• Subjects for whom eligibility assessments could not be completed as planned (eg, for 
technical reasons) within the defined Screening Period of 35 days may be rescreened.  
• Subjects with individual laboratory screening tests for which the results are exclusionary, can 
be retested.  
Of note, repetition of laboratory screening tests within the Screening Period is permitted for 
technical reasons (eg, frozen sample, expired laboratory kit) without contacting the Medical 
Monitor. 
5.1.1.2 Cross-study screening requirements 
Screening assessments for subjects previously screened for AS0010, who were not eligible for 
AS0010 based on mNY criteria and therefore entered AS0011 Screening for eligibility, must be 
repeated during the Screening Period unless defined in Table 5‒1. The Medical Monitor must be 
contacted for confirmation of the rescreening requirements in all cases. 
Table 5-1: Cross-study screening requirements 
Assessment  
Screening requirements 
Cross-study screening is not permitted in the following cases: 
BASDAI and 
spinal pain 
Screening of a subject not eligible for AS0010 who will be screened for AS0011, 
and who did not meet the related Inclusion Criteria in AS0010. 
PHQ-9, eC-SSRS, 
TB questionnaire 
(Q1) 
Screening of a subject not eligible for AS0010 who will be screened for AS0011, 
and who did not meet the related Exclusion Criteria in AS0010. 
Cross-study screening is permitted in the following cases: 
CRP 
If a subject not eligible for AS0010 will be screened for AS0011, the Screening 
CRP testing must be repeated during Screening for AS0011 only if the result is 
older than 35 days at time of randomization at Baseline (Section 12.6). 
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Table 5-1: Cross-study screening requirements 
Assessment  
Screening requirements 
Cross-study screening is not permitted in the following cases: 
All safety 
laboratory 
assessments 
If a subject not eligible for AS0010 will be screened for AS0011, the Screening 
safety laboratory testing (hematology, biochemistry, urinalysis, urine drug 
screen, pregnancy testing as applicable, HIV, Hepatitis B and C, and IGRA TB 
testing) and HLA-B27 testing must be repeated only during Screening for 
AS0011 if the results are older than 35 days at time of randomization at Baseline 
(Section 12.6). 
Anterior posterior 
pelvis x-ray 
The following will be accepted to qualify subjects with AS for this study: 
Anterior posterior pelvis x-ray centrally read for AS0010 and determined to be 
modified New York Criteria positive (+mNY); neither the x-ray nor the reading 
will be repeated (Section 9.20). The central imaging reader needs to be informed 
by the site about screening activities in order to transfer and confirm eligibility 
for the switch from AS0010 to AS0011. 
AS=ankylosing spondylitis; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; CRP=C-reactive 
protein; eC-SSRS=electronic Columbia-Suicide Severity Rating Scale; HIV=human immunodeficiency virus; 
HLA-B27=human leukocyte antigen B27; IGRA=Interferon-Gamma Release Assay; mNY=modified New 
York; PHQ-9=Patient Health Questionnaire 9; Q=question; TB=tuberculosis 
 
Change #12 
Section 5.1.2.1, Double-Blind Treatment Period, paragraph 3 
Visit windows of ±3 days are allowed from the first dose at all visits through Week 16. The visit 
window is relative to the Baseline Visit, not the previous study visit. The time between doses 
should be ≥25 days and ≤31 days.  
Has been changed to: 
Visit windows of ±3 days are allowed from the first dose at all visits through Week 16. The visit 
window is relative to the Baseline Visit, not the previous study visit. The time between doses 
should be ≥25 days and ≤31 days. When applying the allowed visit windows, it must be 
ensured that the time between these 2 visits does not exceed the allowed time between 
doses. 
 
Change #13 
Section 5.1.2.2, Maintenance Period, paragraph 3 
Visit windows of ±4 days are allowed for all visits after Week 16. The time between doses 
during the Maintenance Period should be ≥24 days and ≤32 days.  
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Has been changed to: 
Visit windows of ±4 days are allowed for all visits after Week 16. The time between doses 
during the Maintenance Period should be ≥24 days and ≤32 days. When applying the allowed 
visit windows, it must be ensured that the time between these 2 visits does not exceed the 
allowed time between doses. 
 
Change #14 
Section 5.1.3, Nonbiologic rescue therapy 
The entire section has been deleted from Section 5 and merged with Table 7-2. Subsequent 
sections have been re-numbered and in-text references were updated. 
 
Change #15 
Section 5.1.5, Study duration per subject, bullet #1 
• Screening Period: ≥14 days to ≤35 days 
Has been changed to: 
• Screening Period: minimum duration of approximately 14 days (unless a screenfailed 
subject from AS0010 will be screened in AS0011) to ≤35 days 
 
Change #16 
Section 5.1.6, Planned number of subjects and site(s) 
Approximately 300 subjects will be randomly assigned in a 2:1 ratio to the following treatment 
groups: bimekizumab 160mg sc Q4W (200 subjects) or placebo sc Q4W (100 subjects). The 
planned number of study sites is approximately 85.  
Has been changed to: 
Approximately 300 subjects will be randomly assigned in a 2:1 ratio to the following treatment 
groups: bimekizumab 160mg sc Q4W (200 subjects) or placebo sc Q4W (100 subjects). The 
planned number of study sites is approximately 85 95.  
 
Change #17 
Section 5.2, Table 5-2, Schedule of assessments, footnotes n and q  
n 
If a subject has had a recent x-ray of the chest within 3 months prior to the Screening Visit, it 
may be used as the Screening chest x-ray. The chest x-ray has to be read by a pulmonologist 
and any significant finding is exclusionary. Any findings suggestive of active TB are 
exclusionary. 
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q 
Sacroiliac joint and spine MRIs will be performed for subjects participating in the MRI 
substudy. Baseline sacroiliac joint and spine MRIs should be performed after confirmation of 
eligibility based on screening assessments for the study and before the first dose of IMP. If 
preferred, the sacroiliac joint and spine MRIs can be performed prior to the actual Baseline 
Visit. Further sacroiliac joint and spine MRIs will be performed at Weeks 16 and 52, within a 
window of ±5 days for sacroiliac joint MRI-positive subjects at Baseline participating in the 
substudy. 
Has been changed to: 
n 
If a subject has had a recent x-ray of the chest within 3 months prior to the Screening Visit, it 
may be used as the Screening chest x-ray. The chest x-ray has to be read by a pulmonologist 
and any significant finding is exclusionary. Any findings suggestive of active TB are 
exclusionary. 
q 
Sacroiliac joint and spine MRIs will be performed for subjects participating in the MRI 
substudy. Baseline sacroiliac joint and spine MRIs should be performed after confirmation of 
eligibility based on screening assessments for the study and before the first dose of IMP. If 
preferred, The sacroiliac joint and spine MRIs can be performed at Baseline or prior to the 
actual Baseline Visit. Further sacroiliac joint and spine MRIs will be performed at Weeks 16 
and 52, within a window of ±5 days for all subjects participating in the substudy. 
 
Change #18 
Section 6.1, Inclusion criteria 1 and 2 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the subject or legal representative. 
2. Subject/legal representative is considered reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries), visit schedule, or medication intake according 
to the judgment of the Investigator. 
Have been changed to: 
1a. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the subject or legal representative. 
2a. Subject/legal representative is considered reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries), visit schedule, or medication intake according 
to the judgment of the Investigator. 
 
Change #19 
Section 6.2, Exclusion criteria #3 and #17 
3. Subject previously participated in another study of a medication (systemic) under 
investigation within the 12 weeks or at least 5 half-lifes prior to the Screening Visit, 
whichever is greater, or is currently participating in another study of a medication (systemic) 
under investigation, with the exception of subjects who were screen failures in AS0010. 
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17. Subject has a diagnosis of inflammatory conditions other than AS, including but not limited 
to rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, and reactive arthritis. 
Subjects with a diagnosis of Crohn’s disease, ulcerative colitis, or other IBD are allowed as 
long as they have no active symptomatic disease at Screening or Baseline. 
Has been changed to: 
3a. Subject previously participated in another study of a medication (systemic) under 
investigation within the 12 weeks or at least 5 half-lifes prior to the Screening Baseline Visit, 
whichever is greater, or is currently participating in another study of a medication (systemic) 
under investigation, with the exception of subjects who were screen failures in AS0010. 
17a. Subject has a diagnosis of inflammatory conditions other than AS, including but not limited 
to psoriatic arthritis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, and 
reactive arthritis. Subjects with a diagnosis of Crohn’s disease, ulcerative colitis, or other 
IBD are allowed as long as they have no active symptomatic disease at Screening or 
Baseline. 
 
Change #20 
Section 6.3.1, Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued.  
The PDILI criteria below require immediate and permanent discontinuation of IMP for subjects 
with either of the following:  
• ALT or AST ≥8x ULN  
• ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN  
The PDILI criterion below requires immediate discontinuation of IMP for:  
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%).  
… 
Evaluation of PDILI must be initiated as described in Section 12.6.1 with repeat tests performed 
in 2 weeks. Upon re-test, if ALT or AST values have reduced to <5xULN, the subject can 
continue with the study. However, if ALT or AST remains ≥5xULN and <8xULN after re-test, 
IMP should be temporarily withheld and subject should undergo a repeat test in 2 weeks. If ALT 
or AST values remain ≥5xULN even after the second re-test, then the subject should be 
permanently withdrawn from IMP and should be followed for possible PDILI.  
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Has been changed to: 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued.  
The PDILI criteria below require immediate and permanent discontinuation of IMP for subjects 
with either of the following:  
• ALT or AST ≥8x ULN  
• ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN  
The PDILI criterion below requires immediate discontinuation of IMP for:  
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%).  
… 
Evaluation of PDILI must be initiated as described in Section 12.6.1 with repeat tests performed 
in 2 weeks. Upon re-test, if ALT or AST values have reduced to <5xULN, the subject can 
continue with the study. However, if ALT or AST remains ≥5xULN and <8xULN after re-test, 
IMP should be temporarily withheld and subject should undergo a repeat test in 2 weeks. If ALT 
or AST values remain ≥5xULN even after the second re-test, then the subject should be 
permanently withdrawn immediately discontinued from IMP and should be followed for 
possible PDILI. 
 
Change #21 
Section 7.1, Description of investigational medicinal products, first bullet 
• 
 
 
 
Has been changed to: 
• 
 
 
 
 
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Change #22 
Section 7.8, Concomitant medications/treatments, paragraph 2 
The following sentence has been added. 
Medications listed in Table 7‒2 are prohibited, restricted, or used as nonbiologic rescue 
therapy. 
 
Change #23 
Section 7.8, Concomitant medications/treatments, paragraph 2 
Table 7‒2 has been amended to include exclusionary and nonbiologic rescue therapy.  
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Table 7-2: Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
Analgesics 
• 
Acetaminophen/ 
paracetamol 
Any change in dose/dose 
regimen within 14 days 
prior to BL 
Stable dose/regimen permitted  
Ad hoc/PRN/“as needed use” 
permitted, but: 
No ad hoc/PRN/“as needed use” 
in the 24h prior to any study visit 
Ad hoc/PRN/“as needed use” permitted, but: 
No ad hoc/PRN/“as needed use” in the 24h prior to 
any study visit 
 
NSAID/COX-2 inhibitors  
Any change in dose/dose 
regimen within 14 days 
prior to BL 
Stable dose/ regimen permitted 
No change until Week 20 Visit 
Nonbiologic rescue therapy will be at the 
Investigator’s discretion with the following options for 
symptoms: 
• 
For subjects taking an NSAID/COX-2 inhibitor 
dosing can be optimized; a change can be made to 
a different NSAID/COX-2 inhibitor; changes 
from an NSAID to a COX-2 inhibitor or from a 
COX-2 inhibitor to an NSAID are also permitted 
up to the maximum approved or tolerated dose, 
whichever is lower. Only 1 NSAID/COX-2 
inhibitor may be taken at a given time. 
• 
For subjects not taking NSAID/COX-2 inhibitors 
either 1 NSAID, or 1 COX-2 inhibitor can be 
initiated, up to the maximum approved or 
tolerated dose, whichever is lower. Only 
1 NSAID/COX-2 inhibitor may be taken at a 
given time. 
• 
For subjects who cannot take NSAIDs/COX-2 
inhibitors, topical NSAIDs are also a potential 
nonbiologic rescue therapy in regions where they 
are approved, up to the maximum approved or 
tolerated dose, whichever is lower.  
Mild potency opioids permitted 
only: 
• 
Tramadol/any dose up to 
maximum approved dose 
• 
Codeine/only <90mg of 
codeine per dosage unit 
Any change in dose/dose 
regimen within 14 days 
prior to BL 
Dosing/schedule should remain 
stable for the first 20 weeks of 
the study 
Prohibited for rescue therapy 
 
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Table 7-2: Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
Oral corticosteroids/average daily 
dose of ≤10mg/day prednisone or 
equivalent 
Any change in dose/dose 
regimen within 14 days 
prior to BL 
Permitted, but: 
• 
No steroid bursts/tapers 
• 
No increase in steroid 
dosing 
• 
No initiation of steroids 
until the Week 20 Visit 
Prohibited for rescue therapy 
Topical corticosteroids 
None 
Permitted 
Not applicable 
Corticosteroids: 
• 
Intramuscular 
• 
Intravenous 
• 
Intra-articular  
• 
Bursal 
 
Use within 28 days prior to 
BL 
Prohibited unless used as rescue 
therapy from Week 20 or later 
Nonbiologic rescue therapy will be at the 
Investigator’s discretion with the following options for 
symptoms: 
• 
Sacroiliac joint steroid injection(s), either 
unilateral or bilateral. 
For non-axial symptoms: 
• 
One peripheral joint (or bursa) may be injected 
with a steroid at or after any visit where 
nonbiologic rescue therapy eligibility is assessed; 
however, the same joint may not be injected more 
than once during the study and should not be 
injected within 4 weeks of a sacroiliac joint 
injection(s). 
Intra-articular hyaluronic acid 
Use within 8 weeks prior 
to the BL Visit or during 
the study 
Prohibited 
Not applicable 
Any established antidepressant 
regimen 
Any change in dose/dose 
regimen within 8 weeks 
prior to BL 
Permitted 
Not applicable 
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Table 7-2: Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
csARDs/formerly known as 
DMARDs 
 
 
 
• 
Azathioprine 
• 
Cyclosporine 
• 
Cyclophosphamide 
• 
Mycophenolic acid 
• 
Mycophenylate mofetil 
• 
Any other small molecule 
DMARDs 
Use within 8 weeks prior 
to BL 
Prohibited 
Prohibited for rescue  
• 
Methotrexate (MTX) 
 
Use within 12 weeks prior 
to BL unless Inclusion 
Criterion #9 is met 
Permitted 
MTX (≤25mg/week) 
For non-axial symptoms: 
• 
MTX may be added or increased to a maximum 
dose of 25mg/week, or the maximum tolerated 
dose, whichever is lower, in accordance with local 
standard of care. The route of administration may 
be changed from oral to sc or from sc to oral, at 
any visit at Week 20 or later. It is strongly 
recommended that subjects taking MTX are also 
taking folic acid supplementation. 
• 
Leflunomide (LEF) 
Use in the 6 months prior 
to the BL Visit (unless a 
cholestyramine washout 
has been performed; in 
which case, use up to 
28 days prior to the BL 
Visit is acceptable) unless 
Inclusion Criterion 
Criterion #9 is met 
Permitted 
LEF (≤20mg/day or an average 
of 20mg/day if not dosed daily) 
For non-axial symptoms: 
• 
Leflunomide may be given at a maximum dose of 
20mg/day (or an average of 20mg/day if not 
dosed daily), or the maximum tolerated dose, 
whichever is lower.  
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Table 7-2: Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
• 
Hydroxychloroquine (HCQ) 
(and other anti-malarials) 
• 
Sulfasalazine (SSZ) 
• 
Apremilast 
 
Use within 8 weeks prior 
to BL unless Inclusion 
Criterion #10 is met 
Permitted 
For non-axial symptoms: 
• 
HCQ may be added or increased to a maximum 
dose of 400mg/day or the maximum tolerated 
dose, whichever is lower. Other anti-malarials 
may be used in accordance with local standard of 
care. 
• 
SSZ may be added or increased up to a maximum 
dose of 3g/day (up to 4g/day if in accordance with 
local standard of care), or the maximum tolerated 
dose, whichever is lower.  
• 
Apremilast may be given at a maximum dose of 
60mg/day and dosed as per Investigator’s 
discretion or local label. 
Combination DMARDs are allowed except that LEF 
and MTX may not be given together. 
JAK inhibitors 
 
 
 
• 
Eg, tofacitinib 
• 
Upadacitinib 
Use within 8 weeks prior 
to BL 
Prohibited 
Not applicable 
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Table 7-2: Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
Biologic DMARDs 
 
 
 
TNFα inhibitors: 
• 
Infliximab (IFX) 
• 
Golimumab (GOL) 
• 
Certolizumab pegol (CZP) 
• 
Adalimumab (ADA) 
• 
Etanercept (ETN) 
• 
Biosimilar versions of any 
TNFα inhibitor 
For IFX, ADA, GOL, and 
CZP, any use within the 
12 weeks prior to the BL 
Visit 
For ETN, use within the 
28 days prior to the BL 
Visit 
Any use of >1 TNFα in the 
history 
Subjects not meeting 
Inclusion Criterion #11. 
Prohibited 
Not applicable 
Other biologics: 
• 
Abatacept 
Any use within 12 weeks 
prior to BL 
Prohibited 
Not applicable 
• 
Alefacept 
 
 
• 
Efalizumab 
 
 
• 
Guselkumab 
 
 
• 
Sarilumab 
 
 
• 
Sirukumab 
 
 
• 
Tocilizumab 
 
 
• 
Others in development 
targeting IL-6 or IL-6R 
 
 
• 
Ustekinumab 
 
Any use within 24 weeks 
prior to BL 
Prohibited 
Not applicable 
• 
Tildrakizumab 
Any use within 4 months 
prior to BL 
Prohibited 
Not applicable 
• 
Risankizumab 
Any use within 5 months 
prior to BL 
Prohibited 
Not applicable 
• 
Briakinumab 
 
Any use within 6 months 
prior to BL 
Prohibited 
Not applicable 
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Table 7-2: Exclusionary, concomitant, and rescue medication 
Drug class/dose 
Exclusion criteria 
Study visits/during the 
study 
Nonbiologic rescue therapy as add-on therapy 
to bimekizumab from Week 20 or latera 
• 
Rituximab (incl. biosimilars), 
ocrelizumab 
Any use within 12 months 
prior to BL 
Prohibited 
Not applicable 
Anti-IL-17 therapy: 
• 
Bimekizumab 
• 
Secukinumab 
• 
Ixekizumab 
• 
Brodalumab 
• 
Others in development 
Any exposure history 
Prohibited 
Not applicable 
BL=Baseline; ADA=adalimumab; COX-2=cyclooxygenase 2; csARD=conventional synthetic antirheumatic drug; CZP=certolizumab pegol; 
DMARD=disease-modifying antirheumatic drug; ETN=etanercept; GOL=golimumab; h=hour; HCQ=hydroxychloroquine; IFX=infliximab; JAK=Janus 
kinase; LEF=leflunomide; IL=interleukin; MTX=methotrexate; NSAID=nonsteroidal anti-inflammatory drug; PRN=as needed; sc=subcutaneous; 
SSZ=sulfasalazine; TNFα=tumor necrosis factor alpha 
a 
Note: any medication not listed here for rescue therapy must be approved by the Medical Monitor prior to starting that medication. 
 
 
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Change #24 
Section 7.8.1, Permitted concomitant treatments (medications and therapies) 
The following paragraphs have been moved to Table 7‒2. 
Subjects are allowed to use acetaminophen/paracetamol as needed except that PRN/as needed 
doses are not permitted within 24 hours before a study visit where efficacy assessments are 
performed. 
Mild potency opioids are permitted during the study and the dosing/schedule should remain 
stable for the first 16 weeks of the study, but are not permitted as nonbiologic rescue therapy (see 
Section 5.1.3). 
No steroid bursts/tapers, increase in steroid dosing or initiation of steroids are permitted during 
the study. 
Subjects are permitted to decrease NSAID/COX-2 medications, analgesics (including opioids), 
DMARD(s) and/or oral corticosteroids and/or alter their regimen only at/after the Week 20 Visit 
except for reasons of intolerance/AEs/side effects. 
Subjects who are receiving an established antidepressant regimen should be on a stable dose of 
the antidepressant for 8 weeks prior to Baseline. 
The following paragraph has been changed to: 
Whenever possible, physical therapy/physiotherapy/non-medication/complementary and 
alternative treatment(s) (including traditional Chinese medications) of AS should remain stable 
through the Week 16 20 Visit.  
The following paragraph has been deleted: 
Subjects may be withdrawn from IMP at any time and continue treatment using other treatment 
options per the Investigator’s discretion, as described in the Withdrawal criteria Section 6.3. 
 
Change #25 
Section 7.8.2, Prohibited concomitant treatments (medications and therapies) 
Medications listed in Table 7‒2 are prohibited or restricted as follows: 
Has been changed to: 
Prohibited concomitant treatments are described in Table 7‒2. 
 
Change #26 
Section 7.8, Concomitant medications/treatments 
The following changes have been made and are included in Table 7‒2. 
• The dosing/schedule of mild potency opioids should remain stable for the first 16 20 weeks 
of the study 
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• Any change in dose/dose regimen of oral corticosteroids within 14 days prior to BL is 
exclusionary. 
• Intramuscular, intravenous, intra-articular, and bursal corticosteroids use is prohibited unless 
used as rescue therapy. 
• Any use of >1 TNFα in the history is exclusionary. 
• Subjects not meeting Inclusion Criterion #11 are excluded. 
• Apremilast may be given at a maximum dose of 60mg/day and dosed as per Investigator’s 
discretion or local label. 
 
Change #27 
Section 7.8.2, Prohibited concomitant treatments (medications and therapies), Table 7-2 
The outdated Table 7‒2 has been deleted. 
 
Change #28 
Section 7.8.3, Nonbiologic rescue therapy 
The section has been moved from Section 5.1.3 to Section 7.8. The following text has been 
added: 
Nonbiologic rescue therapy will be at the Investigator’s discretion as add-on therapy to 
bimekizumab at any time from Week 20 or later as described in Table 7‒2. 
 
Change #29 
Section 8, Study procedures by visit, paragraph 2 
Visit windows are ±3 days from Baseline (Day 1, first dose of IMP) at all visits through the 
Week 16 Visit and ±4 days from all visits thereafter. For the SFU Visit (20 weeks after the final 
dose), the visit should occur no more than 3 days prior to the scheduled visit date and within 
7 days after the scheduled visit date (-3 days/+7 days). The minimum amount of time between 
bimekizumab doses should be no less than 25 days and no more than 31 days from Baseline to 
Week 16 and 24 to 32 days thereafter.  
Has been changed to: 
Visit windows are ±3 days from Baseline (Day 1, first dose of IMP) at all visits through the 
Week 16 Visit and ±4 days from all visits thereafter. For the SFU Visit (20 weeks after the final 
dose), the visit should occur no more than 3 days prior to the scheduled visit date and within 
7 days after the scheduled visit date (-3 days/+7 days). The minimum amount of time between 
bimekizumab doses should be no less than 25 days and no more than 31 days from Baseline to 
Week 16 and 24 to 32 days thereafter. When applying the allowed visit windows, it must be 
ensured that the time between these 2 visits does not exceed the allowed time between 
doses. 
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Change #30 
Section 8.1, Screening Visit (Visit 1), paragraph 1  
The Screening Period will last for a minimum of 14 days and up to a maximum of 35 days. 
Has been changed to: 
The Screening Period will last for a minimum of approximately 14 days (unless a screenfailed 
subject from AS0010 will be screened in AS0011) and up to a maximum of 35 days. 
The following text has been added. 
An overview on rescreening/retesting requirements is provided in Section 5.1.1.1 and 
Section 5.1.1.2. 
 
Change #31 
Section 8.1, Screening Visit (Visit 1), bullet 18  
Obtain a chest x-ray, unless one has been obtained within 3 months prior to the Screening Visit. 
The chest x-ray must be read by a qualified radiologist and/or pulmonary physician and any 
significant finding is exclusionary. Any findings suggestive of active TB are exclusionary. 
Has been changed to: 
Obtain a chest x-ray, unless one has been obtained within 3 months prior to the Screening Visit. 
The chest x-ray must be read by a qualified radiologist and/or pulmonary physician and any 
significant finding is exclusionary. Any findings suggestive of active TB are exclusionary. 
 
Change #32 
Section 9.7, MOS-12, paragraph 1, second sentence 
The frequency with which each problem has been experienced during the previous 4 weeks is 
rated on a 6-point scale ranging from “none of the time” to “all of the time,” except sleep 
quantity, which is reported in hours. 
Has been changed to: 
The frequency with which each problem has been experienced during the previous 4 weeks is 
rated on a 5-point scale ranging from “none of the time” to “all of the time,” except sleep 
quantity, which is reported in hours. 
 
Change #33 
Section 9.19, PHQ-9 
Has been moved from Section 9.19 to Section 12.7.7 without any content change. 
 
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Change #34 
Section 9.19, Occurrence of extra-articular manifestations 
Information regarding dactylitis, PSO, uveitis, and IBD occurrences during the study will be 
captured as AEs. Enthesitis will be assessed regularly via the MASES performed at site visits as 
specified in Table 5-2.  
Has been changed to: 
Information regarding dactylitis, PSO, uveitis, and IBD occurrences events during the study will 
be captured as AEs. Enthesitis will be assessed regularly via the MASES performed at site visits 
as specified in Table 5-2.  
 
Change #35 
Section 9.20.1, Sacroiliac joint x-ray (AP Pelvis Joint Film for modified New York Criteria, 
paragraph 2, bullet 1 
• Anterior posterior pelvis x-ray centrally read for one of the Phase 3 studies AS0010 or 
AS0011 and determined to be modified New York Criteria positive (+mNY); neither the 
reading nor the x-ray will be repeated. 
Has been changed to: 
• Anterior posterior pelvis x-ray centrally read for one of the Phase 3 studies AS0010 or 
AS0011 and determined to be modified New York Criteria positive (+mNY); neither the 
reading x-ray nor the x-ray reading will be repeated.  
 
Change #36 
Section 9.20.3, Sacroiliac joint and spine MRI assessment substudy, paragraphs 1, 2, and 3 
While radiography can detect chronic bony changes (eg, sclerosis, erosions, bridging, and 
ankyloses), structural changes generally occur slowly and x-rays are insensitive; therefore, 
changes are difficult to detect in the relatively short duration of a randomized clinical study. 
Unlike radiography, MRI can be used to visualize inflammation in the sacroiliac joints and spine 
in addition to structural lesions. Inflammation of the sacroiliac joints and spine is a key feature of 
axSpA that is potentially amenable to treatment with bimekizumab. If bimekizumab is effective, 
it is expected that reduction in inflammation in the sacroiliac joints and spine can be detected 
using MRI within the 52-week Treatment Period of this study. Recently, a Danish study 
demonstrated significant changes in in ASspiMRI-a (Berlin modification) and SPARCC MRI 
assessed inflammation scores and in SPARCC MRI-assessed erosion scores within 12 weeks 
after initiation of adalimumab (see below for further description of these MRI scoring methods). 
The researchers concluded that MRI-assessed structural lesions change rapidly and may have 
value for assessing the effects of disease-modifying treatment in clinical trials (Pedersen et al, 
2016). 
... 
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Magnetic resonance imaging of the spine and sacroiliac joints will be performed in a substudy 
with approximately 15% of subjects at Baseline after confirmation of eligibility based on 
screening assessments and before the first dose of IMP. If needed, the sacroiliac joint and spine 
MRIs can be performed prior to the actual Baseline Visit after confirmation of eligibility based 
on Screening assessments. 
... 
A central reader will assess the Baseline MRIs to identify MRI-positive subjects as per the 
OMERACT criteria. Further MRIs of the spine and sacroiliac joint will be performed at Week 16 
and Week 52 within a window of ±5 days only for those subjects who were MRI positive in the 
sacroiliac joint MRI at Baseline, and will be centrally read. 
Has been changed to: 
While radiography can detect chronic bony changes (eg, sclerosis, erosions, bridging, and 
ankyloses), structural changes generally occur slowly and x-rays are insensitive; therefore, 
changes are difficult to detect in the relatively short duration of a randomized clinical study. 
Unlike radiography, MRI can be used to visualize active inflammation in the sacroiliac joints 
and spine in addition to structural lesions. Inflammation of the sacroiliac joints and spine is a key 
feature of axSpA that is potentially amenable to treatment with bimekizumab. If bimekizumab is 
effective, it is expected that reduction in inflammation in the sacroiliac joints and spine can be 
detected using MRI within the 52-week Treatment Period of this study. Recently, a Danish study 
demonstrated significant changes in in ASspiMRI-a (Berlin modification) and SPARCC MRI 
assessed inflammation scores and in SPARCC MRI-assessed erosion scores within 12 weeks 
after initiation of adalimumab (see below for further description of these MRI scoring methods). 
The researchers concluded that MRI-assessed structural lesions change rapidly and may have 
value for assessing the effects of disease-modifying treatment in clinical trials (Pedersen et al, 
2016). In this study, MRI changes will be evaluated in the sacroiliac joint and spine to 
evaluate the effect of bimekizumab on objective signs of inflammation through the 
SPARCC and ASspiMRI scores as outlined below. In addition, exploratory evaluation of 
other chronic MRI features, such as erosions and fatty lesions, will be performed as 
indicators of disease modification associated with structural disease progression 
(Baraliakos et al, 2014). 
... 
Magnetic resonance imaging of the spine and sacroiliac joints will be performed for consenting 
subjects in the MRI substudy after confirmation of eligibility based on screening assessments 
and before the first dose of IMP. If needed, the sacroiliac joint and spine MRIs can be performed 
at Baseline or prior to the actual Baseline Visit after confirmation of eligibility based on 
Screening assessments. 
A central reader will assess the Baseline MRIs to identify MRI-positive subjects as per the 
OMERACT criteria. Further MRIs of the spine and sacroiliac joint for MRI-positive and 
MRI-negative subjects will be performed at Week 16 and Week 52 within a window of ±5 days 
for subjects participating in the MRI substudy. All MRIs will be centrally read. 
Refusal to participate in the substudy will not affect a subject’s opportunity to participate 
in the main study. 
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Change #37 
Section 10.2, Pharmacogenomic variables, paragraph 3, sentence 2 
...Candidate biomarker evaluations may include, but are not limited to, IL-17A/IL17-F pathway 
signaling and AS biology (eg, IL-17A, IL-17F, IL-23, IL-6, tumor necrosis factor, dendritic cell-
specific transmembrane protein, and circulating osteoclast precursors). ... 
Has been changed to: 
...Candidate biomarker evaluations may include, but are not limited to, IL-17A/IL-17F pathway 
signaling and AS axSpA biology (eg, IL-17A, IL-17F, IL-23, IL-6, tumor necrosis factor, 
dendritic cell-specific transmembrane protein, and circulating osteoclast precursors). ... 
 
Change #38 
Section 12.2, Pregnancy 
Should a subject become pregnant while participating in the study, the subject may be offered the 
option to enroll in a separate observational pregnancy follow-up study sponsored by UCB and 
conducted independently from AS0011. If the study is available locally, the AS0011 Investigator 
will be provided with locally approved information about the observational pregnancy follow-up 
study to inform the subject at the time the pregnancy is reported. Participation in this separate 
study will be voluntary and will not impact the therapeutic management of the subject nor 
interfere with termination and follow-up procedures as described in protocol AS0011. 
This paragraph has been deleted. 
 
Change #39 
Section 12.6, Laboratory measurements, paragraph 1 and bullets 
Clinical laboratory assessments consist of biochemistry, hematology, urinalysis, and pregnancy 
tests (serum or urine) (Table 12‒2). A centralized laboratory will be used to supply all laboratory 
test supplies and analyze all blood and urine samples (except the urine pregnancy test). Any 
unscheduled laboratory testing should also be collected using the central laboratory (with the 
exception of urgent safety laboratory measurements which should be performed locally and 
centrally simultaneously). Testing to exclude hepatitis B, hepatitis C, and HIV (see Exclusion 
Criterion #12, Section 6.2) will be performed at Screening in addition to those measurements 
listed in Table 12‒2. A urine dipstick will be used for pregnancy testing. Rescreening 
requirements pertaining to laboratory assessments are summarized below: 
• For CRP: If a subject will be rescreened for AS0011, the Screening CRP testing does not 
have to be repeated during Screening for AS0011 if the result is not older than 35 days at 
time of randomization at Baseline, otherwise, the CRP must be repeated. 
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• For all safety laboratory assessments: If a subject from AS0010 will be rescreened for 
AS0011, the Screening safety laboratory testing (hematology, biochemistry, urinalysis, urine 
drug screen, pregnancy testing as applicable, and IGRA TB testing) does not have to be 
repeated during Screening for AS0011 if the results are not older than 35 days at time of 
randomization at Baseline. Otherwise, if the results are older than 35 days, these tests must 
be repeated. 
Has been changed to: 
Clinical laboratory assessments consist of biochemistry, hematology, urinalysis, and pregnancy 
tests (serum or urine) (Table 12‒2). A centralized laboratory will be used to supply all laboratory 
test supplies and analyze all blood and urine samples (except the urine pregnancy test). Any 
unscheduled laboratory testing should also be collected using the central laboratory (with the 
exception of urgent safety laboratory measurements which should be performed locally and 
centrally simultaneously). Testing to exclude hepatitis B, hepatitis C, and HIV (see Exclusion 
Criterion #12, Section 6.2) will be performed at Screening in addition to those measurements 
listed in Table 12‒2. A urine dipstick will be used for pregnancy testing. Rescreening 
requirements pertaining to laboratory assessments are summarized below: 
Rescreening and retesting rules are provided in Section 5.1.1.1 and Section 5.1.1.2. 
• For CRP: If a subject will be rescreened for AS0011, the Screening CRP testing does not 
have to be repeated during Screening for AS0011 if the result is not older than 35 days at 
time of randomization at Baseline, otherwise, the CRP must be repeated. 
• For all safety laboratory assessments: If a subject from AS0010 will be rescreened for 
AS0011, the Screening safety laboratory testing (hematology, biochemistry, urinalysis, urine 
drug screen, pregnancy testing as applicable, and IGRA TB testing) does not have to be 
repeated during Screening for AS0011 if the results are not older than 35 days at time of 
randomization at Baseline. Otherwise, if the results are older than 35 days, these tests must 
be repeated. 
 
Change #40 
Section 12.6.1, Evaluation of PDILI, last paragraph 
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. If a 
subsequent alternative diagnosis fully explains the hepatic findings, and the requirements 
provided in Section 12.6.1.2.1 are met, rechallenge with IMP may be appropriate. 
Has been changed to:  
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. If a 
subsequent alternative diagnosis fully explains the hepatic findings, and the requirements 
provided in Section 12.6.1.2.1 are met, rechallenge with IMP may be appropriate. 
 
 
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Change #41 
Section 12.6.1, Evaluation of PDILI, Table 12-3 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis of 
hyper-
sensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULNb 
NA 
Hepatology consultc 
Medical Monitor must 
be notified within 
24 hours (eg, by 
laboratory alert) and 
subject discussed with 
Medical Monitor ASAP. 
Immediate, 
permanent IMP 
discontinuation. 
 
Essential: Must have 
repeat liver 
chemistry values and 
additional testing 
completed ASAP 
(see 
Section 12.6.1.3); 
recommended to 
occur at the site with 
HCP. 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
values.d 
≥3xULN 
NA 
Yes 
≥8xULN 
NA 
NA 
Need for hepatology 
consult to be discussed 
(required if ALT or AST 
≥8xULN) 
Medical Monitor must 
be notified within 
24 hours (eg, by 
laboratory alert) and 
subject discussed with 
Medical Monitor ASAP. 
Immediate, 
permanent IMP 
discontinuation 
 
≥5xULN 
(and ≥2x 
Baseline) 
and 
<8xULN  
<2xULN 
No 
Discussion with Medical 
Monitor required. 
Consider need for 
hepatology consult if 
there is no evidence of 
resolution (see Follow 
up requirements).c 
Further investigation 
– immediate IMP 
discontinuation not 
required (see 
Section 12.6.1.2). 
 
IMP discontinuation 
required if any of the 
following occur: 
Essential: Every 
attempt must be 
made to have repeat 
liver chemistry 
values and 
additional testing 
completed within 
48 hours at the site 
with HCP (see 
Section 12.6.1.3). 
Monitoring of liver chemistry 
values at least twice per week for 
2 weeks.d 
• 
Immediate IMP 
discontinuation required if 
liver chemistry values 
continue to increase. 
After 2 weeks of monitoring 
liver chemistry values: 
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Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis of 
hyper-
sensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
• 
Subject cannot 
comply with 
monitoring 
schedule. 
• 
Liver chemistry 
values continue 
to increase 
• 
Liver chemistry 
values remain 
≥5xULN (and 
≥2x baseline) 
after 4 weeks 
of monitoring 
without 
evidence of 
resolution 
• 
ALT or AST remains 
≥5xULN <8xULN, IMP 
should be temporarily 
withheld and subject 
should undergo repeat test 
in 2 weeks. 
Continue IMP if ALT or 
AST values <5xULN; 
continue to monitor at least 
twice per week until values 
normalize, stabilize, or 
return to within baseline 
values. 
If ALT or AST remains 
≥5xULN after second re-
test, immediate, permanent 
IMP discontinuation 
required. 
Continue to monitor until values 
normalize, stabilize, or return to 
within baseline values.d 
 
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Has been changed to: 
Laboratory value 
 
Immediate 
Follow up 
ALT or AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULNb 
NA 
Hepatology consultc 
Medical Monitor must 
be notified within 
24 hours (eg, by 
laboratory alert) and 
subject discussed with 
Medical Monitor ASAP. 
Need for hepatology 
consult to be discussed 
(required if ALT or AST 
≥8xULN). 
Medical Monitor must 
be notified within 
24 hours (eg, by 
laboratory alert) and 
subject discussed with 
Medical Monitor ASAP. 
Immediate permanent 
IMP discontinuation.d 
Immediate, permanent 
IMP discontinuation. 
 
Essential: Must have 
repeat liver chemistry 
values and additional 
testing completed 
ASAP (see 
Section 12.6.1.3); 
recommended to occur 
at the site with HCP. 
Monitoring of liver 
chemistry values at least 
twice per week until values 
normalize, stabilize, or 
return to within baseline 
values.e 
≥3xULN 
NA 
Yes 
≥8xULN 
NA 
NA 
≥5xULN (and 
≥2x baseline) 
and <8xULN  
<2xULN 
No 
Discussion with Medical 
Monitor required. 
Consider need for 
hepatology consult if 
there is no evidence of 
resolution (see Follow 
up requirements).c 
Further investigation – 
immediate IMP 
discontinuation not 
required (see 
Section 12.6.1.2). 
 
IMP discontinuation 
required if any of the 
following occur: 
 
• Subject cannot 
comply with 
monitoring schedule. 
Essential: Every 
attempt must be made 
to have repeat liver 
chemistry values and 
additional testing 
completed within 
48 hours at the site 
with HCP (see 
Section 12.6.1.3). 
Monitoring of liver 
chemistry values at least 
twice per week for 2 weeks.e 
• 
Immediate IMP 
discontinuation required 
if liver chemistry values 
continue to increase. 
After 2 weeks of monitoring 
liver chemistry values: 
• 
ALT or AST remains 
≥5xULN <8xULN, IMP 
should be temporarily 
withheld and subject 
should undergo repeat 
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Laboratory value 
 
Immediate 
Follow up 
ALT or AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
• Liver chemistry 
values continue to 
increase. 
• Liver chemistry 
values remain 
≥5xULN (and 
≥2x baseline) after 4 
weeks of monitoring 
without evidence of 
resolution. 
test in 2 weeks. 
 
Continue IMP if ALT 
or AST values 
<5xULN; continue to 
monitor at least twice 
per week until values 
normalize, stabilize, or 
return to within baseline 
values. 
 
If ALT or AST remains 
≥5xULN after second 
re-test, immediate, 
permanent IMP 
discontinuation 
required. 
Continue to monitor until 
values normalize, stabilize, 
or return to within baseline 
values.e 
 
 
 
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Change #42 
Section 12.6.1, Evaluation of PDILI, Table 12-3, footnotes 
The following footnote has been added: 
d 
Details are provided in Section 12.6.1.2. 
Subsequent footnotes have been adjusted accordingly. 
 
Change #43 
Section 12.6.1.2, Immediate action: determination of IMP discontinuation, paragraph 2 
All PDILI events require immediate action, testing, and monitoring.  
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 12‒3 for details). 
Has been changed to:  
All PDILI events require immediate action, testing, and monitoring.  
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 12‒3 for details). 
 
Change #44 
Section 12.6.1.2.1, IMP restart/rechallenge, paragraph 1 
Subjects who are immediately discontinued from IMP due to having met certain criteria for 
PDILI (as described in Section 6.3.1 and Table 12‒3), but for whom an alternative diagnosis is 
confirmed, ie, drug-induced liver injury is excluded, can rarely restart IMP. Rechallenge with 
IMP can occur only if ALL of the following requirements are met: 
Has been changed to:  
Subjects who are immediately discontinued from IMP due to having met certain criteria for 
PDILI (as described in Section 6.3.1 and Table 12‒3), but for whom an alternative diagnosis is 
confirmed, ie, drug-induced liver injury is excluded, can rarely restart IMP. Rechallenge with 
IMP can occur only if ALL of the following requirements are met at the time of the 
rechallenge: 
 
Change #45 
Section 12.7.7, PHQ-9 
The following text was moved to Section 12.7.7. 
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring, and measuring 
the severity of depression. The PHQ-9 scores for depression range from 0 to 27 with higher 
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scores indicating worse state. A score of 5 to 9 is considered to be minimal symptoms of 
depression. A score of 10 to 14 is considered minor depression, dysthymia, or mild major 
depression. A score of 15 to 19 is considered to indicate moderately severe major depression, 
and a score ≥20 is considered to be severe major depression.  
The PHQ-9 will be completed by the subject at the visits specified in Table 5-2.  
Refer to Section 6.3 for PHQ-9-related withdrawal criteria. 
 
Change #46 
Section 13.2, Medical and ankylosing spondylitis history 
The Investigator or designee will obtain a complete medical history and a medical history related 
to AS (including EAMs, the date of diagnosis, and past treatments for AS as part of the 
Screening assessment and include all clinically relevant past or coexisting medical conditions, 
responses to AS treatment as available, Baseline GI-related symptoms, and surgeries. Findings 
will be recorded in the eCRF. 
Has been changed to:  
The Investigator or designee will obtain a complete medical history and a medical history related 
to AS (including EAMs, the date of diagnosis, and past treatments for AS, and ASAS 
classification criteria as referenced in Section 19.1) as part of the Screening assessment and 
include all clinically relevant past or coexisting medical conditions, responses to AS treatment as 
available, Baseline GI-related symptoms, and surgeries. Findings will be recorded in the eCRF. 
 
Change #47 
Section 15.3.1, Figure 15-1, Sequential testing procedure of primary/secondary efficacy 
endpoints  
The time point (Week 16) was added to hypothesis #9 in the sequential testing procedure. 
 
Change #48 
Section 15.3.3, Subgroup analyses, bullet #3 
Subgroup analyses using descriptive statistics will be performed on the primary efficacy 
variable. The following variables for subgroup analyses will be defined:  
• ... 
• Disease duration (<2 years; ≥2 years) 
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Has been changed to:  
Subgroup analyses using descriptive statistics will be performed on the primary efficacy 
variable. The following variables for subgroup analyses will be defined:  
• ... 
• Disease duration (<5 years; ≥5 years) 
 
Change #49 
Section 16.1, Informed consent, paragraph 3  
Prior to participation in the study, the Informed Consent Form should be signed and personally 
dated by the subject, or his/her legal representative, and by the person who conducted the 
informed consent discussion (Investigator or designee). The subject or his/her legal 
representative must receive a copy of the signed and dated Informed Consent Form. As part of 
the consent process, each subject must consent to direct access to his/her medical records for 
study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. 
Has been changed to:  
Prior to participation in the study, the Informed Consent Form should be signed and personally 
dated by the subject, or his/her legal representative, and by the person who conducted the 
informed consent discussion (Investigator or designee). The subject or his/her legal 
representative must receive a copy of the signed and dated Informed Consent Form. As part of 
the consent process, each subject must consent to direct access to his/her medical records for 
study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. 
 
Change #50 
Section 16.2, Subject identification cards  
Upon signing the Informed Consent Form, the subject or legal representative will be provided 
with a subject identification card in the language of the subject. The Investigator will fill in the 
subject identifying information and medical emergency contact information. The Investigator 
will instruct the subject to keep the card with him/her at all times. 
Has been changed to:  
Upon signing the Informed Consent Form, the subject or legal representative will be provided 
with a subject identification card in the language of the subject. The Investigator will fill in the 
subject identifying information and medical emergency contact information. The Investigator 
will instruct the subject to keep the card with him/her at all times. 
 
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Change #51 
Section 18, References 
The following reference has been added: 
Baraliakos X, Heldmann F, Callhoff J, Listing J, Appelboom T, Brandt J, et al. Which spinal 
lesions are associated with new bone formation in patients with ankylosing spondylitis treated 
with anti-TNF agents? A long-term observational study using MRI and conventional 
radiography. Ann Rheum Dis. 2014;73:1819-25. 
The following reference has been deleted: 
Sieper J, Poddubnyy D. Axial spondyloarthritis.Lancet. 2017;1;390(10089):73-84. 
 
Change #52 
Section 19.1, ASAS Classification Criteria for axial SpA  
The following table has been added: 
Table 19-1: ASAS classification criteria for axial SpA (for subjects with chronic 
back pain of at least 3 months and age at onset <45 years) 
Imaging criteria 
ASAS clinical criteria for axial SpA 
Sacroiliitis (MRI or radiographsa) plus ≥1 SpA feature 
HLA-B27 plus ≥2 other SpA features 
SpA featuresb 
 
Inflammatory back painc  
Psoriasis 
Arthritis 
Crohn’s disease/ulcerative colitis 
Enthesitis (heel)  
HLA-B27 
Uveitis  
Elevated CRP 
Dactylitis 
 
ASAS=Assessment of SpondyloArthritis International Society; axSpA=axial spondyloarthritis; CRP=C-reactive 
protein; HLA-B27=human leukocyte antigen B27; MRI=magnetic resonance imaging; NSAID=nonsteroidal 
anti-inflammatory drug; SpA=spondyloarthritis 
a Active inflammatory lesions of sacroiliac joints with definite bone marrow oedema/osteitis suggestive of 
sacroiliitis associated with spondyloarthritis in MRI or radiographic sacroiliitis Grade 2 to 4 bilaterally or 
Grade 3 to 4 unilaterally according to modified NY criteria. For this study, only MRI will be permitted for 
study entry for the imaging criterion. 
b “Family history for SpA” and “Good response to NSAIDs” are excluded as SpA feature criteria. 
c Inflammatory back pain according to ASAS criteria for axSpA defined as the presence of 4 out of 5 of the 
following parameters: 
1. age at onset <45 years 
2. insidious onset 
3. improvement with exercise 
4. no improvement with rest 
5. pain at night (with improvement upon getting up) 
 
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19.4 
Protocol Amendment 2 
Rationale for the amendment 
The purpose of this protocol amendment is an update of Inclusion criterion #6 to reflect the 
treatment guidelines for axSpA, as presented in the recent EULAR/ASAS and ACR/SPARTAN 
guidelines. The List of Abbreviations has been updated accordingly. In addition, a minor update 
for consistency has been made. 
 
Modifications and changes 
Global changes 
No global changes have been made. 
 
Specific changes 
Change #1 
Section 6.1, Inclusion criterion #6 
6. Subjects must have at least 1 of the following: 
− Inadequate response to NSAID therapy, or  
− Intolerance to administration of at least 1 NSAID, or 
− Contraindication(s) to NSAID therapy 
Inadequate response to an NSAID is defined as lack of response for at least 4 weeks of 
continuous NSAID therapy at the highest tolerated dose of the administered NSAID or the 
lack of response to treatment with at least 2 NSAIDs at the maximum tolerated dose for at 
least 4 weeks total duration.  
Has been changed to: 
6a. Subjects had to have either failed to respond to 2 different NSAIDs given at the 
maximum tolerated dose for a total of 4 weeks or have a history of intolerance to or a 
contraindication to NSAID therapy. 
Change #2 
Section 9.15, ASDAS 
The variables related to ASDAS improvement are defined as follows: 
• ASDAS-CII: ASDAS reduction (improvement) of ≥1.1 relative to Baseline 
• ASDAS-MI: ASDAS reduction (improvement) of ≥2.0 relative to Baseline 
The ASDAS variables will be derived from assessments at the visits specified in Table 5‒2. 
 
 
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Has been changed to: 
The variable related to ASDAS improvement is defined as follows: 
• ASDAS-MI: ASDAS reduction (improvement) of ≥2.0 relative to Baseline 
The ASDAS variables will be derived from assessments at the visits specified in Table 5‒2. 
 
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19.5 
Protocol Amendment 3 
Rationale for the amendment 
The purpose of this amendment is to change the sponsor company name from “UCB Biopharma 
SPRL” to “UCB Biopharma SRL” since the name of the legal form of the entity UCB 
Biopharma has changed into “société à responsabilité limitée” abbreviated “SRL”. 
In addition, a minor correction has been made. 
Modifications and changes 
Global changes 
No global changes have been made. 
Specific changes 
Change #1 
Sponsor name on the title page in the study contact information 
Sponsor 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Has been changed to: 
Sponsor 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
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19.6 
Protocol Amendment 4 
Rationale for the amendment 
The major purpose of this protocol amendment is to update the handling of missing data for the 
statistical analysis of the primary endpoint in response to a recent agency request. The 
COVID-19-free set was added in response to industry recommendations for evaluating the 
impact of the pandemic. In addition, other previously planned supportive analyses defined in the 
SAP were added for completeness. 
Further key changes are summarized below. 
• The introduction in Section 2 presenting a high level summary of bimekizumab indications in 
development and an overview of clinical studies has been updated to reflect the latest status.  
• For some secondary and other endpoints in Section 4.2.1 and Section 4.3.1 (BASDAI, 
nocturnal spinal pain, ASQoL, SF-36, MOS12-item scale, and FACIT-Fatigue), wording 
changes have been implemented for consistency with the user manuals and to reflect precise 
description of the PRO tool and scoring (change in terminology but no change in the 
method). Similarly, corresponding small changes in Section 8 and Section 15.9.2 have been 
made for clarity and consistency with the revised description of the assessments.  
• The definition of the secondary safety variables related to SAEs and AEs leading to 
withdrawal was changed to clarify these variables are related to treatment-emergent events. 
This definition is consistent with the SAP and common practice. 
• Interim analyses as described in Section 5.1 and Section 15.8.1 have been updated to clarify 
that interim analyses will include data from the planned number of randomized study 
participants who completed the corresponding treatment period. In Section 15.8.1, the 
amendment clarifies that additional interim analyses or data cuts for regulatory purposes are 
permitted.  
• A typographical error in Table 5‒1 showing cross-study screening requirements for the 
PHQ-9, eC-SSRS, and the TB questionnaire (Q1) related criterion has been corrected.  
• In line with the Exclusion Criterion 11 regarding infections, a specific infection related 
withdrawal criterion was added to clarify that subjects with serious or recurrent infections not 
responding to standard therapies are not exposed to immunomodulatory therapies until their 
infection is resolved. This is in line with most biologic therapies, including other anti-IL17s. 
• In Table 7‒2, the section providing details for mild potency opioids has been updated to 
clarify that the listed opioids reflect examples. 
• Section 7.8.1 listing permitted concomitant treatments has been amended to enhance clarity 
on allowed medications including biologics for permanently discontinued subjects after at 
least 28 days of the final IMP dose. 
• Throughout the protocol, vital sign assessments reported as pulse and blood pressure 
measurements were replaced with “vital sign” measurements for internal consistency. This 
update does not reflect a procedural change. 
• The description of the ASQoL assessment in Section 9.2 has been amended with details 
regarding scoring.  
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• Language describing the BASFI component of the ASAS response has been updated for 
clarity to specifically mention “physical function” as opposed to “function”. The header for 
Section 9.5 was updated accordingly. 
• The presentation of the SF-36 assessment in Section 9.6 has been corrected to ensure 
consistency with the user manual and the author’s recommendation (Maruish, 2011). 
Subsequently, wording changes for consistency throughout the protocol, mainly in 
Section 4.2.1 and Section 8 have been made. 
• The presentation of the FACIT-Fatigue subscale in Section 9.10 has been corrected to ensure 
consistency with the user manual (FACIT.org). Subsequently, wording changes for 
consistency throughout the protocol, mainly in Section 4.3.1 and Section 8 have been made. 
• The proposed SPARCC and ASspiMRI scoring systems to assess the level of MRI 
inflammation in the SIJ and spine, respectively, are currently well accepted.  Methodology 
for scoring of MRI inflammation in the SIJ or spine is evolving, and the additional methods 
to evaluate the MRI inflammation data (for instance spine SPARCC) may be considered. 
Based on this approach, Section 9.20.3 has been amended accordingly. 
• With progressive development of bimekizumab and based on the ongoing review of 
emerging safety data, depression has been removed as a safety topic of interest. Nevertheless, 
depression will continue to be monitored as a safety parameter by the PHQ9 and will be 
captured via routine AE reporting during the study. This update is considered a procedural 
change. 
• Action to be taken in the event that a subject reports a pregnancy as described in Section 12.2 
has been updated for consistency with protocols in other indications. 
• Action to be taken if a subject presents with a PDILI event as described in Section 12.6.1 has 
been updated for consistency with protocols in other indications. 
• Section 15.8.2 was amended to allow other adjudication committees as necessary. 
• Study contact details have been updated to reflect recent changes.  
At the same time, a few updates including consistency changes within the bimekizumab 
program, minor corrections, the list of abbreviations, a reference has been added for the 
FACIT-Fatigue, and minor formatting changes for the purpose of clarity have been made. 
 
Modifications and changes 
Global changes 
The following change was made throughout the protocol: 
• All instances that referred to “Administer the SF-36 PCS and MCS” have been corrected 
to “Administer the SF-36 questionnaire”. 
• All instances that referred to “FACIT-F” have been corrected to “FACIT-Fatigue”, all 
instances that referred to “Administer the FACIT-F” have been corrected to “Administer 
the FACIT-Fatigue subscale” and the definition of the abbreviation was updated 
accordingly. 
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Specific changes 
Change #1 
Protocol/Amendment number details on the cover page 
Protocol Amendment 4.2 (Germany) 
Has been changed to: 
Protocol Amendment 3.2 (Germany) 
 
Change #2 
STUDY CONTACT INFORMATION 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim am Rhein 
GERMANY 
Phone: 
 
Has been changed to: 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim am Rhein 
GERMANY 
Phone: 
 
 
Change #3 
Section 2.2, Bimekizumab, paragraph 1, sentence 5 
Bimekizumab is being developed for the treatment of patients with inflammatory diseases such 
as PsA, psoriasis (PSO), and axSpA. 
Has been changed to: 
Bimekizumab is being developed for the treatment of patients with inflammatory diseases such 
as PsA, psoriasis (PSO), and axSpA and hidradenitis suppurativa. 
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Change #4 
Section 2.2.2.1, Completed studies, paragraph 1 
Thirteen clinical studies of bimekizumab have been completed: UP0008 in 39 subjects with mild 
to moderate plaque PSO, RA0124 in 30 healthy volunteers, PA0007 in 53 subjects with PsA, 
UP0031 in 12 healthy volunteers, UP0042 in 48 Japanese and Caucasian healthy volunteers, 
RA0123 in 159 subjects with moderate-to-severe RA, PS0010 in 250 subjects with moderate-to-
severe chronic plaque PSO and the corresponding extension study (PS0011), PS0016 in 49 
subjects with moderate-to-severe chronic plaque PSO and the corresponding extension study 
(PS0018), UC0011 in 23 subjects with moderate-to severe active ulcerative colitis, AS0008 in 
303 subjects with AS, and PA0008 in 206 subjects with PsA. 
Has been changed to: 
Thirteen Twenty clinical studies of bimekizumab have been completed: UP0008 in 39 subjects 
with mild to moderate plaque PSO, RA0124 in 30 healthy volunteers, PA0007 in 53 subjects 
with PsA, UP0031 in 12 healthy volunteers, UP0033 in 189 healthy volunteers, UP0034 in 
56 healthy volunteers, UP0042 in 48 Japanese and Caucasian healthy volunteers, UP0074 in 
37 healthy volunteers, RA0123 in 159 subjects with moderate-to-severe RA, PS0010 in 250 
subjects with moderate-to-severe chronic plaque PSO and the corresponding extension study 
(PS0011), PS0016 in 49 subjects with moderate-to-severe chronic plaque PSO and the 
corresponding extension study (PS0018), UC0011 in 23 subjects with moderate-to severe active 
ulcerative colitis, HS0001 in 90 subjects with moderate to severe hidradenitis suppurativa, 
AS0008 in 303 subjects with AS, and PA0008 in 206 subjects with PsA, PS0008 in 478 subjects 
with moderate to severe chronic plaque PSO, PS0009 in 567 subjects with moderate to 
severe chronic plaque PSO and PS0013 in 435 subjects with moderate to severe chronic 
plaque PSO. 
 
Change #5 
Section 2.2.2.2, Ongoing studies, paragraph 1 
Several additional studies of bimekizumab in subjects with AS are ongoing:  
Has been changed to: 
Several additional studies of bimekizumab in subjects with AS axSpA are ongoing:  
In addition, the following bullet has been added: 
• AS0014 is a Phase 3, open-label extension study for AS0010 and AS0011.  
 
Change #6 
Section 4.2, Secondary variables 
Section 4.2.1, Secondary efficacy variables 
• … 
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• Change from Baseline in BASDAI at Week 16  
• … 
• Change from Baseline in nocturnal spinal pain (NRS) at Week 16 
• Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) at Week 16  
• Change from Baseline in the Short Form 36-Item Health Survey (SF-36) physical component 
summary (PCS) at Week 16  
• … 
Section 4.2.2, Secondary safety variables 
… 
• Incidence of serious adverse events (SAEs) 
• Adverse events (AEs) leading to withdrawal from IMP 
Has been changed to: 
Section 4.2.1, Secondary efficacy variables 
• … 
• Change from Baseline in BASDAI total score at Week 16  
• … 
• Change from Baseline in nocturnal spinal pain score (NRS) at Week 16 
• Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) total score at 
Week 16  
• Change from Baseline in the Short Form 36-Item Health Survey (SF-36) physical component 
summary (PCS) score at Week 16  
• … 
Section 4.2.2, Secondary safety variables 
… 
• Incidence of treatment-emergent serious adverse events (SAEs) 
• Adverse events (AEs) TEAEs leading to withdrawal from IMP 
 
Change #7 
Section 4.3.1, Other efficacy variables 
• … 
• Change from Baseline in BASDAI 
• … 
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• Change from Baseline in total and nocturnal spinal pain (NRS)  
• Change from Baseline in the average of Questions 5 and 6 of the BASDAI concerning 
morning stiffness  
• … 
• Change from Baseline in the SF-36 PCS  
• Change from Baseline in the SF-36 mental component summary (MCS)  
• Change from Baseline in sleep quality (Medical Outcomes Study [MOS 12-item] scale)  
• Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F)  
• Change from Baseline in ASQoL  
• … 
Has been changed to: 
• … 
• Change from Baseline in BASDAI total score  
• … 
• Change from Baseline in total and nocturnal spinal pain score (NRS)  
• Change from Baseline in the average score of Questions 5 and 6 of the BASDAI concerning 
morning stiffness  
• … 
• Change from Baseline in the SF-36 PCS score 
• Change from Baseline in the SF-36 mental component summary (MCS) score 
• Change from Baseline in sleep quality score (Medical Outcomes Study [MOS 12-item] 
scale)  
• Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F)-Fatigue subscale score 
• Change from Baseline in ASQoL total score  
• … 
 
Change #8 
Section 5.1, Study description, paragraph 6, sentence 1 
Interim analyses of all available data (including efficacy, safety, and PK) will be conducted after 
all randomized subjects have completed 24 weeks and 52 weeks of treatment or have withdrawn 
from IMP or the study.  
Has been changed to: 
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Interim analyses of all available data (including efficacy, safety, and PK) will be conducted after 
all the planned number of randomized subjects have completed 24 weeks and 52 weeks of 
treatment or have withdrawn from IMP or the study.  
 
Change #9 
Section 5.1.1.2 Cross-study screening requirements 
Table 5-1: Cross-study screening requirements, fourth row, second column 
Table 5-1: 
Cross-study screening requirements 
Assessment  
Screening requirements 
… 
PHQ-9, eC-SSRS, 
TB questionnaire 
(Q1) 
Screening of a subject not eligible for AS0010 who will be screened for AS0011, 
and who did not meet the related Exclusion Criteria in AS0010. 
… 
Has been changed to: 
Table 5-1: 
Cross-study screening requirements 
Assessment  
Screening requirements 
… 
PHQ-9, eC-SSRS, 
TB questionnaire 
(Q1) 
Screening of a subject not eligible for AS0010 who will be screened for AS0011, 
and who did not meet the related Exclusion Criteria in AS0010. 
… 
 
Change #10 
Section 5.2, Schedule of study assessments 
Table 5‒2: Schedule of study assessments, 22nd row, first column 
Protocol activity 
… 
• 
FACIT-F 
… 
Has been changed to: 
Protocol activity 
… 
• 
FACIT-F-Fatigue subscale 
… 
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Change #11 
Section 6.3, Withdrawal criteria 
The following bullet has been added: 
12.  Any subject who develops a clinically important infection or recurrent infections not 
responsive to standard therapy during the study must discontinue IMP until resolution of the 
infection. The Investigator should use clinical judgement in deciding whether the subject 
should restart IMP and contact the Medical Monitor and UCB study physician to confirm the 
subject’s suitability for continued participation in the study. 
 
Change #12 
Section 7.8, Concomitant medications/treatments 
Table 7‒2: Exclusionary, concomitant, and rescue medication, fourth row, first column 
Drug class/dose 
… 
Mild potency opioids permitted 
only: 
• 
Tramadol/any dose up to 
maximum approved dose 
• 
Codeine/only <90mg of 
codeine per dosage unit 
… 
Has been changed to: 
Drug class/dose 
… 
Mild potency opioids permitted 
only eg,: 
• 
Tramadol/any dose up to 
maximum approved dose 
• 
Codeine/only <90mg of 
codeine per dosage unit 
… 
 
Change #13 
Section 7.8.1, Permitted concomitant treatments (medications and therapies) 
The following text has been added: 
Subjects are allowed to use any other medications, including biologics, after at least 28 days of 
their final dose of the IMP. This is applicable for subjects who discontinue from the study early, 
including those permanently withdrawn from IMP, or subjects who have completed the study 
treatment without entering the extension study and are in the SFU Period. 
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Change #14 
Section 8.2, Baseline (Visit 2, Day 1, first dose of IMP), last bullet  
and  
 Section 8.3.6, Week 16 (±3 days) (Visit 8), last bullet 
• Measure BP and pulse approximately 30 minutes and 1 hour after dosing. 
Has been changed to: 
• Measure BP and pulse vital signs approximately 30 minutes and 1 hour after dosing. 
 
Change #15 
Section 9.1, ASAS20, 40, ASAS 5/6 response, and ASAS-PR, third bullet point 
• Function section (represented by BASFI, Section 9.5) 
Has been changed to: 
• Physical Function section (represented measured by BASFI, Section 9.5) 
 
Change #16 
Section 9.2, ASQoL, first paragraph 
The ASQoL, a validated disease-specific 18-item questionnaire, has been developed specifically 
for measuring health-related quality of life (HRQoL) in subjects with AS (Doward et al, 2003). 
The ASQoL has been used and has shown to be responsive in axSpA (Barkham et al, 2009; 
Haibel et al, 2008). The ASQoL score ranges from 0 to 18 with a higher score indicating worse 
HRQoL.  
Has been changed to: 
The ASQoL, a validated disease-specific 18-item questionnaire, has been developed specifically 
for measuring health-related quality of life (HRQoL) in subjects with AS (Doward et al, 2003). 
The ASQoL has been used and has shown to be responsive in axSpA (Barkham et al, 2009; 
Haibel et al, 2008). The Each statement on the ASQoL is given a score ranges of 1 = Yes or 0 
= No. A score of "1" is given where the item is affirmed, indicating adverse quality of life. 
All item scores are summed to total score ranging from 0 to 18 with a higher score indicating 
worse HRQoL.  
 
Change #17 
Section 9.4, BASDAI, second paragraph 
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The BASDAI is calculated as follows:  
Has been changed to: 
The BASDAI total score is calculated as follows:  
 
Change #18 
Section 9.5, Function – BASFI, heading 
Has been changed to: 
Section 9.5, Physical Ffunction – BASFI 
 
Change #19 
Section 9.6, SF-36, paragraphs 1 and 2 
The SF-36 (Version 2, standard recall) is a 36-item generic HRQoL instrument that uses a recall 
period of 4 weeks. Items are grouped into 8 domains as follows: Physical Functioning (10 items), 
Role Physical (4 items), Bodily Pain (2 items), General Health (5 items), Vitality (4 items), 
Social Functioning (2 items), Role Emotional (3 items), Mental Health (5 items), and 1 item for 
perceived stability or change in health (Health Transition) during the last year. The concepts 
represented by these domains contribute to physical, mental, and social aspects of HRQoL. 
In addition to domain scores, the Physical Component Summary and Mental Component 
Summary scores are calculated from the 8 domains (excluding the Health Transition item). 
Component scores appreciate the impact of each domain on physical and mental health status 
(Maruish, 2011). Each of the 8 domain scores and the component summary scores range from 
0 to 100, with a higher score indicating a better health status. The 2 component summary scores 
are standardized with a mean of 50 and a standard deviation (SD) of 10 in the general 
US population.  
Has been changed to: 
The SF-36 (Version 2, standard recall) is a 36-item generic HRQoL instrument that uses a recall 
period of 4 weeks. Items are grouped into 8 domains as follows: Physical Functioning (10 items), 
Role Physical (4 items), Bodily Pain (2 items), General Health (5 items), Vitality (4 items), 
Social Functioning (2 items), Role Emotional (3 items), Mental Health (5 items), and 1 One 
additional item for perceived stability or change in asks respondents about health change 
(Health Transition) during over the last past year. The concepts represented by these domains 
contribute to physical, mental, and social aspects of HRQoL. 
In addition to domain scores, the Physical Component Summary and Mental Component 
Summary scores are calculated from the 8 domains (excluding the Health Transition item). 
Component scores appreciate the impact of each domain on physical and mental health status 
(Maruish, 2011). Each of the 8 domain scores and the component summary scores range from 
0 to 100, with a higher score indicating a better health status. The norm-based T-scores for the 
2 SF-36 component summary (PCS and MCS) and the 8 domain scores are standardized with a 
mean of 50 and a standard deviation (SD) of 10 in the general US population (Maruish, 2011). 
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An individual respondent’s score that falls outside the T-score range of 45 to 55 should be 
considered outside the average range for the US general population. When considering 
group-level data, a score below 47 should be considered indicative of impaired functioning 
within that health domain or dimension. Similar to individual respondent data, group 
mean scores of 47 or greater should be considered average or above average as compared 
to the general US population. Higher scores indicate a better health status. 
 
Change #20 
Section 9.10, FACIT-F, heading and all paragraphs 
The FACIT-F is a self-administered quality of life questionnaire targeted to the management of 
chronic illness within the past 7 days. The FACIT-F contains 13 questions with responses scored 
on a 5-point Likert scale from 0 (not at all) to 4 (very much). Scores range from 0 to 52 (Mease 
et al, 2011). 
The FACIT-F will be assessed by the subject at the visits specified in Table 5-2. 
Has been changed to: 
Section 9.10, FACIT-F-Fatigue subscale 
The FACIT-F is a self-administered quality of life questionnaire targeted to 40-item measure 
that assesses self-reported fatigue and its impact upon daily activities and function over the 
management of chronic illness within the past 7 days (FACIT.org). The scale consists of 
5 subscales (physical well-being, social/family well-being, emotional well-being, functional 
well-being, and fatigue). The fatigue subscale is the only one used in this study. The FACIT-
F contains It is composed of 13 questions with responses items, all scored on a 5-point Likert 
scale from 0 (nNot at all) to 4 (vVery much). Scores range The FACIT-Fatigue subscale score 
ranges from 0 to 52 (Mease et al, 2011) with 0 being the worst possible score and 52 being 
the best possible score. To obtain a score from 0 to 52, all negatively worded questions have 
to be recoded, so that responses range from worst (0) to the best (4) outcome.  
The FACIT-F-Fatigue subscale will be assessed completed by the subject at the visits specified 
in Table 5-2. 
 
Change #21 
Section 12.1.1.4 Other safety topics of interest, paragraph 1 
Pre-specified safety topics of interest for the study are: infections (serious, opportunistic, fungal, 
and TB), neutropenia, hypersensitivity, suicidal ideation and behavior, depression, major 
cardiovascular events, liver function test changes/enzyme elevations, malignancies, and 
inflammatory bowel diseases (with gastroenterology referral, as appropriate).  
Has been changed to: 
Pre-specified safety topics of interest for the study are: infections (serious, opportunistic, fungal, 
and TB), neutropenia, hypersensitivity, suicidal ideation and behavior, depression, major 
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cardiovascular events, liver function test changes/enzyme elevations, malignancies, and 
inflammatory bowel diseases (with gastroenterology referral, as appropriate).  
 
Change #22 
Section 9.20.3, Sacroiliac joint and spine MRI assessment substudy 
The following sentence has been added at the end of the last paragraph: 
Additional scoring systems of inflammation may be used as appropriate methodology becomes 
accepted. 
 
Change #23 
Section 12.2 Pregnancy, paragraph 1 and bullet points 
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the Investigator must immediately notify UCB’s PS department by entering all pregnancy 
information into the eCRF. An automatic notification will be sent to UCB’s PS department. The 
subject should be withdrawn from the study as soon as pregnancy is known (by positive 
pregnancy test), and the following should be completed: 
• The subject should return for the ET Visit. 
• The subject should immediately stop the intake of the IMP.  
• A Safety Follow-Up Visit should be scheduled 20 weeks after the subject has discontinued 
her IMP. 
Has been changed to: 
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the Investigator must immediately (within 24 hours) notify UCB’s PS department by entering 
all pregnancy information into the eCRF. An automatic notification will be sent to UCB’s PS 
department. The subject should be permanently withdrawn from the study IMP as soon as 
pregnancy is known (by positive pregnancy test), and the following should be completed: 
• The subject should return for the ET Visit. 
• The subject should immediately stop the intake of the IMP.  
• The subject should return for an early ad-hoc study visit. 
• A Safety Follow-Up Visit should be scheduled 20 weeks after the subject has discontinued 
her final dose of IMP. 
The Investigator should discuss with the subject the possibility to continue the study by 
attending the scheduled visits for assessments without IMP administration. The tests or 
assessments, which are considered contraindicated during the pregnancy should not be 
performed. The early ad-hoc study visit will be considered as the ET Visit if the subject 
does not wish to pursue the study investigations. 
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The Investigator must inform the subject of information currently known about potential 
risks and about available treatment alternatives. 
 
Change #24 
Section 12.6.1 Evaluation of PDILI, paragraph 1 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and Sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 12.1.1.3), and, if applicable, also reported as an 
SAE (see Section 12.1.1.2). 
Has been changed to: 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and PDILI events meeting SAE criteria should be reported to the 
study site and Sponsor within 24 hours of learning of their occurrence. Any PDILI event that 
meets the criterion for potential Hy’s Law must be reported within 24 hours of learning of their 
occurrence as an AE of special interest (see Section 12.1.1.3), and, if applicable, also reported 
as an SAE (see Section 12.1.1.2).  
 
Change #25 
Section 12.7.1 Vital signs 
The Investigator or designee should measure all vital signs (systolic and diastolic BP, 
temperature [oral, axillary, or otic], pulse rate) prior to dosing after the subject has been sitting 
for at least 5 minutes, and the subject should remain seated during the measurements. At 
Baseline/Day 1 and Week 16 collect pulse and BP prior to drug administration and then at 
approximately 30 minutes and 1 hour after dosing.  
Has been changed to: 
The Investigator or designee should measure all vital signs (systolic and diastolic BP, 
temperature [oral, axillary, or otic], pulse rate) prior to dosing after the subject has been sitting 
for at least 5 minutes, and the subject should remain seated during the measurements. At 
Baseline/Day 1 and Week 16, collect pulse and BP vital signs prior to drug administration and 
then at approximately 30 minutes and 1 hour after dosing.  
 
Change #26 
Section 15.1, Definition of analysis sets, fifth bullet 
• The Per-Protocol Set (PPS) will consist of all subjects in the RS who had no important 
protocol deviation affecting the primary efficacy variable. Important protocol deviations will 
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be predefined and subjects with important protocol deviations will be evaluated during a data 
evaluation meeting prior to unblinding of the data.  
Has been changed to: 
• The Per-Protocol Set (PPS) will consist of all subjects in the RS who had no important 
protocol deviation affecting the primary efficacy variable. Important protocol deviations will 
be predefined and subjects with important protocol deviations will be evaluated during a data 
evaluation meeting prior to unblinding of the data. Exclusions from the FAS will be 
considered important protocol deviations that also result in exclusion from the PPS. 
In addition, the following bullet has been added: 
The coronavirus disease 2019 (COVID-19) free set will consist of all subjects in the RS who had 
no COVID-19 impact up to the primary efficacy endpoint. Further details will be defined as part 
of the SAP. 
 
Change #27 
Section 15.3.1.1 Analysis of the primary efficacy variable, paragraph 2, bullet #1, bullet #3 
and paragraph 4 
… 
The primary endpoint is the ASAS40 response at Week 16. The primary efficacy analysis will 
evaluate the composite estimand in the RS. The composite estimand combines the clinically 
meaningful improvement from Baseline based on the ASAS40 response and not discontinuing 
treatment early due to an AE or lack of efficacy. 
… 
1. Population = Subjects meeting the protocol-specified inclusion/exclusion criteria. 
… 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to an AE or lack of efficacy prior to Week 16. A composite strategy will be 
implemented in which a positive clinical outcome is defined as achieving ASAS40 at 
Week 16 and not discontinuing study treatment due to an AE or lack of efficacy through 
Week 16.  
… 
Any missing data at Week 16 that are not preceded by an intercurrent event (ie, discontinuation 
of study medication due to an AE or lack of efficacy) will be imputed based on a predefined 
multiple imputation (MI) model. In MI, the missing value is replaced by a set of plausible values, 
where each value is a Bayesian draw from the conditional distribution of the missing data given 
the observed data. Intermittent missing data will be imputed using the Markov-Chain Monte 
Carlo (MCMC) method, followed by logistic regression for monotone missing data.  
… 
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Has been changed to: 
… 
The primary endpoint is the ASAS40 response at Week 16. The primary efficacy analysis will 
evaluate the composite estimand in the RS. The composite estimand combines the clinically 
meaningful improvement from Baseline based on the ASAS40 response and not discontinuing 
treatment early due to an AE or lack of efficacy. In practice, this composite estimand is 
similar to non-responder imputation (NRI), referred to here as modified NRI.  
… 
1. Population = Subjects meeting enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP. 
… 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to an AE or lack of efficacy prior to Week 16. A composite strategy will be 
implemented in which a positive clinical outcome is defined as achieving ASAS40 at 
Week 16 and not discontinuing study treatment due to an AE or lack of efficacy through 
Week 16. 
… 
Any mMissing data at Week 16 that are not preceded by an intercurrent event, and any data 
after an intercurrent event will be imputed as non-responders (ie, discontinuation of study 
medication due to an AE or lack of efficacy) will be imputed based on a predefined multiple 
imputation (MI) model. In MI, the missing value is replaced by a set of plausible values, where 
each value is a Bayesian draw from the conditional distribution of the missing data given the 
observed data. Intermittent missing data will be imputed using the Markov-Chain Monte Carlo 
(MCMC) method, followed by logistic regression for monotone missing data.  
… 
 
Change #28 
Section 15.3.1.1.1 Supportive analyses 
Supportive analyses for the primary efficacy variable will be conducted: 
1. The analysis will be repeated based on the PPS to evaluate the effect of important protocol 
deviations on the analysis.  
2. The analyses will be repeated for all subjects in the FAS to evaluate the consistency between 
the RS and the more restrictive FAS. This analysis will only be performed if the number of 
subjects in RS and FAS are different. 
3. The analyses will also be repeated for all individual components of the ASAS40 response to 
explore the effect of the signs and symptoms of the individual components on the composite 
endpoint. Since all ASAS components are continuous variables (eg, change from Baseline in 
total spinal pain), an analysis of covariance (ANCOVA) with treatment, region, and prior 
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TNFα inhibitor exposure as fixed effects and the Baseline values as covariate will be used for 
the analysis. 
Additional supportive analyses to evaluate varying assumptions related to the handling of 
missing data will also be performed and are described in Section 15.7. 
Has been changed to: 
Supportive analyses for the primary efficacy variable will be conducted. The analyses will be 
repeated: 
1. The analysis will be repeated bBased on the PPS to evaluate the effect of important protocol 
deviations on the analysis.  
2. The analyses will be repeated fFor all subjects in the FAS to evaluate the consistency 
between the RS and the more restrictive FAS. This analysis will only be performed if the 
number of subjects in RS and FAS are different. 
3. The analyses will also be repeated fFor all individual components of the ASAS40 response to 
explore the effect of the signs and symptoms of the individual components on the composite 
endpoint. Since all ASAS components are continuous variables (eg, change from Baseline in 
total spinal pain), an analysis of covariance (ANCOVA) with treatment, region, and prior 
TNFα inhibitor exposure as fixed effects and the Baseline values as covariate will be used for 
the analysis. 
4. Using a modified composite estimand where intercurrent events are defined only as 
discontinuation due to adverse event or lack of efficacy. 
5. Using a treatment policy imputation. 
6. Using a tipping point analysis. 
7. Using observed cases only (OC). 
8. Using the COVID-19-free set. 
Further specification of Aadditional supportive analyses to evaluate varying assumptions 
related to the handling of missing data will also be performed and are described in Section 15.7. 
 
Change #29 
Section 15.3.1.2 Analyses of the secondary efficacy variables, paragraph 2, first bullet point 
and paragraphs 4 and 5 
… 
Binary variables will be analyzed to evaluate the composite estimand in the RS as done for the 
primary efficacy variable. The composite estimand combines (1) achieving the given binary 
response and (2) not discontinuing prior to Week 16 due to an AE or lack of efficacy. The 
statistical hypothesis for the binary variables at Week 16 is that the conditional odds ratio for 
binary variables in the bimekizumab treatment group compared with the placebo treatment group 
is equal to 1. 
… 
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• Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to an AE or lack of efficacy prior to Week 16. A hypothetical strategy for 
addressing intercurrent events will be implemented. This estimand targets the treatment 
difference in a scenario where withdrawal from study treatment due to an AE or lack of 
efficacy does not occur, such that outcomes for subjects without an intercurrent event are as 
observed, and outcomes for subjects with an intercurrent event are treated as though they had 
completed the randomized study treatment through Week 16. A multiple imputation strategy 
will be used to impute data following an intercurrent event. 
… 
Any missing data at Week 16 that is not preceded by an intercurrent event (ie, discontinuation of 
study medication due to an AE or lack of efficacy) will be imputed based on a predefined MI 
model. The missing value will be replaced by a set of plausible values, where each value is a 
Bayesian draw from the conditional distribution of the missing data given the observed data. 
Intermittent missing data will be imputed using the MCMC method, followed by monotone 
regression for monotone missing data. The statistical model for the comparison of bimekizumab 
and placebo will be an ANCOVA with treatment, region, and prior TNFα inhibitor exposure as 
fixed effects and the Baseline value as covariate. The statistical hypothesis for the continuous 
variables at Week 16 is that the treatment difference between the bimekizumab treatment group 
and placebo is equal to 0. 
All secondary efficacy variables will also be summarized based on observed case data. 
 
Has been changed to: 
… 
Binary variables will be analyzed to evaluate the composite estimand in the RS, as done for the 
primary efficacy variable. The composite estimand combines (1) achieving the given binary 
response and (2) not discontinuing treatment prior to Week 16 due to an AE or lack of efficacy. 
The statistical hypothesis for the binary variables at Week 16 is that the conditional odds ratio for 
binary variables in the bimekizumab treatment group compared with the placebo treatment group 
is equal to 1. 
… 
• Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to an AE or lack of efficacy prior to Week 16. A hypothetical strategy for 
addressing intercurrent events will be implemented. This estimand targets the treatment 
difference in a scenario where withdrawal from study treatment due to an AE or lack of 
efficacy does not occur, such that outcomes for subjects without an intercurrent event are as 
observed, and outcomes for subjects with an intercurrent event are treated as though they had 
completed the randomized study treatment through Week 16. A multiple imputation strategy 
will be used to impute data following an intercurrent event. 
… 
Any missing data at Week 16 that is not preceded by an intercurrent event (ie, discontinuation of 
study medication due to an AE or lack of efficacy) will be imputed based on a 
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predefined multiple imputation (MI) model. The missing value will be replaced by a set of 
plausible values, where each value is a Bayesian draw from the conditional distribution of the 
missing data given the observed data. Intermittent missing data will be imputed using the 
Markov-Chain Monte Carlo (MCMC) method, followed by monotone regression for monotone 
missing data. The statistical model for the comparison of bimekizumab and placebo will be an 
ANCOVA with treatment, region, and prior TNFα inhibitor exposure as fixed effects and the 
Baseline value as covariate. The statistical hypothesis for the continuous variables at Week 16 is 
that the treatment difference between the bimekizumab treatment group and placebo is equal to 
0. 
All secondary efficacy variables will also be summarized based on observed case data. Binary 
outcomes will also be summarized using the modified composite estimand. 
 
Change #30 
Section 15.3.2 Analyses of other efficacy variables, bullet #3, paragraph 3 and the second 
bullet #3 
… 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to adverse event or lack of efficacy prior to the time point being summarized. A 
composite strategy will be implemented in which a positive clinical outcome is defined as 
achieving the given variable at the specified time point and not discontinuing study treatment 
due to adverse event or lack of efficacy through that time point. 
… 
Any missing data that are not preceded by an intercurrent event as described above will be 
imputed based on a predefined multiple imputation model as described for the primary efficacy 
variable. 
… 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to an AE or lack of efficacy prior to the time point being summarized. A 
hypothetical strategy will be implemented in which outcomes for subjects without an 
intercurrent event are as observed at the given time point, and outcomes for subjects with an 
intercurrent event are treated as though they had completed the randomized study treatment 
through the time point being summarized. A multiple imputation strategy will be used to 
impute data following an intercurrent event. 
… 
Has been changed to: 
… 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to adverse event or lack of efficacy prior to the time point being summarized. A 
composite strategy will be implemented in which a positive clinical outcome is defined as 
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achieving the given variable at the specified time point and not discontinuing study treatment 
due to adverse event or lack of efficacy through that time point. 
… 
Any missing data that are not preceded by an intercurrent event as described above will be 
imputed based on a predefined multiple imputation model NRI as described for the primary and 
secondary efficacy variables. 
… 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to an AE or lack of efficacy prior to the time point being summarized. A 
hypothetical strategy will be implemented in which outcomes for subjects without an 
intercurrent event are as observed at the given time point, and outcomes for subjects with an 
intercurrent event are treated as though they had completed the randomized study treatment 
through the time point being summarized. A multiple imputation strategy will be used to 
impute data following an intercurrent event. 
… 
 
Change #31 
Section 15.7, Handling of dropouts or missing data, paragraphs 1 and 2, bullet #1 and 
paragraph 4 
The analysis for the primary and secondary efficacy variables will include the use of MI. In MI, 
the missing value is replaced by a set of plausible values, where each value is a Bayesian draw 
from the conditional distribution of the missing data given the observed data. Intermittent 
missing data will be imputed using the MCMC method, followed by regression for monotone 
missing data. The multiple imputation procedures planned for the primary and secondary 
efficacy analyses are based on an assumption of data missing at random (MAR).  
The sensitivity of results to the approach for handling missing data will be evaluated via 
supportive analyses using different missing data mechanisms. The following supportive analyses 
for the primary efficacy variable and for those secondary efficacy variables that are part of the 
hierarchical testing will be conducted: 
1.  Deviations from the MAR pattern will be evaluated using a reference-based MI approach. 
Intermittent missing data will be imputed using the MCMC method. The remaining monotone 
missing data will be assumed to follow a missing not at random (MNAR) pattern. These data 
will be imputed using a reference-based approach in which the MI model is based on data 
from the placebo group, thereby assuming that monotone missing data follow a trajectory 
similar to the placebo group (Mallinckrodt, 2013). The estimand in this procedure is the 
difference in outcome improvement in all randomized subjects at the planned endpoint of the 
study attributable to the initially randomized medication (Mallinckrodt et al, 2012).  
… 
The same procedure described as in the primary efficacy analyses will be used. 
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… 
Has been changed to: 
The primary analysis for the primary and secondary efficacy variables will use a conservative 
approach to handling missing data that is similar to non-responder imputation. The 
sensitivity of results to the approach for handling missing data will be evaluated via 
supportive analyses using different missing data mechanisms. 
In instances where include the use of MI. In MI is used, the missing value is replaced by a set 
of plausible values, where each value is a Bayesian draw from the conditional distribution of the 
missing data given the observed data. Intermittent missing data will be imputed using the 
MCMC method, followed by regression for monotone missing data. The planned multiple 
imputation procedures planned for the primary and secondary efficacy analyses are based on an 
assumption of data missing at random (MAR).  
The sensitivity of results to the approach for handling missing data will be evaluated via 
supportive analyses using different missing data mechanisms. The following supportive analyses 
for the primary efficacy variable and for those secondary efficacy variables that are part of the 
hierarchical testing will be conducted: 
1.  Deviations from the MAR pattern will be evaluated using a reference-based MI approach. 
Intermittent missing data will be imputed using the MCMC method. The remaining monotone 
missing data will be assumed to follow a missing not at random (MNAR) pattern. These data 
will be imputed using a reference-based approach in which the MI model is based on data 
from the placebo group, thereby assuming that monotone missing data follow a trajectory 
similar to the placebo group (Mallinckrodt, 2013). The estimand in this procedure is the 
difference in outcome improvement in all randomized subjects at the planned endpoint of the 
study attributable to the initially randomized medication (Mallinckrodt et al, 2012). Multiple 
imputation as described above will be performed using the modified composite estimand 
as specified for the use with the secondary variables. The definition of an intercurrent 
event is changed from all treatment discontinuation, to discontinuation of treatment due 
to AE or lack of efficacy. 
… 
The same procedure described as in the primary efficacy analyses will be used. For the 
secondary and other efficacy variables, the binary endpoints will be analyzed using 
modified NRI, MI and OC, and the continuous endpoints will be analyzed using MI and 
OC. 
… 
 
Change #32 
Section 15.8.1, Interim analyses, paragraph 1 
Two interim analyses will be performed: one after all randomized subjects have completed the 
Double-Blind Treatment Period and the Week 24 assessments, and one after all subjects have 
completed Week 52. 
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Has been changed to: 
Two interim analyses will be performed: one after all the planned number of randomized 
subjects have completed the Double-Blind Treatment Period and the Week 24 assessments, and 
one after all the planned number of subjects have completed Week 52.  
In addition, the following text has been added: 
Additional interim analyses and data cuts may be performed for regulatory purposes. 
 
Change #33 
Section 15.8.2 Data monitoring and Adjudication Committees  
The following text has been added: 
Other adjudication committees may be added as necessary. 
 
Change #34 
Section 15.9.2, Power calculations for secondary endpoints in the hierarchical testing 
… 
For change from Baseline in BASDAI at Week 16, an adjusted between-treatment difference 
of - 1.38 with an SD=1.8 for bimekizumab and SD=1.4 for placebo was used. With those 
assumptions, the endpoint is powered with >99% at the planned sample size. 
… 
For change from Baseline in nocturnal spinal pain at Week 16, the AS data from the 
certolizumab pegol study AS001 were used. An adjusted between-treatment difference of -1.88 
with an SD=2.9 for bimekizumab and SD=2.4 for placebo was used. With those assumptions, the 
endpoint is powered with >99% at the planned sample size. 
For change from Baseline in ASQoL at Week 16, an adjusted between-treatment difference 
of - 2.39 with an SD=4.5 for bimekizumab and placebo was used. With those assumptions, the 
endpoint is powered with >99% at the planned sample size. 
For change from Baseline in SF-36 at Week 16, an adjusted between-treatment difference of 4.56 
with an SD=8.1 for bimekizumab and SD=5.8 for placebo was used. With those assumptions, the 
endpoint is powered with >99% at the planned sample size. 
… 
Has been changed to: 
… 
For change from Baseline in BASDAI total score at Week 16, an adjusted between-treatment 
difference of - 1.38 with an SD=1.8 for bimekizumab and SD=1.4 for placebo was used. With 
those assumptions, the endpoint is powered with >99% at the planned sample size. 
… 
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For change from Baseline in nocturnal spinal pain score at Week 16, the AS data from the 
certolizumab pegol study AS001 were used. An adjusted between-treatment difference of -1.88 
with an SD=2.9 for bimekizumab and SD=2.4 for placebo was used. With those assumptions, the 
endpoint is powered with >99% at the planned sample size. 
For change from Baseline in ASQoL total score at Week 16, an adjusted between-treatment 
difference of - 2.39 with an SD=4.5 for bimekizumab and placebo was used. With those 
assumptions, the endpoint is powered with >99% at the planned sample size. 
For change from Baseline in SF-36 PCS score at Week 16, an adjusted between-treatment 
difference of 4.56 with an SD=8.1 for bimekizumab and SD=5.8 for placebo was used. With 
those assumptions, the endpoint is powered with >99% at the planned sample size. 
… 
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20 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements. 
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol. 
I have received and read all study-related information provided to me. 
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB. 
All rights of publication of the results reside with UCB, unless other agreements were made in a 
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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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Version:
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Document Number:
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Title:
AS0011 Protocol Amendment 4 - Phase 3 - Placebo-controlled - Double-blind
Approved Date:
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15 NOV 2021 
Statistical Analysis Plan 
Bimekizumab  
AS0011 
 
 
 
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Page 1 of 140 
STATISTICAL ANALYSIS PLAN  
Study: AS0011  
Product: Bimekizumab 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY EVALUATING THE 
EFFICACY AND SAFETY OF BIMEKIZUMAB IN THE 
TREATMENT OF STUDY PARTICIPANTS WITH ACTIVE ANKYLOSING SPONDYLITIS 
SAP/Amendment Number Date 
Final SAP 
05 Jun 2019 
SAP Amendment 1 
05 Aug 2021 
SAP Amendment 2 
15 Nov 2021 
 
 
Confidentiality Statement 
Confidential 
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reproduced, published, or otherwise used without the express permission of UCB. 
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Bimekizumab  
AS0011 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 9 
1 
INTRODUCTION ........................................................................................................... 14 
2 
PROTOCOL SUMMARY ............................................................................................... 14 
2.1 
Study objectives ........................................................................................................... 14 
2.1.1 
Primary objective ................................................................................................. 14 
2.1.2 
Secondary objectives ........................................................................................... 14 
2.1.3 
Other objectives ................................................................................................... 14 
2.2 
Study variables ............................................................................................................. 15 
2.2.1 
Efficacy variables ................................................................................................ 15 
2.2.1.1 
Primary efficacy variable .......................................................................... 15 
2.2.1.2 
Secondary efficacy variables ..................................................................... 15 
2.2.1.3 
Other efficacy variables ............................................................................. 15 
2.2.2 
Pharmacokinetic variable ..................................................................................... 17 
2.2.3 
Pharmacogenomic variables ................................................................................ 17 
2.2.4 
Immunological variables ..................................................................................... 17 
2.2.5 
Safety variables .................................................................................................... 17 
2.2.5.1 
Secondary safety variables ........................................................................ 17 
2.2.5.2 
Other safety variables ................................................................................ 18 
2.3 
Study design and conduct ............................................................................................ 18 
2.4 
Determination of sample size ....................................................................................... 20 
2.4.1 
Power calculation for primary endpoint .............................................................. 20 
2.4.2 
Power calculations for secondary endpoints in the hierarchical testing .............. 21 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 22 
3.1 
General presentation of summaries and analyses ........................................................ 22 
3.2 
General study level definitions .................................................................................... 25 
3.2.1 
Analysis time points ............................................................................................ 25 
3.2.1.1 
Relative day ............................................................................................... 25 
3.2.1.2 
End date of the Treatment Period .............................................................. 26 
3.2.2 
Study periods ....................................................................................................... 26 
3.2.2.1 
Study periods for safety and efficacy data ................................................ 26 
3.2.2.2 
Coronavirus Disease 2019 (COVID-19) pandemic periods ...................... 28 
3.2.3 
Mapping of assessments performed at Early Termination Visit ......................... 28 
3.3 
Definition of Baseline values ....................................................................................... 28 
3.4 
Treatment Discontinuation Date and Intercurrent Event Date .................................... 30 
3.5 
Protocol deviations....................................................................................................... 30 
3.6 
Analysis sets................................................................................................................. 31 
3.6.1 
Enrolled Set ......................................................................................................... 31 
3.6.2 
Randomized Set ................................................................................................... 31 
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3.6.3 
Safety Set ............................................................................................................. 31 
3.6.4 
Maintenance Set ................................................................................................... 31 
3.6.5 
Full Analysis Set .................................................................................................. 31 
3.6.6 
Per Protocol Set ................................................................................................... 31 
3.6.7 
Pharmacokinetic Per-Protocol Set ....................................................................... 32 
3.6.8 
Immunogenicity Safety Set .................................................................................. 32 
3.6.9 
COVID-19 Free Set ............................................................................................. 32 
3.7 
Treatment assignment and treatment groups ............................................................... 32 
3.8 
Center pooling strategy ................................................................................................ 33 
3.9 
Coding dictionaries ...................................................................................................... 33 
3.10 
Changes to protocol-defined analyses ......................................................................... 34 
3.11 
Changes related to COVID-19 ..................................................................................... 34 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 34 
4.1 
Adjustments for covariates .......................................................................................... 34 
4.2 
Handling of dropouts or missing data .......................................................................... 35 
4.2.1 
Handling of Missing data for efficacy analyses................................................... 35 
4.2.1.1 
Handling of Missing data for the Primary Endpoint ................................. 36 
4.2.1.2 
Handling of Missing Data for Secondary and Other Efficacy Endpoints . 38 
4.2.1.3 
Composite Estimand - Non-Responder Imputation (NRI) analysis .......... 39 
4.2.1.4 
Modified Composite Estimand - Multiple Imputation (MI) ..................... 39 
4.2.1.5 
Calculation of adjusted responder rates, odds ratio and CIs for binary 
endpoints. .................................................................................................. 42 
4.2.1.6 
Reference-Based Multiple Imputation (MI) .............................................. 43 
4.2.1.7 
Hypothetical Estimand - Multiple Imputation (MI) .................................. 45 
4.2.1.8 
Tipping Point analysis ............................................................................... 46 
4.2.1.9 
Treatment Policy Strategy ......................................................................... 48 
4.2.1.10 
Observed Cases analysis ........................................................................... 48 
4.2.1.11 
Last Observation Carried Forward ............................................................ 48 
4.2.1.12 
Allowed ranges for continuous efficacy variables .................................... 48 
4.2.2 
Handling of missing data for AE ......................................................................... 49 
4.2.3 
Handling of missing data for prior and concomitant medications ....................... 51 
4.3 
Interim analysis and data monitoring ........................................................................... 51 
4.3.1 
Interim analyses ................................................................................................... 51 
4.3.2 
Data Monitoring Committee ................................................................................ 55 
4.4 
Multicenter studies ....................................................................................................... 55 
4.5 
Multiple comparisons/multiplicity ............................................................................... 55 
4.6 
Use of an efficacy subset of study participants ............................................................ 56 
4.7 
Active-control studies intended to show equivalence .................................................. 56 
4.8 
Examination of subgroups ........................................................................................... 56 
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AS0011 
 
 
 
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5 
STUDY POPULATION CHARACTERISTICS ............................................................. 58 
5.1 
Study participant disposition........................................................................................ 58 
5.2 
Impact of COVID-19 ................................................................................................... 59 
5.3 
Protocol deviations....................................................................................................... 60 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 60 
6.1 
Demographics .............................................................................................................. 60 
6.2 
Baseline characteristics ................................................................................................ 61 
6.2.1 
Baseline efficacy variables .................................................................................. 61 
6.2.2 
Other baseline characteristics .............................................................................. 62 
6.3 
Medical history and concomitant diseases ................................................................... 63 
6.4 
Prior and concomitant medications .............................................................................. 64 
6.5 
Rescue medication ....................................................................................................... 64 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 65 
8 
EFFICACY ANALYSES ................................................................................................ 65 
8.1 
Statistical analysis of the primary efficacy variable .................................................... 65 
8.1.1 
Derivation of ASAS40 response .......................................................................... 65 
8.1.1.1 
Derivation of the patient’s global assessment of disease activity (PGADA)66 
8.1.1.2 
Derivation of the pain assessment domain ................................................ 66 
8.1.1.3 
Derivation of the physical function domain of the Bath Ankylosing 
Spondylitis Functional Index (BASFI) ...................................................... 66 
8.1.1.4 
Derivation of the inflammation domain (mean of questions 5 and 6 of the 
BASDAI) ................................................................................................... 66 
8.1.2 
Primary analysis of the primary efficacy variable ............................................... 67 
8.1.3 
Secondary analyses of the primary efficacy variable .......................................... 68 
8.1.4 
Supportive analyses of the primary efficacy variable .......................................... 68 
8.1.4.1 
Analysis on the PPS .................................................................................. 68 
8.1.4.2 
Analysis on the FAS .................................................................................. 68 
8.1.4.3 
Analysis on individual components of ASAS40 ....................................... 69 
8.1.4.4 
Analysis using modified composite estimand - MI ................................... 70 
8.1.4.5 
Analysis using treatment policy strategy imputation for missing data...... 70 
8.1.4.6 
Analysis on observed cases ....................................................................... 71 
8.1.4.7 
Tipping point analysis ............................................................................... 71 
8.1.4.8 
Analyses including COVID-19 impact ..................................................... 72 
8.2 
Statistical analysis of the secondary efficacy variables ............................................... 72 
8.2.1 
Derivation of secondary efficacy variables ......................................................... 72 
8.2.1.1 
Other assessment in Axial SpondyloArthritis international Society 
response criteria (ASAS20, ASAS5/6, and ASAS-PR) ............................ 72 
8.2.1.2 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ............ 72 
8.2.1.3 
Ankylosing Spondylitis Disease Activity Score major improvement 
(ASDAS-MI) ............................................................................................. 73 
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8.2.1.4 
Nocturnal spinal pain (NSP) ...................................................................... 74 
8.2.1.5 
Ankylosing Spondylitis Quality of Life (ASQoL) .................................... 74 
8.2.1.6 
Short-Form 36-item Health Survey (SF-36) Physical Component 
Summary (PCS) ......................................................................................... 74 
8.2.1.7 
Bath Ankylosing Spondylitis Disease Metrology Index (BASMI) ........... 75 
8.2.1.8 
Maastricht Ankylosing Spondylitis Enthesitis (MASES) index ............... 76 
8.2.2 
Analysis of secondary efficacy variables............................................................. 77 
8.2.3 
Additional statistical analysis of selected secondary efficacy variables.............. 78 
8.3 
Analysis of other efficacy variables ............................................................................. 79 
8.3.1 
Derivation of other efficacy endpoints ................................................................ 79 
8.3.1.1 
Time to ASAS20/40 response ................................................................... 79 
8.3.1.2 
ASDAS status ............................................................................................ 79 
8.3.1.3 
BASDAI50 response ................................................................................. 79 
8.3.1.4 
Physician’s Global Assessment of Disease Activity (PhGADA) ............. 79 
8.3.1.5 
High-sensitivity C-Reactive Protein (hs-CRP) .......................................... 80 
8.3.1.6 
European Qol-5Dimensions 3-Level (EQ-5D-3L) .................................... 80 
8.3.1.7 
Short Form-36 (SF-36) Mental Component Summary (MCS) and the 8 
domains scores (Physical Functioning, Role Physical, Bodily Pain, 
General Health, Vitality, Social Functioning, Role Emotional, and Mental 
Health) ....................................................................................................... 80 
8.3.1.8 
Medical Outcomes Study (MOS) sleep scale ............................................ 80 
8.3.1.9 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
subscale ..................................................................................................... 81 
8.3.1.10 
Work Productivity and Activity Impairment Questionnaire–Specific 
Health Problem (WPAI-SHP) ................................................................... 82 
8.3.1.11 
Tender joint count (TJC) and swollen joint count (SJC) ........................... 83 
8.3.1.12 
Ankylosing Spondylitis spine MRI-activity (ASspiMRI-a) (Berlin 
modification) score .................................................................................... 85 
8.3.1.13 
Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac 
joint (SIJ) MRI score ................................................................................. 86 
8.3.2 
Analyses of other efficacy endpoints ................................................................... 86 
8.3.3 
Additional statistical analysis of selected other efficacy variables...................... 89 
9 
PHARMACOKINETICS AND IMMUNOGENICITY .................................................. 90 
9.1 
Pharmacokinetics ......................................................................................................... 90 
9.1.1 
Definition of ADAb Sample Status (positive, negative, missing) ....................... 90 
9.1.2 
Definition of Cumulative ADAb Status .............................................................. 90 
9.1.3 
PK Sample Inclusion and Exclusion Rules ......................................................... 90 
9.1.4 
Summary of Analyses .......................................................................................... 92 
9.2 
Immunology (Immunogenicity) ................................................................................... 92 
9.2.1 
Anti-bimekizumab antibody ................................................................................ 92 
9.2.1.1 
Definition of ADAb Sample Status (Positive, Negative, Missing) ........... 93 
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9.2.1.2 
Definition of Overall ADAb Status (Positive, Negative, Missing) ........... 93 
9.2.1.3 
Definition of ADAb Categories................................................................. 93 
9.2.1.4 
ADAb status groups for Efficacy Endpoint Summaries ........................... 94 
9.2.1.5 
ADAb Sample Inclusion and Exclusion Rules .......................................... 95 
9.2.2 
Summary of Analyses .......................................................................................... 95 
9.2.2.1 
Immunogenicity Summaries ...................................................................... 95 
9.2.2.2 
Efficacy Endpoint by ADAb Summaries .................................................. 96 
9.2.3 
Neutralizing anti-bimekizumab antibodies .......................................................... 98 
10 SAFETY ANALYSES ..................................................................................................... 99 
10.1 
Extent of exposure ....................................................................................................... 99 
10.1.1 
Duration of exposure and time at risk in the Double-Blind Treatment Period 
(DBTP) .............................................................................................................. 100 
10.1.2 
Duration of exposure and time at risk in the Maintenance Period .................... 101 
10.1.3 
Duration of exposure and time at risk in the combined Double-Blind Treatment 
and Maintenance Periods ................................................................................... 102 
10.1.4 
Duration of exposure by COVID-19 pandemic period ...................................... 103 
10.1.5 
Time at risk in subject-years by COVID-19 pandemic period .......................... 104 
10.1.5.1 
Time at risk in the pre-COVID-19 pandemic period .............................. 104 
10.1.5.2 
Time at risk in the COVID-19 pandemic period ..................................... 104 
10.1.5.3 
Time at risk in the post-COVID-19 pandemic period ............................. 105 
10.2 
Adverse events ........................................................................................................... 106 
10.2.1 
Standard AE summaries .................................................................................... 108 
10.2.2 
Other safety topics of interest summaries .......................................................... 109 
10.2.3 
Extra-Articular Manifestations .......................................................................... 114 
10.2.4 
Impact of COVID-19 ......................................................................................... 114 
10.3 
Clinical laboratory evaluations .................................................................................. 115 
10.4 
Vital signs, physical findings, and other observations related to safety .................... 120 
10.4.1 
Vital signs, weight and physical findings .......................................................... 120 
10.4.2 
Electrocardiograms ............................................................................................ 121 
10.4.3 
Other safety variables ........................................................................................ 121 
11 REFERENCES .............................................................................................................. 125 
12 APPENDICES ............................................................................................................... 126 
APPENDIX 1. 
MEDDRA ALGORITHMIC APPROACH TO ANAPHYLAXIS ......... 127 
APPENDIX 2. 
UCB-DEFINED SEARCH CRITERIA FOR IDENTIFYING 
OPPORTUNISTIC INFECTIONS ................................................................................ 130 
13 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) .................... 131 
13.1 
AMENDMENT 1....................................................................................................... 131 
13.1.1 
Efficacy variables (Section 2.2.1) ...................................................................... 132 
13.1.2 
Immunological variables (Section 2.2.4) ........................................................... 132 
13.1.3 
Safety variables (Section 2.2.5) ......................................................................... 132 
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13.1.4 
General presentation of summaries and analyses (Section 3.1)......................... 132 
13.1.5 
Study periods (Section 3.2.2) ............................................................................. 132 
13.1.6 
Definition of baseline variables (Section 3.3) ................................................... 132 
13.1.7 
Treatment Discontinuation Date and Intercurrent event date (Section 3.4) ...... 133 
13.1.8 
Protocol deviations (Section 3.5, Section 5.3) ................................................... 133 
13.1.9 
Analysis sets (Section 3.6) ................................................................................. 133 
13.1.10 
Treatment assignment and treatment groups (Section 3.7)................................ 133 
13.1.11 
Changes to protocol-defined analyses (Section 3.10) ........................................ 133 
13.1.12 
Changes related to COVID-19 (Section 3.11, Section 5.2) ............................... 133 
13.1.13 
Handling of missing data for efficacy analyses (Section 4.2.1) ........................ 134 
13.1.14 
Handling of missing data for AE (Section 4.2.2) .............................................. 134 
13.1.15 
Handling of missing data for prior and concomitant medications (Section 4.2.3)134 
13.1.16 
Examination of subgroups (Section 4.8) ........................................................... 134 
13.1.17 
Study participant disposition (Section 5.1) ........................................................ 134 
13.1.18 
Demographics (Section 6.1) .............................................................................. 135 
13.1.19 
Baseline characteristics (Section 6.2) ................................................................ 135 
13.1.20 
Medical history and concomitant diseases (Section 6.3) ................................... 135 
13.1.21 
Statistical analysis of the primary efficacy variables (Section 8.1) ................... 135 
13.1.22 
Statistical analysis of the secondary efficacy variables (Section 8.2) ............... 136 
13.1.23 
Analysis of other efficacy variables (Section 8.3) ............................................. 136 
13.1.24 
Pharmacokinetics (Section 9.1) ......................................................................... 137 
13.1.25 
Immunology (Section 9.2) ................................................................................. 137 
13.1.26 
Extent of exposure (Section 10.1) ..................................................................... 137 
13.1.27 
Adverse events (Section 10.2) ........................................................................... 137 
13.1.28 
Clinical laboratory evaluations (Section 10.3) .................................................. 137 
13.1.29 
Other safety variables (Section 10.4.3) .............................................................. 138 
13.2 
AMENDMENT 2....................................................................................................... 138 
13.2.1 
Summary of Analyses (Section 9.1.4) ............................................................... 138 
13.2.2 
Definition of ADAb categories (Section 9.2.1.3) .............................................. 138 
13.2.3 
Handling of missing data for efficacy analyses (Section 4.2.1) ........................ 138 
13.2.4 
Clinical laboratory evaluations (Section 10.3) .................................................. 138 
13.2.5 
Other safety variables (Section 10.4.3) .............................................................. 138 
13.2.6 
Baseline characteristics (Section 6.2) ................................................................ 138 
13.2.7 
Examination of subgroups (Section 4.8) ........................................................... 138 
13.2.8 
Definition of baseline variables (Section 3.3) ................................................... 139 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ................................................... 140 
 
 
 
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LIST OF TABLES 
Table 3‒1: 
Region definitions ............................................................................................ 33 
Table 4‒1: 
Missing data handling methods for efficacy endpoints ................................... 35 
Table 4‒2: 
Allowable ranges for continuous efficacy variables ........................................ 49 
Table 4‒3: 
Summary of efficacy and safety analyses for each interim analysis ............... 53 
Table 4‒4: 
Categories of variable for efficacy subgroup analyses .................................... 57 
Table 8‒1: 
BASMI linear definition .................................................................................. 75 
Table 8‒2: 
BASMI linear definition (pre-defined ranges) ................................................. 75 
Table 8‒3: 
MOS sleep subscales........................................................................................ 81 
Table 8‒4: 
Swelling and tenderness grading ..................................................................... 84 
Table 10‒1: 
Laboratory measurements .............................................................................. 115 
Table 10‒2: 
Definitions of markedly abnormal biochemistry values ................................ 118 
Table 10‒3: 
Definitions of markedly abnormal hematology values .................................. 118 
Table 10‒4: 
Definitions of markedly abnormal liver function values ............................... 119 
Table 10‒5: 
Definitions of markedly abnormal blood pressure values ............................. 120 
 
 
LIST OF FIGURES 
Figure 2‒1: 
Study design ..................................................................................................... 20 
Figure 4‒1: 
Sequential testing procedure of primary and key secondary efficacy 
endpoints .......................................................................................................... 56 
 
 
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LIST OF ABBREVIATIONS 
ADAb 
Anti - drug antibody 
ADaM 
Analysis Dataset Model 
AE 
Adverse event  
ANCOVA 
Analysis of covariance  
AS 
Ankylosing spondylitis 
ASAS 
Assessment of SpondyloArthritis International Society 
ASAS20,40,5/6 
Assessment of SpondyloArthritis International Society 20%, 40%, 5 out 
of 6 response criteria 
ASAS-PR 
ASAS partial remission 
ASDAS-CRP 
Ankylosing Spondylitis Disease Activity Score C-reactive protein  
ASDAS-MI 
Ankylosing Spondylitis Disease Activity Score major improvement 
ASQoL 
Ankylosing Spondylitis Quality of Life 
ASspiMRI-a 
Ankylosing Spondylitis spine MRI-activity 
ATC 
Anatomical Therapeutic Chemical Classification  
axSpA 
Axial spondyloarthritis 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index 
BASDAI50 
Bath Ankylosing Spondylitis Disease Activity Index 50% 
improvement 
BASFI 
Bath Ankylosing Spondylitis Functional Index 
BASMI 
Bath Ankylosing Spondylitis Disease Metrology Index  
BLQ 
Below the limit of quantification  
BKZ 
bimekizumab 
BMI 
Body mass index 
BP 
Blood pressure 
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BSA 
Body surface area 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CFS 
COVID-19 Free Set 
CRF 
Case report form 
CRP 
C-reactive protein 
CV 
Coefficient of Variation 
DBTP 
Double-blind Treatment Period 
DILI 
Drug-induced liver injury 
DMARD 
Disease-modifying antirheumatic drug 
DMC 
Data Monitoring Committee 
EAER 
Exposure adjusted event rate 
EAIR 
Exposure adjusted incidence rate 
ECG 
Electrocardiogram 
eC-SSRS 
electronic Columbia-Suicide Severity Rating Scale 
ES 
Enrolled Set 
EQ-5D-3L 
EuroQol-5D-3-Level  
ET 
Early termination 
FACIT 
Functional Assessment of Chronic Illness Therapy  
FAS 
Full analysis set 
HLA-B27 
Human leukocyte antigen B27 
HLT 
High level term 
HRQoL 
Health-related quality of life 
hs-CRP 
High-Sensitivity C-Reactive Protein  
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IBD 
Inflammatory Bowel Disease  
IMP 
Investigational Medicinal Product 
IPD 
Important protocol deviation 
IWRS 
Interactive Web Response System 
LLOQ 
Lower limit of quantification 
LOCF 
Last observation carried forward 
LSM 
Least Square Means 
MACE 
Major adverse cardiac events 
MAR 
Missing at random 
MASES 
Maastricht Ankylosing Spondylitis Enthesitis  
MCMC 
Markov-Chain Monte Carlo 
MCS 
Mental Component Summary 
MDA 
Minimal Disease Activity 
MedDRA 
Medical Dictionary for Regulatory Activities  
MI 
Multiple Imputation 
MOS 
Medical outcome Study 
MRI 
Magnetic resonance imaging 
MS 
Maintenance Set 
NAb 
Neutralizing anti-drug antibody 
NI 
Negative immunodepletion 
NRI 
Non-responder imputation 
NRS 
Numeric Rating Scale 
NS 
Negative screen 
NSP 
Nocturnal spinal pain 
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OC 
Observed cases 
OLE 
Open label extension 
OR 
Odds ratio 
PCS 
Physical Component Summary  
PGADA  
Patient’s Global Assessment of Disease Activity 
PhGADA 
Physician’s Global Assessment of Disease Activity 
PHQ-9 
Patient Health Questionnaire-9  
PI 
Positive immunodepletion 
PK-PPS 
Pharmacokinetics Per-Protocol Set 
PPS 
Per-Protocol Set 
PS 
Positive screen 
PSO 
Psoriasis 
PT 
Preferred term 
Q4W 
Every 4 weeks 
RD 
Risk difference 
RS 
Randomized set 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
sc 
Subcutaneously  
SD 
Standard deviation 
SIB 
Suicidal Ideation and Behavior 
SJC 
Swollen joint count 
SF-36 
Short-Form 36-item Health Survey  
SMQ 
Standardized MedDRA Query 
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SOC 
System Organ Class 
SPARCC 
Spondyloarthritis Research Consortium of Canada 
SS 
Safety Set 
TEAE 
Treatment emergent adverse event 
TEMA 
Treatment-emergent markedly abnormal 
TFLs 
Tables, Listings and Figures 
TJC 
Tender joint count 
TNFα 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
VAS 
Visual Analog Scale 
WHO-DD 
World Health Organization Drug Dictionary 
WPAI-SHP 
Work Productivity and Activity Impairment Questionnaire - Specific 
Health Problem  
 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) provides the necessary information to perform the final 
statistical analysis as well as the interim analyses for study AS0011. It also defines the summary 
tables, listings and figures (TFLs) to be generated for the interim and final clinical study report.  
The SAP is based on the Protocol Amendment 4 (16 FEB 2021). 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 Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH)/Food and Drug 
Administration (FDA) E9 Guidance documents (ICH E9, 1998). 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective is to demonstrate the efficacy of bimekizumab administered 
subcutaneously (sc) every 4 weeks (Q4W) compared with placebo in the treatment of study 
participants with active ankylosing spondylitis (AS). 
2.1.2 
Secondary objectives 
The secondary objectives are as follows: 
• To assess the efficacy of bimekizumab compared with placebo 
• To assess the safety and tolerability of bimekizumab 
• To assess the impact of bimekizumab on patient-reported quality of life 
• To assess the impact of bimekizumab on spinal mobility  
• To assess the impact of bimekizumab on enthesitis and peripheral arthritis 
2.1.3 
Other objectives 
Other objectives are as follows: 
• To assess the immunogenicity of bimekizumab 
• To assess the pharmacokinetics of bimekizumab 
• To assess the maintenance of efficacy of bimekizumab 
• To assess the relationship between exploratory biomarkers, drug treatment, and AS disease 
biology 
• To assess the impact of bimekizumab on work productivity 
• To assess the effect of bimekizumab on inflammatory changes using magnetic resonance 
imaging (MRI) 
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2.2 
Study variables 
2.2.1 
Efficacy variables 
2.2.1.1 
Primary efficacy variable 
The primary efficacy variable is the ASAS40 (Assessment of SpondyloArthritis International 
Society 40%) response at Week 16. 
2.2.1.2 
Secondary efficacy variables 
The secondary efficacy variables are as follows: 
• ASAS40 response at Week 16 in the Tumor Necrosis Factor alpha (TNFα) inhibitor-naïve 
study participants 
• ASAS20 response at Week 16 
• Change from Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
total score at Week 16 
• ASAS partial remission (ASAS-PR) at Week 16 
• Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI) at Week 
16 
• ASAS5/6 response at Week 16 
• Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 16 
• Change from Baseline in nocturnal spinal pain (NSP) score (based on Numeric Rating Scale) 
at Week 16 
• Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) total score at 
Week 16 
• Change from Baseline in the Short-Form 36-item Health Survey (SF-36) Physical 
Component Summary (PCS) score at Week 16 
• Change from Baseline in Bath Ankylosing Spondylitis Disease Metrology Index (BASMI) at 
Week 16 
• Change from Baseline in the Maastricht Ankylosing Spondylitis Enthesitis (MASES) index 
at Week 16 in the subgroup of study participants with enthesitis at Baseline  
• Enthesitis-free state based on the MASES index at Week 16 in the subgroup of study 
participants with enthesitis at Baseline  
2.2.1.3 
Other efficacy variables 
The following other efficacy variables will be assessed. These variables will be assessed at the 
time points defined in Table 5-2 of the protocol. All time points not specified in Section 2.2.1.1 
or Section 2.2.1.2 of the SAP are considered exploratory. 
• ASAS40 response  
• Time to ASAS40 response  
• ASAS20 response  
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• Time to ASAS20 response  
• ASAS5/6 response  
• ASAS-PR  
• Change from Baseline in Ankylosing Spondylitis Disease Activity Score C-reactive protein 
(ASDAS-CRP)  
• ASDAS status (eg, inactive disease [ID], low disease [LD], high disease [HD], and very high 
disease [vHD])  
• ASDAS-MI  
• Change from Baseline in BASDAI total score 
• BASDAI50 response  
• Change from Baseline in the average score of Questions 5 and 6 of the BASDAI concerning 
morning stiffness  
• Change from Baseline in BASFI  
• Change from baseline in the MASES index in the subgroup of study participants with 
enthesitis at Baseline  
• Enthesitis-free state based on the MASES index in the subgroup of study participants with 
enthesitis at Baseline  
• Change from Baseline in BASMI  
• Change from Baseline in Physician’s Global Assessment of Disease Activity (PhGADA)  
• Change from Baseline in Patient’s Global Assessment of Disease Activity (PGADA)  
• Change from Baseline in total spinal pain score (based on Numeric Rating Scale) 
• Change from Baseline in nocturnal spinal pain score (based on Numeric Rating Scale) 
• Change from Baseline in high sensitivity C-reactive protein (hs-CRP)  
• Responses to the European Quality of Life-5 Dimensions 3-Level (EQ-5D-3L) version  
• Change from Baseline in EQ-5D-3L Visual Analog Scale (VAS) scores  
• Change from Baseline in the EQ-5D-3L utility score  
• Change from Baseline in the SF-36 PCS score 
• Change from Baseline in the SF-36 Mental Component Summary (MCS) score 
• Change from Baseline in Sleep Disturbance and Sleep Problems Index II score (Medical 
Outcomes Study [MOS 12-item] scale)  
• Change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) -
Fatigue subscale score 
• Change from Baseline in ASQoL total score 
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• Change from Baseline in Work Productivity and Activity Impairment Questionnaire–Specific 
Health Problem (WPAI-SHP)  
• Change from Baseline in (44/44) tender joint count (TJC) and swollen joint count (SJC)  
• Change from Baseline in Ankylosing Spondylitis spine MRI-activity (ASspiMRI-a) in the 
Berlin modification score (Note that this endpoint will be analyzed for study participants in 
the MRI substudy only) 
• Change from Baseline in sacroiliac joint Spondyloarthritis Research Consortium of Canada 
(SPARCC) score (Note that this endpoint will be analyzed for study participants in the MRI 
substudy only) 
2.2.2 
Pharmacokinetic variable 
The pharmacokinetic (PK) variable is the plasma concentration of bimekizumab. Study 
participants are asked to provide blood samples for these measurements at Baseline, Week 2, 4, 
8, 12, 16, 20, 24, 36, 52, ET (Early Termination) and SFU visits.  
2.2.3 
Pharmacogenomic variables 
Where local regulations permit, additional blood samples will be collected at specific time points 
from study participants consenting to participate in a pharmacogenomic sub-study.  
The pharmacogenomic variables are the blood or blood derivative (eg, serum) concentrations of 
cytokines and chemokines of relevance to IL-17A/F signaling pathway and axSpA biology and 
will be assessed at Baseline, at Week 16 and at Week 52.  
Stool samples will also be collected at Baseline and Week 52. These samples may be used to 
assess biomarkers of gut inflammation including but not limited to calprotectin and microbiome 
testing. 
These variables will be described in a separate statistical analysis plan. The nature and format of 
these sub-study analyses will be determined at a later date. 
2.2.4 
Immunological variables 
Immunological variables allow evaluation of immunogenicity. The immunological variables are:  
• The anti-bimekizumab antibody status, 
• The treatment-emergent antibody positivity derived from anti-drug antibody (ADAb) assays. 
• The neutralizing anti-drug antibody (NAb) status. 
The anti-drug antibody status will be assessed at Baseline, Week 4, 8, 12, 16, 20, 24, 36, 52, ET 
and SFU, and the treatment-emergent antibody positivity at the same post-Baseline timepoints. 
Note that the NAb analysis results are not planned to be part of the CSR for the Week 24 interim 
analysis.  
2.2.5 
Safety variables 
2.2.5.1 
Secondary safety variables 
Secondary safety variables to be assessed are as follows: 
• Incidence of treatment-emergent adverse events (TEAEs) 
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• Incidence of treatment-emergent serious adverse events (SAEs) 
• TEAEs leading to withdrawal from Investigational Medicinal Product (IMP) 
2.2.5.2 
Other safety variables 
Other safety variables to be assessed are: 
• Change from Baseline in vital signs (blood pressure [BP], temperature, and pulse rate) 
• Standard 12-lead electrocardiogram (ECG) results 
• Change from Baseline in clinical laboratory values (hematology, biochemistry and 
urinalysis) 
• Change from Baseline in Patient Health Questionnaire-9 (PHQ-9)  
Physical examination findings considered clinically significant changes since the physical 
examination at the Screening Visit will be recorded as AEs 
2.3 
Study design and conduct 
AS0011 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study. To be 
eligible to participate in this study, study participants must meet the following key inclusion 
criteria: 
• Adult study participants with a diagnosis of active AS, determined by documented radiologic 
evidence (x-ray) fulfilling the Modified New York criteria for AS (1984), including at least 3 
months of symptoms,  
• Age at symptom onset < 45 years old,  
• Study participant must have moderate-to-severe active disease as defined by BOTH of the 
following at screening AND at Baseline: 
− BASDAI ≥4 AND Spinal pain ≥4 on a 0 to 10 Numeric Rating Scale (NRS) (from 
BASDAI Item 2) 
Study participants treatment assignment will be stratified by prior TNFα inhibitor exposure 
(yes/no) and region (4 categories). 
Detailed study entrance criteria are described in the protocol. 
The study consists of the following periods: 
• a Screening Period (≥14 days to ≤35 days),  
• a 52-Weeks Treatment Period, consisting of: 
− a 16-Week Double-Blind Treatment Period, and 
− a 36-Week Maintenance Period 
• and a Safety Follow-Up (SFU) Period, 20 weeks after the final dose of IMP (for study 
participants who complete the study and do not enter the open-label extension (OLE) study 
or for study participants who discontinue early, including those withdrawn from IMP).  
The maximum study duration per study participant will be up to 73 weeks. The end of the study 
is defined as the date of the last visit of the last study participant in the study.  
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At the end of the Baseline visit, eligible study participants will be randomized in a 2:1 ratio 
(stratified by region [Asia, Eastern Europe, North America, Western Europe] and prior TNFα 
inhibitor exposure [yes, no]) to receive one of the two following blinded treatment groups:  
• Bimekizumab 160mg sc Q4W,  
• Placebo 
Study treatment will be administered by unblinded study personnel at the study site.  
Approximately 300 study participants are planned to be randomized (200 study participants in 
bimekizumab treatment group, and 100 study participants in placebo group). Study participants 
will remain on their allowable background medication through the study conduct.  
The Double-Blind Treatment Period ends after Week 16 assessments. At Week 16, study 
participants will transition from the double-blind, placebo-controlled treatment into the 36-week 
Maintenance Period. Study participants receiving placebo during the Double-Blind Treatment 
Period will be re-allocated to bimekizumab treatment at Week 16 after all study assessments 
have been completed.  
From Week 20 onwards, all study participants will be eligible for nonbiologic rescue therapy.  
Prior to the completion of the Maintenance Period, Investigators should discuss treatment 
options with the study participant. Study participants who are not withdrawn from IMP and who 
meet the eligibility criteria will be given the opportunity to enter an extension study to continue 
to receive bimekizumab.  
Study participants discontinuing IMP during the Double-Blind Treatment Period or during the 
Maintenance Period will be encouraged to return for all scheduled visits through Week 52 and 
the SFU Visit, as applicable. 
A schematic representation of the study design is presented in Figure 2‒1.  
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Figure 2‒1: Study design 
 
Refer to the study clinical protocol for more detailed information on the study assessments and 
schedule of procedures. 
2.4 
Determination of sample size 
Approximately 300 study participants will be randomly assigned in a 2:1 ratio to the following 
treatment groups: bimekizumab 160 mg sc (200 study participants) or placebo sc Q4W (100 
study participants). The primary efficacy analysis is based on the bimekizumab dose versus 
placebo for ASAS40 response at Week 16. All sample size and power calculations were done at 
a significance level of 0.05 in a two-sided test.  
All sample size and power calculations were performed using the software nQuery Advisor® 7.0. 
2.4.1 
Power calculation for primary endpoint 
The sample size assumptions for bimekizumab versus placebo are based on the ASAS40 
response data from the Phase 2b bimekizumab study in study participants with active AS 
(AS0008).  
An ASAS40 response at Week 16 of 40% can be assumed for the bimekizumab treatment group. 
This assumed treatment response is based on the bimekizumab 160mg dose results of AS0008 at 
Week 12 (46.7%). It was also assumed that the treatment response at Week 12 and Week 16 
would be the same (ie, conservative assumption). In addition, the observed ASAS40 response 
rates were adjusted to account for a higher number of study participants with prior TNFα 
inhibitor exposure and for a higher number of study participants with early withdrawal. Placebo 
ASAS40 response at Week 16 was assumed to be 15% and is more conservative than that of 
AS0008 at Week 12 (ie, ASAS40 response=13.3%). 
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The sample size for showing statistical superiority of bimekizumab versus placebo was 
calculated using a 2-sided 2-sample Chi square test with continuity correction (Fleiss et al, 
1980). With 200 study participants in the bimekizumab treatment group and 100 study 
participants in the placebo group, the test for detecting statistical superiority of bimekizumab 
versus placebo based on ASAS40 response at Week 16 is powered with >99%. 
2.4.2 
Power calculations for secondary endpoints in the hierarchical 
testing 
The assumptions for power calculations of the secondary endpoints are based on the Week 12 
results of AS0008, unless indicated otherwise. It was assumed that the treatment response at 
Week 12 and Week 16 would be the same (ie, conservative assumption). In addition, the 
observed data were adjusted in the same way as the primary endpoint to account for a higher 
number of study participants with prior TNFα inhibitor exposure and for a higher number of 
study participants with early withdrawal. 
All power calculations for binary endpoints were performed using a 2-sided 2-sample Chi-square 
test with continuity correction (Fleiss et al, 1980). All power calculations for continuous 
endpoints were performed using a 2-sided 2-group Satterthwaite t-test (Moser et al, 1989) The 
power calculations provided below represent independent evaluations for each endpoint and do 
not account for multiplicity. 
For ASAS40 response of the TNFα inhibitor-naïve population at Week 16, an ASAS40 response 
of 48% for the bimekizumab group was assumed. Placebo ASAS40 response at Week 16 is 18%. 
It is also assumed that 70% of the study participants in each treatment group are TNFα inhibitor-
naïve. With those assumptions, the endpoint is powered with >99% at the planned sample size 
(ie, 140 and 70 study participants in the bimekizumab and placebo group, respectively).  
For ASAS20 response at Week 16, an ASAS20 response of 70% for the bimekizumab group was 
assumed. Placebo ASAS20 response at Week 16 is 30%. With those assumptions, the endpoint is 
powered with 99% at the planned sample size. 
For change from Baseline in BASDAI at Week 16, an adjusted between-treatment difference of - 
1.38 with an SD=1.8 for bimekizumab and SD=1.4 for placebo was used. With those 
assumptions, the endpoint is powered with >99% at the planned sample size. 
For ASAS-PR at Week 16, an ASAS-PR of 17% for the bimekizumab group was assumed. 
Placebo ASAS-PR at Week 16 was assumed to be 3.3%. With those assumptions, the endpoint is 
powered with 94% at the planned sample size. 
For ASDAS-MI at Week 16, the ASDAS-MI data of AS0008 at Week 12 and Week 16 were 
used and the placebo response was extrapolated to Week 16. The assumed ASDAS-MI are 
36.0% and 13.8% at Week 16 for the bimekizumab and placebo group, respectively. With those 
assumptions, the endpoint is powered with 98% at the planned sample size. 
For ASAS5/6 response at Week 16, an ASAS5/6 response of 44% for the bimekizumab group 
was assumed. Placebo ASAS-PR at Week 16 was assumed to be 5%. With those assumptions, 
the endpoint is powered with >99% at the planned sample size. 
For change from Baseline in BASFI at Week 16, an adjusted between-treatment difference of - 
2.35 with an SD=1.9 for bimekizumab and placebo was used. With those assumptions, the 
endpoint is powered with >99% at the planned sample size. 
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For change from Baseline in nocturnal spinal pain at Week 16, the AS data from the 
certolizumab pegol study AS001 were used. An adjusted between-treatment difference of -1.88 
with an SD=2.9 for bimekizumab and SD=2.4 for placebo was used. With those assumptions, the 
endpoint is powered with >99% at the planned sample size. 
For change from Baseline in ASQoL score at Week 16, an adjusted between-treatment difference 
of -2.39 with an SD=4.5 for bimekizumab and placebo was used. With those assumptions, the 
endpoint is powered with >99% at the planned sample size. 
For change from Baseline in PCS score of the SF-36 at Week 16, an adjusted between-treatment 
difference of 4.56 with an SD=8.1 for bimekizumab and SD=5.8 for placebo was used. With 
those assumptions, the endpoint is powered with >99% at the planned sample size. 
For change from Baseline in BASMI at Week 16, an adjusted between treatment difference 
of -0.55 with an SD=0.8 for bimekizumab and SD=0.7 for placebo was used. With those 
assumptions, the endpoint is powered with >99% at the planned sample size. 
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. The following should be noted in 
this regard: 
• UCB uses SAS in a 64-bit Windows environment, and it is well-documented that in this 
environment the maximum accuracy of any numeric value is 15 significant digits.  
• However, SAS by default does not limit the accuracy of numeric values to 15 significant 
digits which, in certain instances, may result in inaccurate representation of the data and 
cause errors when used in subsequent calculations, particularly when comparing a value to a 
chosen threshold. This, in turn, could potentially result in a change in classification of a study 
participant from a responder to a non-responder (and vice versa) if these values occur near a 
threshold used in the evaluation of response (or a critical laboratory value for example). 
Therefore, in order to avoid issues caused by inaccurate floating point representation of numeric 
values, the Analysis Dataset Model (ADaM) variables AVAL (absolute value), CHG (change) or 
PCHG (percentage change) are rounded to 12 decimal places prior to the comparison to the 
threshold. This is applied exclusively during the derivation of new response parameters 
(subsequently retained in the dataset) or critical value variables and does not imply inherent 
rounding on AVAL, CHG or PCHG variables which are retained unrounded in the final ADaM 
dataset. 
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 data can generally be accounted for using one of the following approaches:  
• 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 
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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 (%)”. 
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 will be presented when the percentage is 100%.  
Unless stated otherwise, continuous endpoints will be expressed as a change from Baseline 
which will be calculated as the value at a specific timepoint minus the value at Baseline.  
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).  
For hs-CRP variable, the summary statistics should contain arithmetic mean, geometric mean, 
geometric coefficient of variation (CV), median, first and third quartile (Q1 and Q3), minimum 
and maximum. The geometric CV (%) will be calculated using the following formula: 
𝐶𝑉= √𝑒𝑆𝐷𝑙𝑛
2 −1 
where 𝑆𝐷𝑙𝑛 represents the standard deviation of the ln-transformed hs-CRP values. 
For bimekizumab PK concentrations, geometric mean, geometric CV, 95% confidence intervals 
for geometric mean (assuming log-normally distributed data) will calculated if at least ⅔ of the 
values of interest are above the LLOQ and N>=3. If this is not the case, only median, minimum 
and maximum will be presented.  
Decimal places for descriptive statistics will always apply the following rules: 
• “n” will be an integer. 
• Mean, SD, SE, and median will use 1 additional decimal place compared to the original raw 
value from the Case Report From (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 of efficacy variables 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. 
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The SAS® outputs supportive of any inferential statistics that are part of the hierarchical testing 
procedure (ie, all inferential statistics associated with the endpoints in figure 4.1) 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. 
Unless specified differently in the SAP, the order of treatment groups to be presented in tables 
from left to right will be: 
• Placebo 
• Bimekizumab 160mg Q4W 
Selected tables may include columns for: 
• all study participants, regardless of study treatment 
• all study participants on bimekizumab, regardless of whether they shifted from placebo after 
the Double-Blind Treatment Period or not 
• study participants randomized on placebo who shifted to bimekizumab after the Double-
Blind Treatment Period  
The abbreviation for bimekizumab is BKZ and will be used in tables and listings headers. In the 
TFLs study participants on bimekizumab 160mg will be displayed as “BKZ 160mg Q4W”.  
All study participants dosed with bimekizumab will be summarized in some TFLs in a treatment 
column labeled as “BKZ 160mg Q4W Total”. 
For all TFLs not dedicated to the Double-Blind treatment period only, the Placebo-randomized 
study participants who shifted to bimekizumab after the Double-Blind Treatment Period will be 
summarized in a treatment column labeled as “Placebo / BKZ 160mg Q4W”. 
Per protocol, 
• visit windows of ±3 days are permissible for all visits through Week 16 (included). The visit 
window is relative to the Baseline Visit. 
• visit windows of ±4 days are permissible for all visits after Week 16, 
• for the SFU Visit, the visit should occur no more than 3 days prior to the scheduled visit date 
and within 7 days after the scheduled visit date.  
Only data collected at the scheduled visit will be included in the analysis. The only deviations 
may concern PK data, unscheduled vendor data collected with a few days of delay, and MRI data 
(see below).  
All by-visit summaries will contain nominal (ie, scheduled) visits only. Unscheduled visits will 
not be mapped to scheduled visits except for some assessments that may occur within 3-day time 
window of a scheduled visit. In that case, the assessment will be mapped to the corresponding 
scheduled visit and will be used for the analysis. Where scheduled visit data is available no 
mapping will be done, but if scheduled visit data is not available while unscheduled visit data 
within the 3-day time window is available, the unscheduled visit data collected on a day nearest 
to the scheduled visit day will be mapped and used in the analysis. This will only occur for PK 
data (see Section 9.1) some vendor data (see Section 10.4.3) and MRI data (see 
Section 8.3.1.12).  
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Assessments collected at unscheduled visits will only be listed, except in the case of determining 
Baseline, treatment-emergent markedly abnormal (TEMA) criteria for laboratory and vital sign 
parameters. For analyses on TEMA laboratory and vital sign, all post-Baseline (scheduled and 
unscheduled) values will be summarized in table outputs.  
For by-visit tables summarizing efficacy data, the SFU visit will not be included. By-visit tables 
summarizing safety data should however include the SFU visit. 
A complete set of data listings containing all documented data and all derived data (eg, change 
from Baseline) will be generated. 
Unless otherwise stated, listings will be sorted by treatment, study participant number within 
each treatment group (not randomization number), variable (if applicable) and visit (if 
applicable; including timing relative to dosing if applicable). For listings including 
nonrandomized study participants, the nonrandomized study participants will be shown first in 
the listing, ordered by study participant number. All listings will include repeat and unscheduled 
measurements; such measurements will appear in chronological order together with the 
scheduled visits, ie, 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’. 
3.2 
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 follows. The way 
that relative day is calculated depends on when the given event occurs relative to the date of 
first IMP administration. If the event start (stop) date occurred on or after the first dose of 
study drug administration, but prior to the study drug stop date, relative day is calculated as 
start (stop) date of the event minus first dose date of study drug dose + 1.  
Relative day 1 is the date of first study drug administration. 
• If the event start (stop) date occurred after the last dose of study drug administration, the 
relative day to the most recent study drug dose is calculated as start (stop) date of the event 
minus most recent study drug dose date. The relative day in this situation should be preceded 
by a ‘+’ 
• If the event start (stop) date occurred before the first dose of study drug administration, the 
relative day is calculated as start (stop) date of the event minus first dose date of study drug 
dose. 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. 
For AEs, relative days for start and stop dates will be calculated as the number of days since the 
first IMP administration. 
For events occurring after Week 16 in study participants who have switched from placebo to 
bimekizumab, an additional relative day will be calculated using the same rules as above but 
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based on the date of first injection of bimekizumab. This additional relative day will be provided 
in listings for concomitant medications and safety data. 
For non-treatment emergent AEs, relative day of onset will be negative if the event started and 
stopped before the first dose. A complete date must be established in order to correctly identify 
the AEs. Section 4.2.2 describes imputation rules in case of missing data for AEs. 
3.2.1.2 
End date of the Treatment Period 
The end of the Treatment Period will be either the date of Week 52 visit (Visit 17) for study 
participants completing the Treatment Period, or the date of the early termination (ET) visit for 
study participants who discontinued early during the Treatment Period.  
Note that study participants who previously discontinued IMP and are continuing for all 
scheduled visits through Week 52 will also be considered as having completed the Treatment 
Period. 
If a study participant does not have a Week 52/ET visit, then either the date of the last scheduled 
or unscheduled visit during the Treatment Period or the date of last known dose of study drug 
during the Treatment Period, whichever is later, will define the end date of the Treatment Period. 
3.2.2 
Study periods 
3.2.2.1 
Study periods for safety and efficacy data  
Based on the specific requirements of safety analyses and efficacy analyses, two concepts of the 
definition of periods need to be considered for the study, which will be defined in detail in the 
sections below. 
3.2.2.1.1 
Study periods for safety data 
The following study periods are defined for the classification of safety data by study period: 
• Pre-treatment Period (Screening Period): Starts at the time of the informed consent date and 
ends prior to the day and time of the first dose administration of study drug.  
• 16-Week Double-Blind Treatment Period (DBTP): Starts on the day of the first IMP 
administration and ends prior to the day of first IMP administration in the maintenance 
period (first IMP in the MP typically occurs at Week 16, but for those that miss the Week 16 
IMP, first IMP in the MP will be the first IMP administration after Week 16). For study 
participants that withdraw from the study prior to start of IMP in the maintenance period, the 
DBTP ends on the day of the ET Visit.  
See Section 3.7 (Treatment assignment and treatment groups) for allocation of AEs that 
occur on the day of IMP administration. 
For vital sign parameters, the DBTP will start at the day and time of first IMP administration 
and ends prior to the day and the time of first IMP administration in the MP as there are 3 
assessments collected at Baseline and Week 16 (one pre-dose, one 30 minutes post-dose and 
one 1-hour post-dose). 
• 36-Week Maintenance Treatment Period (MP): Starts on the day of IMP administration at the 
Week 16 visit and ends 28 days (one dosing interval) after the day of last IMP administration 
before the Week 52 visit. For participants that do not receive IMP at the Week 16 visit, the 
MP starts on the day of first IMP administration after Week 16. For study participants that 
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withdraw from the study after Week 16 but before Week 52, the MP ends on the day of the 
ET Visit. In the event that no ET visit is performed, the MP ends 28 days after the last IMP 
administration.  
For vital sign parameters, the day and the time will be used to define the MP for the same 
reason that given above.  
• Safety Follow-Up Period: The SFU period will be defined for all study participants who 
complete the final IMP administration of the study at Week 48 and do not enter the OLE 
study, or for study participants who discontinue early including those withdrawn from IMP.  
− For study participants who complete the final IMP administration of the study at Week 48 
and do not enter the OLE study, the SFU period starts 29 days after the day of last IMP 
administration before the Week 52 visit and ends on the day of the SFU Visit or on the 
last contact date, whichever happens later.  
− For study participants who discontinue early, the SFU period starts the day after the ET 
Visit and ends on the day of the SFU Visit or on the last contact date, whichever happens 
later. In the event that no ET visit is performed, the SFU period starts 29 days after the 
day of last IMP administration. 
Per study protocol, if the Week 52 Visit or ET visit is done ≥ 20 weeks after the final dose of 
IMP, the SFU Visit is not required. In that case, the last contact date (Week 52, ET or earlier 
if applicable) will be used as end of the SFU period.  
Note that an IMP administration is said to be “final” when it refers to the very last IMP taken 
by the study participant in the study. Otherwise, the IMP administration is said to be “last” 
for a specific study period. 
Safety analyses will be summarized for the DBTP, MP, and Overall Periods. Summaries for 
the MP will also include the SFU period for study participants that do not enter the OLE or 
discontinue early in the MP.  The SFU period for study participants that discontinue in the 
DBTP will only be summarized in the Overall Period tables. 
3.2.2.1.2 
Study periods for efficacy data 
The following study periods are defined for the classification of efficacy data by study period: 
• Screening Period: Starts at the time of the informed consent date and ends prior to the day 
and time of the first IMP administration.  
• 16-Week Double-Blind Treatment Period: Starts on the day of the first IMP administration 
and ends the day of the Week 16 Visit or on the day of the ET Visit for study participants 
withdrawn from the study before Week 16 visit. If Week 16 Visit is missing or skipped, the 
DBTP will end on the day of the last visit before Week 16. 
Efficacy assessments from the Week 16 Visit belong to the DBTP as they are conducted 
prior to the Week 16 IMP administration.  
• 36-Week Maintenance Treatment Period: Starts on the day after the Week 16 Visit and ends 
the day of Week 52 Visit. If the Week 16 Visit is missing, the MP will start the day after the 
date of the last visit before Week 16. For study participants withdrawn from the study after 
Week 16 but before Week 52, the MP will end at the ET Visit.  
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A study participant will be considered to have completed a study period if they complete the last 
planned study visit for that period. 
It is possible for a study participant to discontinue the study after completing the Week 16 
efficacy assessments, (and therefore after completing the DBTP), but prior to entering the MP 
the next day. Therefore, all study participants who discontinue at or after Week 16 and never 
start the MP will be counted as having discontinued in the overall period only. 
3.2.2.2 
Coronavirus Disease 2019 (COVID-19) pandemic periods 
The following COVID-19 pandemic periods will be defined: 
• Prior COVID-19 pandemic period: Period prior to COVID-19 pandemic start date, which is 
defined as 11-Mar-2020 by the World Health organization (WHO), not including the 
pandemic start date. 
• COVID-19 pandemic period: Period from 11-Mar-2020 through the COVID-19 pandemic 
end date (which is currently not defined), including the dates of pandemic start and end. 
• Post COVID-19 pandemic period: Period after the WHO declaration of the end of the 
pandemic, beginning on the day after the pandemic end date. The end of the pandemic had 
not yet been declared at the time of SAP finalization. As a result, this period will only be 
included in analyses if the WHO declares an end to the pandemic prior to the end of the 
study. 
These periods will be used to classify the timing of the following relative to COVID-19 
pandemic: 
• study participant enrolment in the study,  
• study participant Week 16 Visit, 
• AE onset date. 
3.2.3 
Mapping of assessments performed at Early Termination Visit 
If the early termination visit occurs at a scheduled visit as outlined in the schedule of 
assessments, then no mapping is necessary, and any early withdrawal assessments should 
correspond to that scheduled visit. Premature study termination visit assessments that occur on a 
date after a scheduled visit will be assigned to the next scheduled site visit per the protocol 
following the last visit where assessments were available. The only exception to the above rule is 
for anti-bimekizumab antibody assessments, in which all early withdrawal visit assessments will 
be assigned to the next scheduled visit at which anti-bimekizumab antibodies are assessed. 
3.3 
Definition of Baseline values 
A Baseline value for a study participant is defined as the latest measurement for that study 
participant up to and including the day of administration of first study medication (ie, generally 
Visit 2). When no treatment information is available, the randomization date will be used as 
reference in place of the first day of study drug administration. If a Baseline assessment is taken 
on the same day as first administration of study medication, 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 first study medication administration. This is considered acceptable as this 
measurement is still the best representation of the Baseline value of the given assessment since it 
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is highly unlikely that the study medication could have an impact on any measurement in such a 
short period of time. However, such cases should be rare as study center personnel are instructed 
to do all assessments at the Baseline visit prior to administering study medication. One exception 
to this rule is plasma concentration. If Baseline plasma concentration is measured at a time after 
the first administration of study medication, then it should not be eligible to be considered as a 
Baseline plasma concentration. Such cases should be discussed with the quantitative clinical 
pharmacologist.  
For HLA-B27 only, the Baseline value may be based on a value recorded after the first study 
medication administration because the study medication is not expected to have any impact on 
the HLA-B27 measurement.  
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 
receiving study medication, then the Baseline value is treated as missing. Finally, re-test value 
can be considered to define a Baseline, as mentioned in Section 3.1.   
Baseline values for component scores should be computed using components from the same visit 
where the relevant measurements were recorded prior to dosing. However, if the Screening visit 
has all of the components, but the Baseline visit is missing one or more components, the Baseline 
value for the component score will be calculated using the Screening visit values. 
When the time of first dose is derived, it should be based on the first injection of study treatment, 
regardless of whether or not it is an active treatment. 
For study participants randomized to placebo that switched to bimekizumab at the Week 16 visit 
the laboratory data (only for the shift table analyses, the analyses on TEMA and Hy’s Law cases) 
and the vital sign data (only for the TEMA analyses) will have an additional Baseline for the 
Maintenance Period that will correspond to the latest measurement on or prior to the first 
bimekizumab dose in that period. This Baseline will be called “Baseline Week 16”. To avoid any 
confusion in the outputs where both Baseline values will be used, the Baseline relative to the 
administration of first study medication will be called “Baseline Day 1”.  
For the MRI substudy, Baseline will also be defined as the latest measurement for that study 
participant up to and including the day of administration of first study medication. However, the 
efficacy analyses for the substudy will be performed using two sets of study participants based 
on the date of the Baseline MRI relative to first study medication administration: 1) all eligible 
substudy participants with an MRI any time prior to first study medication administration, and 2) 
eligible substudy participants with an MRI performed any time from 3 weeks prior to the first 
administration of study medication up to the day of administration of first study medication. 
Ideally, the Baseline MRI would be performed as close to the first administration of study 
medication as possible to allow accurate measurement of disease status at Baseline by SPARCC 
and ASpiMRI-a (Berlin modification) score.  However, several factors including rescreening and 
cross-screening of participants, the COVID-19 pandemic, and other unforeseen issues resulted in 
several participant MRI scans that were >3 weeks prior to the first administration of study 
medication. Because there is no generally accepted window for the definition of Baseline for 
MRI endpoints, two sets of participants were identified to include: 1) all eligible substudy 
participants, and 2) only participants with MRI’s performed close to the first study drug 
administration.  The threshold of 3 weeks prior to the first study drug administration was selected 
after consultation with imaging experts. 
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For spine x-ray, the Baseline value may be based on an x-ray performed up to 6 months prior to 
first administration of study drug. 
3.4 
Treatment Discontinuation Date and Intercurrent Event Date 
The concept of intercurrent event is one of the estimand attributes as defined in Section 8.1.2 and 
Section 8.1.3. For non-responder imputation (NRI) analyses of binary efficacy endpoints, the 
intercurrent event date will be defined as the date of treatment discontinuation due to any reason. 
For multiple imputation (MI) analyses of binary efficacy endpoints, the intercurrent event date 
will be defined as the date of treatment discontinuation due to AE (including death) or lack of 
efficacy, while for the multiple imputation analyses of continuous and categorical efficacy 
endpoints (including the reference-based and hypothetical MI analyses), the intercurrent date will 
be defined as the date of treatment discontinuation due to any reason. Since treatment 
discontinuation date is not collected, the treatment discontinuation date is defined as:  
Treatment end date + dosing interval (28 days) + visit window (3 days for DBTP, 4 days 
for the MP) 
With “Treatment end date” derived from the “Study Medication Discontinuation” CRF.    
3.5 
Protocol deviations 
Important protocol deviations (IPD) are deviations from the protocol which potentially could 
have a meaningful impact on study conduct or on the primary efficacy, key safety, or PK 
outcomes for an individual study participant. The criteria for identifying IPD will be defined 
within the appropriate protocol-specific document. IPD will be reviewed as part of the ongoing 
data cleaning process and data evaluation. IPD will be identified and documented prior to 
unblinding to confirm exclusion from Per-Protocol Set (PPS) and Pharmacokinetics Per-Protocol 
Set (PK-PPS). 
Since the PPS will be used for a supportive analysis of the primary endpoint which is assessed at 
Week 16, the exclusion from PPS is limited to the double-blind period, ie, only study participants 
with IPD or a decrease in dosing or dosing frequency of axSpA background medication due to 
intolerance/ AE/ side-effects, as permitted per study protocol, with potential impact on primary 
efficacy endpoint prior to and at Visit 8 (Week 16) can be excluded from the PPS. Study 
participants with IPD or a protocol-permitted decrease in dosing or dosing frequency of axSpA 
background medication due to intolerance/ AE/ side-effects, as permitted per study protocol, 
with potential impact on primary efficacy endpoint after Visit 8 (Week 16) will not be excluded 
from the PPS. 
Also, an IPD will not always necessitate the removal of a study participant from the PPS. 
Depending on the type of protocol deviation, the study participant may remain in the PPS. The 
protocol deviation specification document developed by the clinical study team should clearly 
state which deviations will result in a removal from the PPS. See details in Section 3.6.6. 
The impact of the COVID-19 pandemic on study procedures/conduct (eg, missed visits, remote 
visits, interruption of study treatment) will be documented using the information collected on a 
dedicated eCRF page.  
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3.6 
Analysis sets 
The primary efficacy variable will be analyzed for all study participants in the Randomized Set 
(RS), and supportive analyses of the primary efficacy variable will be performed on the Full 
Analysis Set (FAS) and the PPS. All other efficacy variables will be based on the RS  
Demographics tables will be performed on the RS as well as on the Safety Set (SS), if SS is 
different from RS. Safety variables will be summarized on the SS. PK variables will be analyzed 
for all study participants in the safety set and/or PK-PPS. 
The analysis sets are defined in the following sections.  
3.6.1 
Enrolled Set 
The Enrolled Set (ES) consists of all study participants who have given informed consent. 
3.6.2 
Randomized Set 
The Randomized Set (RS) consists of all randomized study participants.  
3.6.3 
Safety Set 
The Safety Set (SS) consists of all randomized study participants who received at least one dose 
of the IMP. 
3.6.4 
Maintenance Set 
The Maintenance Set (MS) will consist of all study participants who have received at least 1 dose 
of bimekizumab treatment in the Maintenance Treatment period.  
3.6.5 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all randomized study participants who received at least 
one dose of the IMP and have a valid measurement of all components of the primary efficacy 
variable at Baseline.  
3.6.6 
Per Protocol Set 
The Per-Protocol Set (PPS) consists of all study participants in the RS who had no important 
protocol deviations affecting the primary efficacy variable. Important protocol deviations will be 
predefined and study participants with important protocol deviations will be evaluated during 
ongoing data cleaning meetings prior to unblinding of the data. See Section 3.5 for further 
details. Exclusions from the FAS will be considered important protocol deviations that also result 
in exclusion from the PPS. Additional exclusions from the PPS due to protocol-permitted 
decrease in dosing or dosing frequency of axSpA background medication due to 
intolerance/AE/side-effects may also be possible in case a potential impact on the primary 
endpoint cannot be excluded.  
In addition, if after unblinding it is determined that there are study participants who were dosed 
with bimekizumab in place of placebo, then these study participants will be removed from PPS. 
Study participants who received a single dose with placebo in place of bimekizumab will remain 
in the PPS, but participants that received more than a single dose with placebo (or received one 
dose with placebo and also missed one or more additional doses, therefore fulfilling the IPD 
criteria of more than 1 missed dose up to week 12 during double-blind phase) when randomized 
to bimekizumab will be excluded from the PPS. 
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3.6.7 
Pharmacokinetic Per-Protocol Set 
The Pharmacokinetic Per Protocol Set (PK-PPS) consists of all randomized study participants 
who received at least one dose of the IMP and provided at least one quantifiable plasma 
concentration post-dose (after first IMP administration) without important protocol deviations 
that would affect the concentration of all samples obtained.   
3.6.8 
Immunogenicity Safety Set 
ADAb and NAb analyses will use the safety set defined above. In the event that sample 
exportation in China is not approved, thereby preventing the NAb and ADAb analyses of 
samples of Chinese participants in the specified laboratories located outside of China, a separate 
immunogenicity safety set will be defined to include all randomized study participants, 
excluding China participants, who received at least one dose of the IMP. 
3.6.9 
COVID-19 Free Set  
The COVID-19 Free Set (CFS) will consist of all study participants in the RS who had no 
COVID-19 impact on the primary efficacy endpoint up to Week 16. This will be defined as study 
participants neither having: 
• a COVID-19 related IPD, 
• nor a data entry on the COVID-19 impact eCRF, 
• nor a COVID-19 related AE (See Section 10.2.4 for definition). 
3.7 
Treatment assignment and treatment groups 
It is expected that study participants receive treatment as randomized for the Double-Blind 
Treatment Period, or as assigned per protocol study design (via reallocation) for the Maintenance 
Period.  
Hence safety analyses will be based: 
• on the SS as randomized, for the Double-Blind Treatment Period (displaying data under 
Placebo and BKZ 160mg Q4W columns), 
• on the MS as assigned treatment, for the Maintenance Period (displaying data under BKZ 
160mg Q4W Total column),  
• on the SS as randomized/assigned treatment for the overall period (displaying data under 
BKZ 160mg Q4W Total column), 
However, if after unblinding it is determined that study participants randomized to placebo 
received bimekizumab at any time during the Double-Blind-Treatment Period, then for safety 
analyses these study participants will be reallocated to the bimekizumab treatment group. Study 
participants randomized to bimekizumab will only be reallocated to the placebo treatment group 
if they never received bimekizumab. For AE analyses, AEs for each study participant will be 
summarized based on the treatment at the onset of each particular AE. AEs that occur on the day 
of first IMP administration will be allocated to the treatment received on that day. For study 
participants randomized on placebo who switch treatment per study design at Week 16 (ie, 
reallocation to bimekizumab treatment), AEs will be allocated to the treatment the study 
participant was on the day the event occurred. If the event occurs on the day of the switch, it will 
be attributed to the initial treatment (ie, Placebo), unless the AE fulfills the criteria for an 
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anaphylactic reaction in which case it will be attributed to the new treatment (ie, bimekizumab). 
Specifically, this includes events meeting any of the following criteria: 
• Events that fulfil the anaphylactic reaction criteria for acute events (refer to Appendix 1) 
• Events, that fulfil the hypersensitivity reaction criteria  
• Events with an HLT of ‘Administration site reactions NEC’ 
• Events with an HLT of ‘Injection site reaction’ 
Efficacy analyses will be performed according to randomization and not actual treatment 
received. That is, if after unblinding it is determined that study participants randomized to 
placebo received bimekizumab at any time during the Double-Blind-Treatment Period efficacy 
analyses for these study participants will not be reallocated to the bimekizumab treatment group. 
Hence efficacy analyses will be based: 
• on the RS as randomized, for the Double-Blind Treatment Period (displaying data under 
Placebo and BKZ 160mg Q4W columns), 
• on the RS as randomized/assigned treatment for the overall period (displaying data under 
Placebo/BKZ and BKZ 160mg Q4W columns). 
The description of all efficacy analyses is detailed in Section 8. 
3.8 
Center pooling strategy 
Geographic regions have been categorized as North America, Western Europe, Eastern Europe, 
and Asia. Table 3‒1 displays the geographic regions with corresponding countries.  
Table 3‒1: 
Region definitions 
Region 
Countries 
North America 
United States 
Western Europe 
Belgium, France, Germany, Netherlands, Spain, 
United Kingdom 
Eastern Europe 
Bulgaria, Czech Republic, Hungary, Poland 
Asia 
China, Japan, Turkey 
If the percentage of randomized study participants is less than 10% in a region, then regions will 
be combined to create a new geographic region stratum for efficacy modeling, so that there are 
no modeling convergence issues across efficacy variables. This new pooled geographic region 
stratum will then be used for any modeling (including MI, logistic regression and mixed model) 
including subgroup analyses. 
3.9 
Coding dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) version 19.0. Medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD) version SEP2020 or later. Medical procedures will not be coded. 
To maintain consistency across studies in the bimekizumab development program, the dictionary 
versions will be held constant to support consistency of coding in the regulatory submissions. 
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3.10 
Changes to protocol-defined analyses 
The following changes from the protocol will be considered: 
• The protocol mentions that subgroup analysis using descriptive statistics will be performed 
on the primary efficacy variable. However OR for the comparison of bimekizumab versus 
placebo and associated 95 % CI will be calculated. See Section 8.1.3 for further details.  
• Race will be analyzed as additional subgroup variable. 
• The Maintenance Set has been added as additional analysis set. 
• The primary/main analysis of continuous secondary efficacy endpoints which are part of the 
sequential testing procedure, as well as the components of the primary ASAS40 endpoint, 
will use a reference-based imputation method.  
3.11 
Changes related to COVID-19  
The impact of the COVID-19 pandemic on study procedures/conduct and on the primary 
efficacy endpoint and safety endpoints (TEAEs, serious TEAEs, and study withdrawal due to 
TEAEs) will be investigated and additional analysis outputs will be provided as appropriate. 
These additional analyses were not planned as part of the protocol as the pandemic was not 
ongoing at the time of protocol finalization. 
These additional analyses will include analyses by period of the COVID-19 pandemic 
(prior/during/post) as defined in Section 3.2.2.2. 
These additional analyses are described in the following sections: 
• Study participant disposition (Section 5.1) 
• Details of impacted visits and effects on collection and reporting of efficacy data 
(Section 5.3) 
• Protocol deviations (Section 5.3) 
• Exposure (Section 10.1.4 and Section 10.1.5) 
• Adverse events (Section 10.2) 
In addition, the primary analysis for the primary efficacy endpoint will be repeated by timing of 
the Week 16 Visit relative to the start and end of the COVID-19 pandemic (see Section 8.1.4.8). 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
The primary efficacy analysis that will investigate the treatment effect will be adjusted for: 
• Prior TNFα inhibitor exposure (yes, no), and  
• Region (Asia, Eastern Europe, North America, Western Europe) 
However, prior TNFα inhibitor exposure may be dropped from the model in order to achieve 
model convergence (ie, in case the likelihood maximization algorithm failed to converge). If 
convergence is still not obtained, then region may instead or also be dropped from the model. 
This will be decided at the time of the table creation and clarified in respective table footnotes. 
Finally, in the case of the continuous secondary endpoints of the testing hierarchy, if the 
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reference-based multiple imputation model still does not converge, the analysis will be replaced 
using LOCF as imputation method (see Section 4.2.1.11) 
Prior TNFα inhibitor exposure and region are the stratification factors of the randomization. In 
the event that a study participant is stratified in the incorrect stratum (ie, the stratum recorded in 
the Interactive voice or web Response System (IXRS) differs from the actual stratum the study 
participant belongs to), the actual stratum will be used for the analysis. 
The secondary analyses will be adjusted on the same categorical factors as the primary analysis. 
For continuous variables, Baseline value (of the variable of interest) will also be included as 
covariate where appropriate.  
4.2 
Handling of dropouts or missing data 
4.2.1 
Handling of Missing data for efficacy analyses 
Different approaches will be used to handle missing data and intercurrent events for all endpoints 
as summarized in Table 4‒1 below. Details of the estimand structures and statistical analyses are 
described in Section 8 and details of the imputation methods are described in the following 
sections.  
Table 4‒1: 
Missing data handling methods for efficacy endpoints 
Variable 
Priority 
Variable 
Type 
Composite 
Estimand 
(NRI) 
Modified 
Composite 
Estimand 
(MI)  
Tipping 
Point 
Treatment 
Policy 
 
Reference-
based 
(MI) 
Hypothetical 
Estimand 
(MI) 
OC 
 
LOCF 
Primary 
Binary 
P  
Sa  
Sa  
Sa 
 
 
S 
 
Secondary 
included in 
statistical 
testing 
procedure 
Binary 
P  
Sa  
 
 
 
 
S 
 
Continuous 
 
 
 
 
 
P 
S 
S 
 
Pg 
Secondary 
not 
included in 
statistical 
testing 
procedure 
Binary 
X 
X 
 
 
 
 
X 
 
Continuous 
 
 
 
 
 
X 
X 
 
Other 
Binary 
X 
X 
 
 
 
 
X 
 
Continuous 
 
 
 
 
Xe 
Xd 
Xb 
 
Categorical 
 
 
 
 
 
Xf 
Xc 
 
P=Primary method, S=Supportive method, X=Method to be used (no priority designated). 
Note: Composite estimand (NRI) refers to the approach in which data preceded by the intercurrent event of study 
treatment discontinuation for any reason are imputed as non-response, and other missing data are also imputed as 
non-response. 
Note: Modified Composite Estimand (MI) refers to the approach in which data preceded by the intercurrent event of 
study treatment discontinuation due to AE (including death) or lack of efficacy are imputed as non-response, and 
other missing data are imputed via a multiple imputation model.  
Note: Tipping Point refers to the approach in which missing data and data preceded by the intercurrent event of 
study treatment discontinuation for any reason are multiply imputed and then adjusted. 
Note: Treatment Policy refers to the approach in which intercurrent events are not considered and all missing data 
are multiply imputed, and all other data are as observed. 
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Note: Hypothetical Estimand (MI) refers to the approach where outcomes for study participants without an 
intercurrent event of study treatment discontinuation are as observed, and outcomes for study participants with 
missing data or with an intercurrent event for any reason are imputed via a multiple imputation model. 
a Imputation method is applied on continuous data, and binary variable is derived from the continuous variable based 
on imputed data set. 
b Required only for by-visit summaries of variables whose value at Week 16 is part of the hierarchical testing 
procedure. 
c For variables with multiple categories, data will be summarized as observed with an additional missing row to 
capture missing data at a given visit. 
d MI will not be performed for the change from baseline in WPAI-SHP, change from baseline in EQ-5D-3L Utility 
Scores, change from Baseline in ASspiMRI-a (Berlin modification) score, or change from baseline in SPARCC 
score where only observed case analysis will be performed. 
e Performed only for components of the primary endpoint. 
f MI analysis will only be required for ASDAS status endpoint. 
g Last Observation Carried Forward (LOCF) will only be used for the secondary continuous endpoints in the 
hierarchy if the Reference-Based Multiple Imputation analyses do not converge.  
In this section, two terms will be defined for binary endpoints:  
• Binary endpoints derived based on one continuous measurement (eg, BASDAI50 at Week 
16) will be called ‘non-composite binary endpoint’.  
• Binary endpoints derived based on several continuous measurements (eg, ASAS40 at Week 
16), will be called ‘composite binary endpoint’.  
4.2.1.1 
Handling of Missing data for the Primary Endpoint 
Because the ASAS40 composite binary primary endpoint is based on 4 different component 
scores, it is necessary to consider various data scenarios that could impact the calculation of the 
response. The rules described here are applicable in the context of the calculation of ASAS40 
response and may differ from the rules applied for calculating and summarizing the components 
individually (some values may need to be imputed for component analysis but are not required 
here to evaluate the ASAS response). It is expected that cases using the following rules will 
occur infrequently, especially cases of 0 results at Baseline, as study participants are required to 
have moderate to severe active AS at study entry. The following rules will be applied prior to 
invoking any imputation analysis at the variable level (including observed case analysis), unless 
when specified differently: 
• If a study participant has any component value that is equal to 0 at Baseline, then the 
following will be done: 
− If the post-Baseline value is equal to 0, then the absolute and percent improvement for 
that component will be treated as 0 for purposes of ASAS response calculations. 
− If the post-Baseline value is greater than 0, then the component is treated as having a 
20% worsening and a 1-unit absolute worsening from Baseline for purposes of ASAS 
response calculation. 
• If a study participant has any component value that is missing at Baseline, then the absolute 
and percent improvement for that component will be treated as 0 across all visits for purposes 
of ASAS response calculation.  
• If at least 3 of the 4 components have observed data collected, the ASAS response will be 
calculated based on observed data. If 3 observed components show improvement, it is 
assumed that the 4th domain will not worsen. 
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For the primary analysis based on NRI (see Section 8.1.2 for details), if there are fewer than 3 
components with observed data at a given post-Baseline visit, then the study participant will be 
classified as "non-responder", consistent with the pre-defined approach for handling intercurrent 
events defined in Section 8.1 For addressing missing components in supportive analyses, the 
following rules will be implemented for the primary endpoint ASAS40 only:  
• Modified Composite Estimand - Multiple Imputation 
Multiple imputation will be applied on missing data, and data that are collected after the date 
of intercurrent event (IE) as defined in Section 3.4. If there are fewer than 3 components with 
observed data (considering all observed data after the IE date as missing), each of the 
components will be imputed separately before deriving the response; the available observed 
values and the imputed values will be used to derive the response. Study participants with 
IEs, will then be considered non-responders at all time points after the IE date. Analysis 
details are presented in Section 4.2.1.4.2 and Section 8.1.4.4. 
• The tipping point approach: 
The tipping point approach implemented if the primary endpoint analysis result is statistically 
significant at alpha=0.05. The tipping point approach will first include a Worst Case 
imputation:   
− All data after the date of IE for treatment discontinuation due to any reason will be set to 
missing. 
o If at least 3 of the 4 components have observed data collected and where possible, the 
ASAS response/non-response will be calculated based on observed data.  
o If fewer than 3 components have observed data, then study participants treated with 
bimekizumab will be classed as non-responders, while study participants treated with 
placebo will be classed as responders.  
If the significant result remains, then no further analysis is necessary. 
− If the result changes as a result of the worst-case approach, then imputation with delta 
adjustments will be made to each missing component before deriving the ASAS endpoint 
to establish the ‘tipping point’ at which the result changes.  
A similar approach to that described above for the Modified Composite Estimand - Multiple 
Imputation will be implemented for the Delta Adjustment approach.  However, study 
participants with treatment discontinuation will not be automatically considered non-
responders at all timepoints after the IE date. Instead, missing data and data after the IE date 
for treatment discontinuation for any reason will be imputed and adjusted, and the imputed 
and adjusted data will be used, together with observed data, to derive the response.  These 
approaches are described in detail in Section 4.2.1.8 and Section 8.1.4.7.  
• The treatment policy strategy:  
A similar approach to that described above for the Modified Composite Estimand - Multiple 
Imputation will be implemented with the difference being that study participants with 
treatment discontinuation will not be set to missing prior to imputation and will not be 
automatically considered non-responders at all time points after the IE date. Specifically: 
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− If at least 3 of the 4 components have observed data collected and where possible, the 
ASAS response/non-response will be calculated based on observed data.  
− If there are fewer than 3 components with observed (on and off treatment) data at a given 
post-Baseline visit, then multiple imputation methods will be applied, where any 
observed data after treatment discontinuation will be as observed (ie, NOT set to missing) 
and will not automatically be switched to non-response. Missing data for each of the 
components will be imputed separately before deriving the response based on imputed 
components. Details of this approach are presented in Section 4.2.1.9 and Section 8.1.4.5. 
• The OC analysis: 
− If at least 3 of the 4 components have observed data collected and where possible, the 
ASAS response/non-response will be calculated based on observed data for study 
participants that are still on the original randomized treatment; data collected after the 
treatment discontinuation for any reason will not be included.  
− If there is partial missing data for ASAS and from the observed data is it clear that the 
study participant could not possibly be a responder, then the study participant will be 
coded as a non-responder and will be counted in the denominator of the OC analysis. For 
example, this could happen if: 
◦ 
there are 2 observed components and at least one shows worsening, or 
◦ 
there are 2 observed components and both show no response, or 
◦ 
there is only one observed component and it shows worsening. 
− In the other cases, the response will be missing and the study participant will not be 
included in the OC analysis. Details of this analysis are described in Section 4.2.1.10 and 
Section 8.1.4.6. 
4.2.1.2 
Handling of Missing Data for Secondary and Other Efficacy 
Endpoints 
Missing data and intercurrent events for secondary and other efficacy endpoints will be handled 
as summarized in Table 4‒1. Details of the imputation methods are described below and details 
of the statistical analyses and estimands are described in Section 8.2.2, Section 8.2.3, 
Section 8.3.2 and Section 8.3.3.  
For composite binary secondary or other endpoints, the MI will be implemented on each 
component variable, before deriving the binary endpoint based on the imputed components (See 
Section 4.2.1.4.2). For each component, multiple imputation will use all visits where the 
individual component is planned to be collected.  However, the binary endpoint will be derived 
(or presented in by-visit tables) only for those visits where all components are planned to be 
conducted per study protocol. In addition:  
• ASAS20, ASAS-PR, and ASAS5/6 will follow the ASAS40 rules for when Baseline is equal 
to zero or baseline is missing as described in Section 4.2.1.1.   
• For ASAS20, if at least 3 of the 4 components have observed data collected, the ASAS20 
response will be calculated based on observed data. If 3 observed components show 
improvement, it is assumed that the 4th domain will not worsen. 
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• For ASAS5/6: 
− If at least 5 of the 6 components have observed data collected, the ASAS5/6 response will 
be calculated based on observed data. If 5 observed components show improvement, it is 
assumed that the 6th domain will not worsen. 
− If there are fewer than 5 components with observed data at a given post-Baseline visit, 
then imputation methods will be applied, consistent with the pre-defined approach for 
handling intercurrent events. See Section 8.2.1.1 for further details. 
For multiple imputation of non-composite binary secondary or other endpoints, the standard 
multiple imputation (MI) methods (See Section 4.2.1.4.1) will be implemented on the raw score 
(eg, BASDAI for the BASDAI50 endpoint) before deriving the binary endpoint based on the 
imputed score.  
4.2.1.3 
Composite Estimand - Non-Responder Imputation (NRI) analysis  
This is the primary analysis for the ASAS40 primary efficacy endpoint. 
In the NRI analysis, study participants will be classified as ‘non-responders’ (ie, as if they have 
not responded to the treatment) at all time points after the date of discontinuation of study 
treatment for any reason.  
In addition, for all endpoints except the ASAS response for which the response is still calculable 
when there is only 1 component with missing data (see Section 4.2.1.1), study participants will 
also be classified as ‘non-responders’ at all timepoints they had missing data.  
4.2.1.4 
Modified Composite Estimand - Multiple Imputation (MI) 
This section describes the algorithms to be implemented for the MI – Markov-Chain Monte 
Carlo (MCMC)/Monotone Regression procedures for non-composite binary and composite 
binary endpoints.  
Unless mentioned otherwise, all study participants from the population set of interest (eg, the 
randomized set) should be included in the MI steps.  
4.2.1.4.1 
Non-composite binary endpoints (Modified Composite Estimand) 
For non-composite binary endpoints, the MI method will be applied as follows based on raw 
values: 
• Step 1: Any observation after date of discontinuation of study treatment for any reason will 
be set to missing. 
• Step 2: Create a dataset, one for each treatment group, of study participants with observed 
values and those needing estimation by multiple imputation. For the imputation step, missing 
values will include non-monotone missing values (ie, intermittent missing values between 
completed assessments) and monotone missing values (ie, where all study participant data is 
missing after a given time point).  
− Step 2a: First, the intermittent missing values in each dataset will be imputed using the 
MCMC method with multiple chains, monotone missing data imputing pattern, and non-
informative priors for all parameters. Unless specified differently, the first 200 iterations 
will not be used (the ‘burn-in’ option). A total of 100 sets of imputations will be 
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performed. The seed used for these imputations will be 2017 and all other multiple 
imputation procedures described in this SAP will use this same seed as well.   
− Step 2b: If an imputed value falls outside of the pre-defined range of values for the given 
variable, the value will be truncated to be within the predefined range of values for the 
endpoint of interest. For example, the imputed value for BASDAI will be updated to 0 or 
10 in the case of an imputed value less than 0 or greater than 10, respectively (see 
Table 4‒2).  
The resulting 100 imputed data sets will have a monotone missing data pattern and will be 
imputed using a method for monotone missingness: 
− Step 2c: For monotone missing data, monotone regression will be used to impute missing 
data. A separate regression model is estimated for each variable with missing values (ie, 
measurement at each time point). Based on the resulting model, a new regression model 
is then drawn and is used to impute the missing values for the variable. Since the data set 
has a monotone missing data pattern, the process is repeated sequentially for variables 
with missing values. The procedure will be based on the 100 imputed datasets generated 
from the MCMC procedure and will be performed by Imputation.  
− Step 2d: If an imputed value falls outside of the pre-defined range of values for the given 
variable, the value will be truncated to be within the predefined range of values for the 
endpoint of interest. 
The SAS® PROC MI procedure will be used for the imputation.  
In both cases, the imputation model will include, in the following order: prior TNFα inhibitor 
exposure, region, the value at Baseline and at each post-Baseline visit (prior to the week of 
interest).  
The visits to include in the MCMC and monotone regression steps will be the same, and will 
correspond to all data available at the time of the analysis, as specified below: 
- 
For dry-runs conducted prior to the Week 24 interim analysis, all weeks up to Week 24 
will be included, 
- 
For the Week 24 interim analysis, all weeks up to Week 24 will be included, 
- 
For the Week 52 interim analysis and final analysis, all weeks up to Week 52 will be 
included.  
The stratification factors (prior TNFα inhibitor exposure and/or region) may be dropped from the 
imputation model to facilitate model convergence if required (and this holds true for all 
imputation models). The post-Baseline values will need to be specified in chronological order in 
the imputation model so that the SAS® PROC MI imputes variables from left to right (ie, the 
Week 1 value will be first imputed using regression based on Baseline value, and then the 
Week 2 value will be imputed using regression based on Baseline and Week 1 values, etc.). 
Study participants with missing Baseline will also be included in the imputation step.  
The resulting datasets for each treatment arm will be combined into one complete dataset based 
on each of the 100 imputations (containing 100 times the number of study participants analyzed).  
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The imputation model based on the MCMC method for intermittent missing values will only 
allow multivariate normal variables. Therefore, region which has 4 levels will be re-coded as 
indicator variable: 
One indicator variable (region1) will be defined as 0 for regions other than North America and 1 
for North America. Two more indicator variables (region2 and region3) will be defined similarly 
replacing North America with Eastern Europe and Western Europe respectively. In the VAR 
statement of the imputation model, the indicator variables will be ordered as follows: region1 
region2 and region3. In the eventuality that two regions required to be pooled due to a low 
percentage of study participants randomized in one region (see Section 3.8), the indicator 
variables defined above will be revised accordingly. 
− One indicator variable will be defined for the prior TNFα inhibitor exposure stratification 
variable: will be coded as 1 for yes and 0 for No.  
To maintain consistency with the MCMC method for intermittent missing values, these 
indicator variables will also be used in the monotone regression step for monotone missing 
values and treated as continuous variables.  
• Step 3: For each of the 100 complete imputed data set obtained from Step 2, the binary 
responder variable will be derived. In practice, the value at the week of interest (eg, Week 
16) in the imputed data sets will be used to categorize the study participant as a responder or 
not. If study participants have a treatment discontinuation due to AE or lack of efficacy, then 
the endpoint will be changed to “non-response” for all visits after the IE date.  
• Step 4: 
− For secondary efficacy endpoints: For each of the datasets obtained in Step 3, the 
responder rate will be analyzed using a logistic regression model with factors of 
treatment group, region, and prior TNFα inhibitor exposure as fixed effects. The 
suitability of including region and prior TNFα inhibitor exposure at Baseline as fixed 
effects will be assessed using goodness-of-fit tests (Deviance and Pearson’s and Hosmer-
Lemeshow) and added if appropriate and allows model convergence.  
− For other efficacy binary endpoints: At each timepoint, the mean proportion of the 
responders and 95% CIs will be calculated from the imputed datasets using SAS® PROC 
MIANALYZE. 
• Step 5 (for secondary efficacy endpoints only): The results obtained from the 100 logistic 
regression analyses in step 4 (ie, the adjusted responder rates for each treatment group and 
the corresponding 95% CI, the odds ratio of the treatment comparison and corresponding 
95% CI) will be combined for overall inference using Rubin’s rules, which account for the 
uncertainty associated with the imputed values (Rubin, 1987). This will be done using SAS® 
PROC MIANALYZE. The method for determining the degrees of freedom when combining 
results will be the freedom default Rubin’s method. 
4.2.1.4.2 
Composite binary Endpoint (Modified Composite Estimand) 
For composite binary endpoints, the MCMC/monotone regression method described above in 
Steps 1 to 3 for handling intermittent and monotone missing data will be performed separately 
for each individual component variable. As mentioned above, study participants with missing 
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Baseline will also be included in the imputation step. Refer to Section 4.2.1.1 for details on the 
handling of missing and zero Baseline for ASAS endpoints. 
Then, based on the multiply imputed data sets obtained for each component, the binary response 
will be derived as follows: 
• The 100 data sets obtained for each component will be merged by imputation number and 
study participant number. 
• For each of the 100 complete imputed data sets, the binary endpoint will be derived for each 
study participant/visit based on the component values. In the case of the ASAS40 and 
ASAS20 where only one component value (among the 4) is missing at a visit, the response 
will be derived without using the imputed value of the missing component.  
• If study participants have a treatment discontinuation due to AE or lack of efficacy, then the 
response associated to the binary endpoint will be changed to “non-response” for all visits 
after the IE date. 
Procedures described for Step 4 to Step 5 will then follow.  
For the primary endpoint, the ‘burn-in’ option in PROC MI will be set to the default value (200 
in this case). The convergence of the MCMC will be assessed graphically, and the results will be 
provided in a SAS® output. 
In addition, for ASDAS-MI endpoint, the following actions should also be taken: 
• in step 2b and 2d, any imputed CRP values <0.5 * the LLOQ (0.1) will be reset to 0.05 after 
each MCMC and monotone steps to account for potentially different LLOQs across 
individuals, 
• when determining ASDAS-MI, ASDAS-CRP values <2 should be reset to 2 only after the 
monotone regression imputation step (i.e., after Step 2d) prior to calculation of the composite 
score. 
4.2.1.5 
Calculation of adjusted responder rates, odds ratio and CIs for 
binary endpoints. 
Estimates of the adjusted responder rates for each treatment group and the associated standard 
errors are obtained from the logistic regression in Step 4 on the logit scale and as such are 
assumed to follow a normal distribution. These estimates will be combined using Rubin’s rules 
and the combined estimates and associated SEs will be used to construct 95% CIs on the logit 
scale. The combined estimates and 95% CIs on the logit scale will be back-transformed using the 
inverse logit link function to obtain the adjusted responder rates (%) and associated 95% CIs. 
Some key points to consider relative to the calculation of the odds ratios and corresponding 
confidence intervals. As the estimates of the odds ratios from the logistic regression model in 
Step 4 follow a lognormal distribution, a log transformation is needed to normalize these 100 
odds ratio estimates since the procedures for combining results from multiple imputed datasets 
are based on the assumption that the statistics estimated from each imputed dataset are normally 
distributed. Therefore, the log of the odds ratio estimates from the logistic regression model are 
used when combining into a single inference (Step 5). Additionally, the standard errors (SE) for 
the odds ratios are transformed as follows: 
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𝑆𝐸= log(𝑈𝐶𝐿) −log(𝐿𝐶𝐿)
2𝑍𝛼/2
 
where UCL and LCL are the upper and lower confidence limit, respectively, for the CI of the 
odds ratio from the logistic regression model, and 𝑍𝛼/2 is the relevant critical value from the 
standard normal distribution (1.96 for a 95% CI). The estimates of the log odds ratio for 
bimekizumab relative to placebo and the corresponding upper and lower confidence limits will 
be provided. The odds ratio will be then estimated by exponentiating the estimate of the log odds 
ratio. The odds ratio and the confidence limits of the odds ratio will be estimated as follows: 
𝑂𝑅= exp(𝐿𝑜𝑔 𝑜𝑑𝑑𝑠 𝑟𝑎𝑡𝑖𝑜 𝑒𝑠𝑡𝑖𝑚𝑎𝑡𝑒 ) 
𝐿𝐶𝐿= 𝑂𝑅∗exp(−𝑆𝐸∗𝑍𝛼/2 ) 
𝑈𝐶𝐿= 𝑂𝑅∗exp(𝑆𝐸∗𝑍𝛼/2 ) 
where OR is the back-transformed estimate of the odds ratio just described, SE is the standard 
error of the log odds ratio and 𝑍𝛼/2 is the relevant critical value from the standard normal 
distribution (1.96 for a 95% CI). For mean proportion of responders or responder rates, the LCL 
will be truncated at 0. These calculations will be done such that odds ratios and corresponding 
CIs are calculated for the odds ratio of bimekizumab versus placebo. 
4.2.1.6 
Reference-Based Multiple Imputation (MI) 
Reference-based MI is an imputation model developed based on data from the placebo group 
only (Mallinckrodt, 2013).  It will be the primary method of analysis for the secondary 
continuous endpoints which are part of the testing hierarchy, and will be also used for the 
components of the primary efficacy variable. 
Reference-based multiple imputation assumes that the statistical behavior of the bimekizumab 
and placebo-treated study participants resembles that of the placebo-treated study participants in 
the study. All time points after discontinuation of the double-blind study treatment for both the 
bimekizumab and placebo groups will be considered missing. Multiple imputations will be used 
to replace missing outcomes for bimekizumab- and placebo-treated study participants who 
discontinued using multiple draws from the posterior predictive distribution estimated from the 
placebo arm, including intermittent missing data point. Missing Baseline values will however be 
imputed using data from all study participants. In the case of continuous endpoints, the procedure 
will be implemented as follows on the raw values: 
• Step 1: Data will be processed sequentially, one timepoint (visit) at a time, by repeatedly 
calling SAS® PROC MI to impute missing outcome data at visits t=1,…, Week 16 (Week 16 
being the time point of interest) using data from all study participants for imputation of 
missing baseline data and using data from the placebo-treated study participants arm only for 
imputation of missing post-baseline data. 
− Step 1a: Impute missing values at Baseline using an imputation model containing prior 
TNFα inhibitor exposure, region and the baseline visit based on all study participants. 
− Step 1b (Initialization): Set t=1 (Baseline visit).  
− Step 1c (Iteration): Set t=t+1. Create a dataset combining records from bimekizumab- 
and placebo-treated study participants with columns for covariates (prior TNFα inhibitor 
exposure and region) and outcomes at visits 1 to t. Outcomes for bimekizumab-treated 
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study participants with missing values at visit t are set to observed or previously imputed 
values at visits 1 to t-1. Bimekizumab-treated study participant with observed values at 
visit t are not included. Outcomes for placebo-treated study participants are set to 
observed at visit t or observed or previously imputed values at visits 1 to t-1. The 
outcomes should be sorted in chronological order in the model. 
− Step 1d (Imputation): Impute missing values for visit t using previous outcomes for visits 
1 to t-1, prior TNFα inhibitor exposure, and region. Note that only placebo data will be 
used to estimate the imputation model since no outcome is available for bimekizumab-
treated study participants at visit t. As a consequence, the input dataset should include all 
study participants from placebo but only study participants from the bimekizumab arm 
that have values at timepoint t missing.  
− Step 1e: Repeat steps 1a-1e for all timepoints, 100 times with different seed values (seeds 
ranging from 201 to 300) to create 100 imputed complete datasets. Study participants 
whose missing values were imputed in the last PROC MI call will be included in the 
input dataset for the next PROC MI call. Standard rounding rules will be applied to the 
imputed values. If the MI procedure yields a value outside of the pre-defined range for 
the given variable, the value will be updated to be within the predefined range of values 
for the endpoint of interest. For example, the imputed value for BASDAI will be updated 
to 0 or 10 in the case of an imputed value less than 0 or greater than 10, respectively (see 
Table 4‒2). 
• Step 2: The analysis will be done on the change from Baseline, and the model will be an 
ANCOVA model with treatment group, region, and prior TNFα inhibitor exposure as fixed 
effects and the Baseline value as covariate.  
For generation of summary statistics, the 100 imputed datasets from Step 1 will be combined, 
and simple means and standard errors will be calculated using Rubin’s rules (via SAS® 
PROC MIANALYZE). For calculation of other descriptive statistics (median, Q1, Q3, 
minimum and maximum), Rubin’s rules do not apply. Multiple imputation estimates will be 
computed by calculating arithmetic means of the estimates from the multiple repetitions of 
the imputation algorithm. Thus, for median, Q1, Q3, minimum and maximum the following 
approach will apply: 
− The data will be summarized by treatment, visit and imputation and the summary 
statistics will be computed.  
− Results will be summarized by taking the mean value of each summary statistic at each 
visit across all imputations.  
− The number of decimal places will remain the same as the original for display purposes 
(ie, if the mean was presented to 1 decimal place, the mean of the means will also be 
presented to 1 decimal place). 
• Step 3: The results obtained from the 100 ANCOVA analyses in Step 2 (i.e. the Least Square 
Means for the treatment difference and the 95% CI for the contrasts) will be combined with 
Rubin’s rules.  
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4.2.1.7 
Hypothetical Estimand - Multiple Imputation (MI) 
For secondary continuous efficacy endpoints, the methods described above in Steps 1 to 5 of 
Section 4.2.1.4.1 for the non-composite binary endpoints will apply based on the values at the 
timepoint of interest, with the following differences:  
• The intercurrent event is study treatment discontinuation due to any reason and the IE date is 
as defined in Section 3.4. 
• Step 3 is not relevant for continuous endpoints. 
• In Step 4 (Excluding hs-CRP), the 100 imputed datasets from Step 2 will be combined, and 
simple means and standard errors will be calculated using Rubin’s rules (via SAS® PROC 
MIANALYZE). For calculation of other descriptive statistics (median, minimum and 
maximum), Rubin’s rules do not apply. Multiple imputation estimates will be computed by 
calculating arithmetic means of the estimates from the multiple repetitions of the imputation 
algorithm. Thus, for median, minimum and maximum the following approach will apply: 
− The data will be summarized by treatment, visit and imputation and the summary 
statistics will be computed.  
− Results will be summarized by taking the mean value of each summary statistic at each 
visit across all imputations.  
− The number of decimal places will remain the same as the original for display purposes 
(ie, if the mean was presented to 1 decimal place, the mean of the means will also be 
presented to 1 decimal place). 
• In Step 4 for hs-CRP only: The CRP data will be presented using the geometric mean, 
median, Q1, Q3, minimum and maximum. The change from Baseline will be expressed as 
the ratio to Baseline in the by-visit summaries. The following approach will be applied: 
− Any imputed CRP values <0.5*LLOQ (0.1) will be reset to 0.05 
− The natural logarithm of the absolute values will be calculated 
− The change from Baseline (based on logged values) will be calculated 
− The change from Baseline (based on logged values) will be summarized by treatment, 
visit and imputation  
− The datasets will be combined using PROC MIANALYZE in order to get the mean for 
the absolute values and change from Baseline (based on logged data) across imputations 
− The estimates of the mean for the absolute values and changes from Baseline will be 
back-transformed to obtain the geometric mean on the original scale. This back-
transformation of the mean change from Baseline (based on logged data) gives the 
geometric mean ratio to Baseline (on the original scale).  
− For the median, Q1, Q3, minimum and maximum the procedure outlined above for the 
other endpoints will be followed (based on logged values). And the resulting summary 
statistics will finally be back-transformed to obtain the values on the original scale.  
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• In Step 4, the analysis will be done on the change from Baseline, and the model will be an 
ANCOVA model with treatment group, region, and prior TNFα inhibitor exposure as fixed 
effects and the Baseline value as covariate.  
• In Step 5, the results obtained from the 100 ANCOVA analyses in Step 4 (ie, the Least 
Square Means for the treatment difference and the 95% CI for the contrasts) will be 
combined with Rubin’s rules.  
For other continuous efficacy endpoints, the following steps will apply: 
• The same Steps 1 to Step 5 as the ones described for non-composite binary efficacy 
endpoints (but excluding Step 3) will be implemented. 
• For ASDAS-CRP endpoint only, the following should also be considered: 
− after each MCMC and monotone steps to account for potentially different LLOQs across 
individuals: any imputed CRP values <0.5 * the LLOQ (0.1) will be reset to 0.05.  
− any imputed CRP values <2 will be rest to 2 only one time after monotone regression 
imputation step and immediately prior to calculation of the component score. 
• The same Step 4 and Step 5 as those described above for secondary endpoints (but excluding 
the “Step 4 for hs-CRP only”) will be implemented.  
4.2.1.8 
Tipping Point analysis 
Tipping point analyses will also be implemented as a supportive analysis for the primary efficacy 
endpoint only. 
The objective of the tipping point analyses is to evaluate the sensitivity of results to departures 
from the missing at random assumption and to identify the point at which departures cause 
results "tip" from statistically significant to statistically insignificant. As such, these tipping point 
analyses will only be performed if the primary efficacy analysis results in a statistically 
significant treatment effect (p<0.05). 
In this sensitivity analysis, data for study participants after date of discontinuation of treatment 
for any reason (as defined in Section 3.4) will be changed to missing prior to imputation but will 
not be changed to non-response after imputation.  
As a first step, the worst-case scenario will be evaluated for the primary endpoint (ASAS40 at 
Week 16). All missing primary endpoint values for study participants randomized to BKZ 
(where missing values are due to, e.g., discontinuation of treatment or missing components of the 
primary endpoint) will be imputed as non-responders, while all missing values for placebo-
randomized study participants will be imputed as responders. While there is little justification for 
such an approach, it makes the most putative assumption possible against a bimekizumab 
treatment effect. After applying this imputation approach, a logistic regression model consistent 
with the one described for the primary analysis will be applied. If the p-value for the odds ratio 
of bimekizumab versus placebo is less than 0.05, then no further tipping point analyses are 
needed. 
If the analysis based on the worst-case scenario results in a p-value greater than 0.05, then 
additional tipping point analyses will be performed to identify the point at which results switch 
from significant to insignificant. In this analysis, a shift parameter or delta adjustment is applied 
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to missing, and subsequently imputed values (where missing values include observations after 
the date of discontinuation of treatment and any other missing values). These delta adjustments 
will be implemented on the Week 16 imputed values only for each component of ASAS40, as 
follows: 
1. Data after date of discontinuation of treatment for any reason will be set to missing. 
2. The same MCMC method described in Section 4.2.1.4.1 Step 2a and 2b will be implemented 
for non-monotone (intermittent) missing pattern values, using the same imputation model. 
This will be based on 100 sets of imputations. 
3. Based on the 100 datasets obtained in Step 2b, a monotone regression model will be applied 
(using the same imputation model as in Step 2a) as described in Section 4.2.1.4.1 Step 2. 
This will be based on 1 imputation.  
4. Delta adjustments will be made to all Week 16 imputed values only, independently in each 
treatment group as described in detail below.   
5. Delta adjusted imputed values will be truncated so that they are within the range of allowable 
values for each component. 
6. Following the delta adjustments for the individual components, the composite binary 
endpoint (ASAS40) will then be derived based on the multiply delta-adjusted imputed data 
sets obtained for each component as described in Section 4.2.1.4.1. 
Each of the 100 imputed datasets will then be analyzed using a logistic regression model with 
factors of treatment group, region, and prior TNFα inhibitor exposure as fixed effects. 
7. The results obtained from the 100 logistic regression analyses in Step 6 will be combined for 
overall inference using Rubin’s rules, and the results obtained for each shift parameter will 
be presented in a single table.  
8. Step 3 to Step 7 will be repeated so that, at each iteration, missing values are adjusted with a 
larger delta than at the previous iteration. Depending on the results obtained, shift parameters 
with more granularity (eg, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9) may also be investigated. 
The process will go on until the p-value for the odds ratio between bimekizumab and placebo 
is no longer statistically significant (ie, ≥ 0.05). The odds ratio, 95% CI, and p-values 
obtained for each value of delta will be combined in one single table.  
The delta adjustments performed here assume that study participants randomized to 
bimekizumab and who have missing data have a lower probability of response compared to study 
participants randomized to placebo with missing data. Therefore, for endpoints where high 
scores are associated with a more favorable outcome:   
• A negative shift is applied to the imputed value for study participants randomized to 
bimekizumab in order to decrease the imputed value and reduce the likelihood of response. 
• A positive shift is applied to the imputed value for study participants randomized to placebo 
in order to increase the imputed value and increase the likelihood of response. 
For endpoints for which high scores are associated with a less favorable outcome:  
• A positive shift is applied to the imputed value for study participants randomized to 
bimekizumab in order to increase the imputed value and reduce the likelihood of response. 
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• A negative shift is applied to the imputed value for study participants randomized to placebo 
in order to decrease the imputed value and increase the likelihood of response. 
To start, imputed values within each continuous component, will be adjusted by the same integer 
value in each treatment arm. Imputed values will initially be adjusted by values of 1, 2, and 3. 
After these initial analyses, additional adjustment values may be tested to better identify the 
point at which results "tip". More robust primary analysis results will require larger adjustments 
to tip the results from significant to insignificant. 
4.2.1.9 
Treatment Policy Strategy  
Another supportive analysis will be performed on the primary efficacy endpoint to address 
intercurrent events.  
The treatment policy strategy will include all available data observed at the week of interest 
(Week 16) regardless of the occurrence of intercurrent events. This means the analysis includes 
on- and off-treatment values collected after study participants prematurely discontinued study 
treatment but agreed to remain on the study and continued to attend visits and provide 
assessments at those visits. Those observed values will be analyzed according to the study 
participant’s randomized treatment. Study participants for whom efficacy data cannot be 
obtained at the week of interest, despite attempts to retain them in the study, will have their data 
imputed using MI under the assumption of MAR (ie, MI-MCMC/Monotone Regression).  
In practice, the Step 1 for the non-composite binary endpoints described in Section 4.2.1.4.1 will 
not apply, and the final ASAS40 response will not be changed to “non-responder” at the end of 
the imputation step (ie, Step 4) for study participants having an intercurrent event.  
4.2.1.10 
Observed Cases analysis 
The observed case analysis only applies where study participants are still on the original 
randomized treatment. Therefore, data collected after the date of study treatment discontinuation 
(for any reason) will not be considered in observed case summaries.  
In addition, for all endpoints except the ASAS response for which the response is still calculable 
when there is only 1 component with missing data (see Section 4.2.1.1), all other missing data 
will also be excluded.  
4.2.1.11 
Last Observation Carried Forward 
The LOCF analysis will only apply for the continuous secondary efficacy endpoints that are part 
of the testing hierarchy, if the reference-based multiple imputation analysis does not converge 
(even after having dropped the covariates).  
Post-Baseline missing data will be imputed by carrying forward the last available observation 
before the missing visit. Baseline data can be carried forward.  
If a study participant has a value that is missing at Baseline, then the study participant will not be 
included in the analysis.  
4.2.1.12 
Allowed ranges for continuous efficacy variables 
The table below indicate the possible range of values for each continuous efficacy variable: 
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Table 4‒2: 
Allowable ranges for continuous efficacy variables 
Variable 
Minimum 
Maximum 
BASDAI 
0 
10 
BASFI 
0 
10 
BASMI 
0 
10 
Lateral spinal flexion 
0.75 
25 
MASES 
0 
13 
PGADA 
0 
10 
Total NSP 
0 
10 
SF-36 MCSa 
-3.33 
80.09 
SF-36 PCS 
5.02 
79.78 
SF-36 Bodily Pain 
21.68 
62 
SF-36 General Health 
18.95 
66.5 
SF-36 Mental Health 
11.63 
63.95 
SF-36 Physical Functioning 
19.26 
57.54 
SF-36 Role Emotional 
14.39 
56.17 
SF-36 Role Physical 
21.23 
57.16 
SF-36 Social Functioning 
17.23 
57.34 
SF-36 Vitality 
22.89 
70.42 
ASQoL 
0 
18 
a SF-36 ranges are used for imputation purposes only. Any observed values outside the ranges based on norm-based 
scores will be reported as calculated in all tables and listings. 
4.2.2 
Handling of missing data for AE 
For analyses of AEs, a complete date must be established to correctly identify the AE as 
occurring during treatment or not. For purposes of imputing missing components of partially 
reported start and stop dates for AEs, the algorithms listed below will be followed. In the event 
of ambiguity or incomplete data which makes it impossible to determine whether the AE was 
treatment emergent, the AE will be considered treatment emergent. If an imputed date occurs 
after a study participant's date of death, the imputed date will be set to the date of death.  
Although the algorithms for treatment-emergence 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 
analyses of AE prevalence or AE duration. 
Start and stop dates of AEs will be displayed as reported in the study participant data listings (ie, 
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 first dose is not the same 
as the month and year of AE onset, then use the 1st of the month 
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• If only the month and year are specified and the month and year of first dose is the same as 
the month and year of AE onset, then use the date/time of first dose 
• If only the month and year are specified, and the study participant did switch treatment 
during that month and year, then use the date of first switch treatment. 
• If only the year is specified, and the year of first dose is not the same as the year of AE onset, 
and if the study participants did not switch from placebo to bimekizumab at Week 16, then 
use January 1 of the year of AE onset 
• If only the year is specified, and the year of first dose is the same as the year of AE onset, 
then use the date/time of first dose 
• If only the year is specified, and the year of first dose is the same as the year the study 
participant did switch treatment, then use the date of first switch treatment. 
• If only the year is specified, and the year of first dose is the same as the year of the AE onset 
and the same as the year the study participant did switch treatment, then use the date of first 
dose. 
• If the imputed stop date is prior to the imputed start date 
− For missing start day and start month:  
◦ 
If the year of start date is the same as the year of first dose and the imputed stop date 
is on or after the date of first dose then set the start date to the date of first dose 
◦ 
Otherwise set to the 1st January of the year of the start date 
− For missing start day only 
◦ 
If the month and year of the start date is the same as the month and year of first dose 
and the imputed stop date is on or after the date of first dose then set the start date to 
the date of first dose 
◦ 
If the month and year of the start date is the same as the month and year of first dose 
and the imputed stop date is before the date of first dose then set the start date to the 
1st of that month 
• If the AE onset date is completely unknown, then use the date of first dose 
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 AE 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 AE in summary tables: 
• If the intensity of an AE is unknown, it will be considered as severe.  
• If the relationship to study drug is missing, it will be considered as related.  
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For seriousness, no imputation rule will be applied for the interim analyses, but the worst-case 
approach will be applied for the final analysis (ie, the missing seriousness will be considered as 
serious if missing). 
4.2.3 
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 first dose is not the same 
as the month and year of the start date, and the study participant did not switch treatment 
during that month and year, then use the 1st of the month 
• If only the month and year are specified and the month and year of first dose is the same as 
the month and year of the start, then use the date of first dose 
− If this is leading to a start date after the stop date of then use the 1st of the month 
• If only the month and year are specified, and the study participant did switch treatment 
during that month and year, then use the date of first switch treatment. 
• If only the year is specified, and the year of first dose is not the same as the year of the start 
date and the study participant did not switch treatment during that year, then use January 1 of 
the year of the start date 
• If only the year is specified, and the year of first dose is the same as the year of the start date, 
then use the date of first dose 
• If the start date is completely unknown, and the stop date is unknown or not prior to the date 
of first dose, then use the date of first dose 
• If the imputed stop date is prior to the imputed start date 
− If the year of start date is the same as the year of first dose and the stop date is after the 
date of first dose then set the start date to the date of first dose 
− Otherwise set to the 1st January of the year of the start date 
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 31 of that year 
• If the stop date is completely unknown, do not impute the stop date 
4.3 
Interim analysis and data monitoring 
4.3.1 
Interim analyses 
Two interim analyses will be conducted:  
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• The first interim analysis will be conducted after the planned number of randomized study 
participants have completed the Double-Blind Treatment Period and the 24 week 
assessments or have withdrawn from IMP or the study. The purpose of this analysis is to 
prepare a regulatory submission for a Marketing Authorization Application based on this 
analysis.  
• The second interim analysis will be conducted after the planned number of study participants 
have completed Week 52 or have withdrawn from IMP or the study. The purpose of this 
second interim analysis is to perform a comprehensive evaluation of all available data for the 
study and to supplement the regulatory submission based on the Week 24 interim analysis. 
The database for the Week 24 interim analysis will include all available data collected up to the 
day the last planned study participant completed the Week 24 Visit (even if this study participant 
has withdrawn from IMP). Study participants who discontinued the study prior to Week 24 will 
be included in this first interim analysis.  
The Week 24 interim analysis will evaluate the primary, secondary and other efficacy variables, 
as well as the safety and PK/immunogenicity variable results. The disposition, demographics and 
other Baseline characteristics, protocol deviations and compliance will also be described. 
The efficacy analyses will present data until Week 24, and the safety analyses will include all 
available data collected up to the day the last planned study participant completed the Week 24 
Visit. This may include safety data beyond the Week 24 timepoint. Events on-going at the time 
of the interim analysis (eg, concomitant medications, or adverse events) will be analyzed as they 
are collected to date (ie, up to Week 24 of last participant for safety endpoints), and analyses 
based on these events will be revised at time of the second interim analysis and/or final analysis.  
For this first interim analysis, a database freeze will be performed, and the treatment codes will 
be made available to the UCB personnel. An interim CSR report will be written to include 
efficacy, safety, PK, and ADAb analyses.  NAb analyses are not planned for inclusion in the 
interim CSR report. The investigators and study participants will remain blinded to the assigned 
bimekizumab dosing regimen until the last study participant completes the study. A blinding 
maintenance plan will be written to evaluate the potential bias of the Maintenance Period and 
describe the process of interim results generation and dissemination. The plan will be finalized 
prior to the freeze of the database at the Week 24 interim analysis. 
The Week 52 interim analysis will be conducted similarly as the first interim analysis: the 
database will include all available data collected up to the day the last study participant 
completed the Week 52 Visit (even if this study participant has withdrawn from IMP). Study 
participants who discontinued the study prior to Week 52 will be included in this second interim 
analysis. The efficacy analyses will present data until Week 52, and the safety analyses will 
include all available data collected up to the day the last study participant completed the Week 
52 Visit.  
No formal alterations to the further study conduct (eg, stopping rules, sample size re-estimation, 
or changes to eligibility criteria) are planned for the two interim analyses. 
No separate SAP for the interim analyses will be provided. The TFL shells for the interim and 
final analyses will be provided in the same document.  
The type of efficacy and safety analyses to be provided for the two interim analyses is detailed in 
Table 4‒3.  
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Table 4‒3: 
Summary of efficacy and safety analyses for each interim analysis 
Variable 
Type of tables 
Analysis 
Sets (study 
period) 
Treatment groups 
Interim 
Analysis 1 
Interim 
Analysis 2 
Primary and secondary efficacy variables 
Tables on primary 
efficacy variable 
RS, FAS, 
PPS 
 
• Placebo  
• BKZ 160mg Q4W 
Yes 
Yes, rerun of 
tables provided 
for interim 
analysis 1 
Tables on secondary 
efficacy variables 
RS  
 
• Placebo  
• BKZ 160mg Q4W 
Yes 
Yes, rerun of 
tables provided 
for interim 
analysis 1 
Other efficacy variables 
Tables/graph on time 
to ASAS response 
RS  
(DB-period 
only) 
• Placebo  
• BKZ 160mg Q4W 
Yes, for all visits 
up to Week 16 
for each 
participant 
 
Yes, rerun of 
analyses 
provided for 
interim analysis 
1 
By-visit tables  
 
RS  
• Placebo  
• BKZ 160mg Q4W 
Yes, for all visits 
up to Week 24 
for each 
participant 
Yes, for all visits 
up to Week 52 
for each 
participant 
Safety Variables 
Tables of adverse 
events 
SS  
(DB-period 
only) 
• Placebo  
• BKZ 160mg Q4W 
Yes, for all visits 
up to Week 16 
for each 
participant 
 
No 
MS 
(MP only) 
• BKZ 160mg Q4W 
Total 
No 
Yes, from Week 
16 up to Week 
52 for each 
participant 
SS (Overall 
period) 
• BKZ 160mg Q4W 
Total 
Yes, for all visits 
up to date of 
Week 24 visit of 
last planned 
participant 
Yes, for all visits 
up to date of 
Week 52 visit of 
last planned 
participant 
By-visit tables on 
laboratory or VS data 
SS (Overall 
period) 
 
• Placebo / BKZ 
160mg Q4W  
• BKZ 160mg Q4W 
Yes, for all visits 
up to date of 
Week 24 visit of 
last planned 
participant  
Yes, for all visits 
up to date of 
Week 52 visit of 
last planned 
participant  
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Variable 
Type of tables 
Analysis 
Sets (study 
period) 
Treatment groups 
Interim 
Analysis 1 
Interim 
Analysis 2 
Shift table or table on 
TEMA for laboratory 
data or Hy’s Law 
cases 
SS  
(DB-period 
only) 
• Placebo  
• BKZ 160mg Q4W 
Yes, for all visits 
up to Week 16 
for each 
participant  
No 
MS a 
(MP only) 
• BKZ 160mg Q4W 
Total 
No 
Yes, from Week 
16 up to Week 
52 
SS a 
(Overall 
period) 
• BKZ 160mg Q4W 
Total 
Yes, for all visits 
up to date of 
Week 24 visit of 
last planned 
participant 
Yes, for all visits 
up to date of 
Week 52 visit of 
last planned 
participant 
Table on TEMA for 
VS data 
SS  
(DB-period 
only) 
• Placebo  
• BKZ 160mg Q4W 
Yes, for all visits 
up to Week 16 
for each 
participant  
No 
MS a 
(MP only) 
• BKZ 160mg Q4W 
Total 
No 
Yes, from Week 
16 up to Week 
52 for each 
participant 
SS a 
(Overall 
period) 
• BKZ 160mg Q4W 
Total 
Yes, for all visits 
up to date of 
Week 24 visit of 
last planned 
participant 
Yes, for all visits 
up to date of 
Week 52 visit of 
last planned 
participant 
Tables on ECG or 
tuberculosis data 
SS (Overall 
period) 
 
• Placebo / BKZ 
160mg Q4W  
• BKZ 160mg Q4W 
Yes, for all visits 
up to date of 
Week 24 visit of 
last planned 
participant 
Yes, for all visits 
up to date of 
Week 52 visit of 
last planned 
participant 
Tables on PHQ-9 
data 
SS (Overall 
period) 
 
• Placebo / BKZ 
160mg Q4W  
• BKZ 160mg Q4W 
Yes, for all visits 
up to date of 
Week 24 visit of 
last planned 
participant 
Yes, for all visits 
up to date of 
Week 52 visit of 
last planned 
participant 
Tables on eC-SSRS 
data 
SS  
(DB-period 
only) 
• Placebo  
• BKZ 160mg Q4W 
Yes, for all visits 
up to Week 16 
for each 
participant 
 
No 
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Variable 
Type of tables 
Analysis 
Sets (study 
period) 
Treatment groups 
Interim 
Analysis 1 
Interim 
Analysis 2 
MS  
(MP only) 
• BKZ 160mg Q4W 
Total 
No 
Yes, from Week 
16 up to Week 
52 for each 
participant 
SS (Overall 
period) 
• BKZ 160mg Q4W 
Total 
Yes, for all visits 
up to date of 
Week 24 visit of 
last planned 
participant 
Yes, for all visits 
up to date of 
Week 52 visit of 
last planned 
participant 
a For placebo-randomized study participants, results are determined based on the Baseline Week 16 (See 
Section 3.3). 
Study participants in the Placebo/ BKZ 160mg Q4W treatment group are taking BKZ 160 mg Q4W treatment after 
Week 16.  
The final analysis will occur once last study participant has completed the SFU Visit. The final 
analysis will consist of a rerun of all listings and all safety summary analyses created for the 
Week 52 interim analysis but will include data occurring during the SFU period that were not 
available for the Week 52 interim analysis. 
4.3.2 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be formed to monitor the ongoing 
safety of the study through period review. The general scope of DMC activities is presented in 
the protocol, and the composition and operation of the DMC will be defined in the DMC charter. 
The presentation and analysis of data for the DMC meetings will be described within a separate 
DMC SAP. 
4.4 
Multicenter studies 
The data from all centers will be pooled for the purposes of the analysis. Centers will be grouped 
in the geographic regions North America, Western Europe, Eastern Europe, and Asia. 
No exploration of treatment by center interaction will be investigated.  
4.5 
Multiple comparisons/multiplicity 
A fixed sequence testing procedure will be applied for the primary endpoint and the key 
secondary endpoints. The testing procedure will account for multiplicity and control the family-
wise type I error rate at alpha=0.05 (2-sided).  
For each test, on each binary efficacy endpoint, the null hypothesis is that the conditional odds 
ratio is equal to one (H0: ORT1T2 = 1). The alternative hypothesis is that the conditional odds ratio 
is not equal to one (HA: ORT1T2 ≠ 1). 
For each test, on each continuous efficacy endpoint, the null hypothesis is that there is no 
difference between treatment groups (H0: T1 – T2 = 0). The alternative hypothesis is that there is 
a difference between treatment groups (HA: T1 – T2 ≠0). 
T1 refers to bimekizumab and T2 to placebo.  
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According to this strategy, the statistical testing of an endpoint can be investigated only if the 
null hypothesis for the previous endpoint has been rejected (ie, if p<0.05).  
Figure 4‒1 shows the testing order for these endpoints. 
Figure 4‒1: Sequential testing procedure of primary and key secondary efficacy 
endpoints 
 
4.6 
Use of an efficacy subset of study participants 
Analysis of the primary endpoint will be performed based on the RS and repeated for all study 
participants in the PPS, and for all study participants in the FAS as supportive analyses. The FAS 
analysis will evaluate whether there are differences in the efficacy analysis between randomized 
study participants and randomized study participants with a Baseline assessment, while the PPS 
analysis will evaluate the effect of IPDs and other possible exclusions on the analysis.  
4.7 
Active-control studies intended to show equivalence 
Efficacy outcomes are based on superiority comparisons of the bimekizumab 160mg sc Q4W to 
placebo, this section is then not applicable for this study. 
4.8 
Examination of subgroups 
Subgroups analyses will be performed for the primary endpoint ASAS40 and ASDAS-MI as 
listed in Table 4‒4. In addition, ASAS40 will be analyzed based on the timing of participant 
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enrollment and timing of the Week 16 visit relative to the COVID-19 pandemic periods. The 
complete list of subgroups is listed in Table 4‒4. 
Furthermore, most of the analyses defined in this SAP will be repeated for the China total study 
population only (and respectively for the Japanese population only) in order to meet the China 
(and respectively the Japan) submission requirements. The details of the analyses to be produced 
for these submissions will be indicated in the TFL shell document. For the analysis based on MI, 
all study participants will be first included in the imputation model, and then the analysis step 
will be restricted to the subset of China (or respectively Japanese) subjects. 
Table 4‒4: 
Categories of variable for efficacy subgroup analyses 
Subgroup 
Categories 
Age (years) 
<45,  
≥45  
Gender 
Male, 
Female 
Race 1 
Black, 
White, 
Other  
Race 2 
White, 
Asian 
Other 
Region 1 a 
Asia,  
Eastern Europe,  
North America,  
Western Europe 
Disease duration (years) 
<2, 
 ≥2  
Body mass index (BMI) (kg/m2) 
<18.5, 
≥ 18.5 to <25, 
≥ 25 to <30, 
≥30 
hs-CRP level 
≤upper limit of normal (ULN) b, 
>ULN 
Prior TNFα inhibitor exposure c 
Yes, 
No 
csDMARDs 
Yes, 
No 
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Subgroup 
Categories 
ASDAS status 
<1.3 [inactive disease],  
1.3 to ≤2.1 [low disease activity], 
>2.1 to ≤3.5 [high disease activity], 
>3.5 [very high disease activity] 
HLA-B27 positivity d 
Yes, 
No 
Timing of study participant enrollment relative to 
COVID-19 pandemic periods as defined in 
Section 3.2.2.2 
Enrolled prior to the COVID-19 pandemic, 
Enrolled during the COVID-19 pandemic, 
Enrolled after the COVID-19 pandemic 
Timing of Week 16 Visit relative to the COVID-
19 pandemic periods as defined in Section 3.2.2.2 
Study participants who had the Week 16 Visit 
prior the COVID-19 pandemic,  
Study participants who had the Week 16 Visit 
during the COVID-19 pandemic, 
Study participants who had the Week 16 Visit 
after the COVID-19 pandemic 
a The categories may be pooled as defined in Section 3.8. 
b ULN refers to the central laboratory ULN definition (ie, 5mg/L). 
c The actual TNF alpha stratum the study participant belongs to will be used for the subgroup analysis. 
d HLA-B27 = human leukocyte antigen B27. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Study participant disposition 
Study participant disposition will be summarized for all study participants screened overall, by 
region and by site. 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, RS, SS, MS, FAS, PPS, PK-PPS, COVID-19 free 
set) will be presented.  
The disposition of study participants into treatments groups and analysis sets (RS, FAS, SS, and 
PPS, COVID-19 free set) will also be summarized on the RS. 
Reasons for screen failures (as collected on the Study Termination Screen Failure CRF page) 
will be summarized for all screened study participants who failed to be randomized.  
The number and percentage of randomized study participants who completed the study, who 
completed the SFU, and who discontinued the study will be tabulated overall on the randomized 
set and by treatment group. The primary reason for study discontinuation as collected on the 
Study Termination CRF page will be provided in this table. The numbers and percentages of 
study participants entering and completing, or who remain ongoing for each of the study periods 
(16-Weeks Double-Blind Treatment Period, 36-Weeks Maintenance Period) will additionally be 
presented in this table. The number of study participants who completed the Double-Blind 
Treatment Period but discontinued prior to entering the Maintenance Period will be displayed in 
this table. The numbers and percentages of randomized study participants entering the extension 
study will also be presented in this table.  
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The disposition and study discontinuations reasons will additionally be provided on the RS up to 
Week 24, as well as on the maintenance set.  
Study participants who prematurely discontinued study medication and are continuing to attend 
their scheduled visits through the end of each study period (DBP or MP) will also be considered 
as having completed the period. However, they will be labeled as ‘completed while not on 
randomized treatment’ in disposition and study discontinuation summaries. The primary reason 
for study medication discontinuation (respectively during the Double-Blind Treatment Period or 
Maintenance Period) as collected on the Study Medication termination CRF page will be 
summarized in separate tables.  
The number of randomized study participants who discontinued the study due to AEs (during the 
Double-Blind Treatment Period or Maintenance Period) will be summarized for EudraCT 
reporting. 
Finally, the number of study participants enrolled during each COVID-19 pandemic period, as 
well as the number of study participants still in the study during each COVID-19 pandemic 
period will be summarized in one table on the randomized set. The table will be done overall and 
by region. Refer to Section 3.2.2.2 for definition of the pandemic periods.  
Study disposition and termination details will be listed for all study participants screened. 
Additional listings 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. A by-study participant will be said to have completed the study if she/he had 
completed the last scheduled study visit, not including SFU visits. 
5.2 
Impact of COVID-19 
A listing of visits affected by COVID-19 will be presented based on the enrolled set including 
the visit, date of visit, relationship to COVID-19, impact category, and a narrative (short 
description) of the event. These data will be presented by treatment group as well as by region. A 
supportive summary table will also be provided on the randomized set by treatment group. The 
table will be done overall and then repeated by country.   
In addition, in order to assess the potential impact of COVID-19 on the collection and reporting 
of efficacy data, two summary tables on the RS will be presented to display missing data and 
data collected via an alternative modality (eg, phone interview, video call), respectively, for 
efficacy endpoints included in the testing hierarchy (Figure 4‒1). For the purpose of these 
displays, missing data will be presented only for visits affected by COVID-19, as reported on the 
dedicated eCRF page. Missing data at other visits and for other reasons will not be included. 
Some assessments must be conducted in person and cannot be assessed when a visit is completed 
remotely (eg, BASMI, TJC or SJC) and therefore these assessments will be missing for those 
visits.  
In addition, for any missed visit or a visit conducted remotely, the CRP assessment will also be 
missing. Such assessments will be considered to be missing as a result of COVID-19. For these 
visits, it will therefore not be possible to assess ASDAS-CRP. 
A listing will be presented showing each impacted visit, based on the Enrolled Set. This will 
include the planned visit, the visit date, and details of the assessments conducted remotely and/or 
those missing as a result of COVID-19. 
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These data will be presented in a summary table by treatment group for the RS.  
For both the listing and the summary table, only visits at which efficacy assessments are 
scheduled will be included.  
5.3 
Protocol deviations 
The definition of an IPD is given in Section 3.5.  
A first summary displaying the number and percentage of study participants with an important 
protocol deviation will be provided on the RS by treatment group and overall. The summary will 
be overall (any IPD) and by type of deviation (inclusion criteria deviation, exclusion criteria 
deviation, withdrawal criteria deviation, prohibited concomitant medication, incorrect treatment 
or dose, treatment non-compliance, procedural non-compliance). The IPDs will also be classified 
as COVID-19 related or not. This summary will be presented on the Double-Blind Treatment 
Period and overall. A second summary displaying the number and percentage of study 
participants excluded from the PPS and PK-PPS will be provided on the Double-Blind Period, on 
the RS, by treatment group and overall. For the PPS exclusion, the table will provide the 
breakdown between study participants who are excluded due to IPD from study participants who 
are excluded because of a decrease in dosing or dosing frequency of axSpA background 
medication due to intolerance/ AE/ side-effects as permitted per study protocol with potential 
impact on primary efficacy endpoint.  
Criteria for exclusion of study participants from the PPS or PK-PPS will be defined in a separate 
document. 
A by-participant listing of important protocol deviations will be provided for all study 
participants in the RS. 
A separate listing of all COVID-19 related PD will be presented based on the RS.  
A listing of study participants excluded from PPS because of a decrease in dosing or dosing 
frequency of axSpA background medication (due to intolerance/ AE/ side-effects as permitted 
per study protocol) will be provided on the RS.   
A listing of study participants excluded from COVID-19 free set and a listing of study 
participants excluded from PK-PPS will also be provided on the RS.   
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
Unless otherwise specified, all summaries will be based on the SS and repeated using the RS. If 
the SS and RS analysis sets are identical, the summaries will not be repeated. Some summaries 
will also be presented on the MS.  
6.1 
Demographics 
The following demographic variables measured at Baseline will be summarized overall and by 
treatment group: age (years), gender, and country, race, ethnicity, height (cm), body weight (kg) 
and BMI (kg/m2). Age, body weight and BMI will be summarized as continuous variables and 
as categorical variables.  
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Any age values collected in the database it will be recalculated for the analysis. The recalculation 
should use the year of birth and the year of randomization. Age calculation for non-randomized 
study participants will not be done. For age, three sets of categories will be defined: 
• ≤18, 19 to <65, ≥65 years (clinicaltrials.gov requirement),  
• 18 to <65, 65 to <85, ≥85 years (EudraCT requirement),  
• <45, ≥ 45 years 
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 since they are considered more accurate. The 
formula for BMI (kg/m2) calculation is: 
BMI = Weight (kg)
(Height (m))2 
BMI categories will be:  
• <25, 25 to <30, ≥30 kg/m2 
• <18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2 
For body weight, the following categories will be used:  
• ≤100, >100 kg 
• <70, 70 to <95, 95 to < 115, ≥115kg 
In addition, the number and percentages of study participants in each stratum for each region 
stratification factor will be included in the demographic summary table, as per the information 
collected in the Stratification CRF page. The actual information on the prior use of TNFα 
inhibitor at Baseline will also be reported. 
To understand the study population during the different periods of the COVID-19 pandemic, the 
reporting of Baseline demographics will be repeated by COVID-19 enrollment period 
(prior/during/post) on the SS. Refer to Section 3.2.2.2 for definition of the periods.  
A separate frequency table will summarize the study participant’s lifestyle on the SS only. 
By-study participant listings on demographics and study participant’s childbearing potential data 
will be provided for all screened study participants. Listing on lifestyle will be provided on the 
RS.  
6.2 
Baseline characteristics 
6.2.1 
Baseline efficacy variables 
The ASAS components at Baseline (PGADA, total spinal pain NRS score, BASFI, mean of the 
BASDAI questions 5 and 6) will be summarized descriptively overall and by treatment group.  
BASDAI spinal pain (question 2 only) and BASDAI total score will also be presented in this 
table, as well as hs-CRP (mg/L) and ASDAS-CRP. Hs-CRP and ASDAS-CRP will be 
summarized as continuous variables and as categorical variables and the same categories as the 
ones defined in Table 4‒4 for the efficacy subgroup analyses will be used.  
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Total spinal pain will be derived from question 1 of the total and nocturnal spinal pain 
questionnaire. 
To understand the study population during the different periods of the COVID-19 pandemic, the 
reporting of Baseline efficacy characteristics will be repeated by COVID-19 enrollment period 
(prior/during/post) on the SS.  
6.2.2 
Other baseline characteristics  
The following categorical variables will also be summarized: 
• HLA-B27 (positive, negative) 
• Past anti-TNF therapy (yes, no) 
• Any past biologic therapy (yes, no) 
• Past biologic therapy other than TNF inhibitor (yes, no) 
• Current nonsteroidal anti-inflammatory drug (NSAID) drug therapies (yes/no) 
• Current number of NSAID drug therapies (0, 1, 2, ≥3) 
• Current conventional synthetic disease-modifying antirheumatic drug (DMARD) (yes, no) 
• Current conventional synthetic DMARD type (methotrexate, sulfasalazine, 
hydroxychloroquine, apremilast, leflunomide, other) 
• Current oral corticosteroid use (yes, no) 
• Current Analgesic/Opioid therapies (yes, no) 
• Disease duration (<2, >= 2 years) 
Additionally, a separate table containing a summary of variables related to ankylosing 
spondyloarthritis (AS) history will be prepared containing the following variables: 
• Time since first diagnosis of AS (years) (continuous and in categories <2, ≥ 2) 
• Time since first symptoms of AS (years) 
• Age at first diagnosis of AS (years) 
• Age at first symptoms of AS (years) 
Time since first diagnosis of AS (years) will be calculated as: 
Randomization date − Date of diagnosis 
365.25
 
using the information collected in the AS Diagnosis CRF form. If the date of diagnosis is partial, 
it should be imputed to the most recent feasible date (ie, last day of the month if only day is 
missing, or the last day of the year if day and month are missing, if this imputation would lead to 
a date of diagnosis after screening date, the screening date will be used for imputation). If the 
date of randomization is missing, then the duration of disease will be derived using the date of 
screening. 
Age at first diagnosis (years) will be calculated as: 
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Date of first diagnosis − Date of birth
365.25
 
Since only the year of birth may be entered into the eCRF, age at diagnosis will be calculated 
after imputing the date of birth to be 01 Jan XXXX. 
Age at first symptoms (years) will be calculated as: 
Date of first symptoms − Date of birth
365.25
 
Time since first symptoms should be calculated in the same manner as time since first diagnosis, 
using the information collected in the AS Diagnosis CRF form as well.  
The percentage of study participants that meet each of three clinical criteria as well as the 
number and percentage of study participants that meet radiologic criterion will be summarized.  
For AS0011 eligibility, study participants must meet criterion defined below. The specific 
definition for these criteria is as follows: 
• Clinical criterion a – Study participant had low back pain and stiffness for more than 3 
months which improves with exercise, but is not relieved by rest 
• Clinical criterion b – Study participant had limitation of motion of the lumbar spine in both 
the sagittal and frontal planes 
• Clinical criterion c – Study participant had limitation of chest expansion relative to normal 
values corrected for age and sex 
• Radiologic criterion – Study participant had sacroiliitis grade ≥2 bilaterally or sacroiliitis 
grade 3 to 4 unilaterally 
To understand the study population during the different periods of the COVID-19 pandemic, the 
reporting of other baseline characteristics and AS history will be repeated by COVID-19 
enrollment period (prior/during/post) on the SS.  
Finally, a by participant-listing will be presented on all baseline characteristics for all screened 
study participants.  
6.3 
Medical history and concomitant diseases 
Previous medical history is defined as conditions that have resolved prior to study entry.  
Ongoing medical history are 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 treatment and overall including the number and 
percentage of study participants with each condition. Axial spondyloarthritis history will not be 
included in this table as it will be presented separately (see Section 6.2). The table summaries 
will be ordered alphabetically for SOC and in terms of decreasing frequency for PT within SOC 
in the bimekizumab treatment group. In the event of ties, PT will be ordered alphabetically.  
Pre-specified medical history coming from ‘the ‘Infection history’ CRF form will be summarized 
in a separate table.  
The above summaries will be presented on the overall study treatment period.  
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Additionally, the extra-articular assessments (including uveitis, inflammatory bowel disease 
(IBD), psoriasis, peripheral arthritis, enthesitis (heel, non-heel), dactylitis) will be summarized at 
Screening and Baseline as collected in EDC. Uveitis and IBD assessments will also be 
summarized at post-Entry Visit (ie Visits after Visit 2). The summary will be presented on the SS 
for the overall period. 
Medical history will be listed by treatment and study participant including the reported term, PT, 
and SOC for the RS. A glossary of all medical history conditions will be presented on the RS 
including the reported term, PT and SOC. Concomitant medical procedures will be listed on the 
RS. 
6.4 
Prior and concomitant medications 
Prior medications include any medications that started prior to the start date of study medication. 
Concomitant medications are medications taken at least one day in common with the study 
medication dosing period (defined as from first dose of study medication [including placebo] up 
to last dose of study medication + 28 days for the double-blind treatment period.  
For study participants who discontinue early, the dosing period ends at the last study medication 
date + 28 days (one dosing interval). For study participants who complete the study as planned, 
the dosing period ends at the later of the following two dates: 
• Last study medication date + 28 days 
• The last scheduled visit date not including SFU 
In the case of missing data, the classification of medications as prior or concomitant will be 
performed as described in Section 4.2.3. Imputations of missing data will be performed before 
calculation of relative study days. 
The number and percentage of study participants in the SS taking prior medications will be 
summarized by treatment group, overall and by ATC class, presenting Anatomical Main Group 
(ATC Level 1), Therapeutic/Pharmacological Subgroup (ATC level 3), and PT. The table 
summary will be ordered alphabetically for the Anatomical Main Group and in terms of 
decreasing frequency for PT within Anatomical Main Group in the bimekizumab treatment 
group. In the event of ties, PT will be ordered alphabetically. 
The number and percentage of study participants taking concomitant medications will be 
summarized similarly in a separate table. The summary will be presented on the SS for the 
Double-Blind Treatment period, as well as on the MS for the Maintenance Treatment Period.  
In addition, separate summary tables for concomitant NSAIDs and for selected concomitant 
medications will be created for each treatment period 
A by-study participant listing of all prior and concomitant medications as well as glossary of all 
medical medications will be provided on RS. 
6.5 
Rescue medication 
Refer to the study protocol for the list of rescue medications. 
The number and percentage of study participants who administered rescue medication will be 
summarized by ATC class, presenting ATC Level 1, ATC level 3, and PT. The table summary 
will be ordered alphabetically for the ATC class and in terms of decreasing frequency for PT 
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within ATC class in the bimekizumab treatment group. In the event of ties, PT will be ordered 
alphabetically. The same rule than the one defined in Section 6.4 will be used to define 
concomitant medications.  
The summaries on rescue medication will be presented on the Maintenance Treatment Period, as 
well as on the overall period up to Week 20. 
Rescue medication will be listed on RS.  
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Due to the method of administration of the treatments, compliance will be examined in terms of 
completed injections. Treatment compliance will be calculated as: 
 𝑇otal number of actual (completed) injections
 Total number of expected injections
 ×  100% 
The total number of expected injections is derived relative to when the study participant finishes 
treatment. If a study participant completes treatment, four injections are expected during the 
Double-Blind Treatment Period and nine during the Maintenance Period. A total of thirteen 
injections are then expected (at Baseline, and at each study visits from Week 4 until Week 48). If 
a study participant discontinues early, then the number of expected injections is based on the 
time of early discontinuation relative to the dosing visits. 
A summary of percent treatment compliance categorized as <75% and ≥75% will be provided by 
treatment group, as well as a by-study participant listing of treatment compliance. 
Compliance will be summarized on the SS for the Double-Blind Period, on the MS for the 
Maintenance Period and on the SS for the overall period.  
Injections missed due to COVID-19 will be summarized and tracked in the listings. 
8 
EFFICACY ANALYSES 
8.1 
Statistical analysis of the primary efficacy variable 
8.1.1 
Derivation of ASAS40 response 
The rules described in Section 4.2.1.1 will be followed in the derivation of the ASAS40 
response. The ASAS40 response at Week 16 is the primary efficacy variable. The ASAS40 
response is defined as: 
• an improvement of at least 40%, and  
• absolute improvement of at least 2 units on a 0 to 10 numeric rating scale (NRS) in at least 3 
of the 4 following domains: 
− Patient’s Global Assessment of Disease Activity (PGADA) 
− Pain assessment (total spinal pain, question 1 from total and nocturnal spinal pain) 
− Physical function (measured by the Bath Ankylosing Spondylitis Functional Index 
(BASFI)) 
− Inflammation (represented by the mean of the Bath Ankylosing Spondylitis Disease 
Activity Index (BASDAI) questions 5 and 6) concerning morning stiffness intensity and 
duration) 
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• and no worsening at all in the remaining domain. 
8.1.1.1 
Derivation of the patient’s global assessment of disease activity 
(PGADA) 
Study participants will score the global assessment of their disease activity in answering the 
following “How active was your spondylitis on average during the last week?” using a NRS 
where 0 is “not active” and 10 is “very active”.  
8.1.1.2 
Derivation of the pain assessment domain  
The pain assessment domain will correspond to the total spinal pain and will be measured by the 
study participant in answering the following question “How much pain of your spine due to 
spondylitis do you have?”. To answer the question, the study participant will consider the 
average amount of pain in the preceding week and use a NRS ranging from 0 to 10, where 0 
represents “no pain” and 10 represents “most severe pain”.  
8.1.1.3 
Derivation of the physical function domain of the Bath Ankylosing 
Spondylitis Functional Index (BASFI) 
The BASFI contains 10 questions and will be measured by the study participant for assessing 
their physical functions during the past week. The first 8 questions evaluate activities related to 
functional anatomical limitations due to the course of AS. The final 2 questions evaluate the 
study participants’ ability to cope with everyday life. An NRS ranging from 0 (“Easy”) to 10 
(“Impossible”) will be used to answer the questions on the test. The arithmetic mean of the 10 
scores gives the BASFI score, which is a value between 0 and 10, with lower scores indicating 
better physical function. 
In case of missing answers to 1 or 2 of the single items within the BASFI questionnaire, the 
BASFI score will be calculated by imputing missing items with the mean of the completed items. 
Then, the BASFI score will be calculated as described above. If more than 2 of the items are 
missing, the BASFI score will be left missing. 
8.1.1.4 
Derivation of the inflammation domain (mean of questions 5 and 6 of 
the BASDAI) 
The BASDAI consists of 6 horizontal NRSs and will be used to measure the disease activity of 
ankylosing spondylitis from the study participant’s perspective. Each NRS contains 10 units to 
measure the severity of the 5 major symptoms: fatigue, spinal pain, peripheral joint pain and 
swelling, enthesitis, and morning stiffness (both severity and duration) over the last week.  
The ASAS inflammation component is calculated as the average of the two scores relating to 
morning stiffness measurements (ie, question 5: “How would you describe the overall level of 
morning stiffness you have had from the time you wake up?” and question 6: “How long does 
your morning stiffness last from the time you wake up?”). The ASAS inflammation score ranges 
from 0 to 10. 
If one of the two morning stiffness measurements is missing, the other one will be used as ASAS 
inflammation score. 
If more than one measurement is missing, the ASAS inflammation score will be set to missing. 
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8.1.2 
Primary analysis of the primary efficacy variable 
The primary efficacy variable (ASAS40 response at Week 16) will be analyzed for all study 
participants in the RS.  
The primary efficacy analysis will evaluate the composite estimand (NRI) that combines the 
clinically meaningful improvement from Baseline in ASAS40 response at Week 16 and the 
intercurrent event of not discontinuing early from study treatment for any reason prior to 
Week 16.  
Note that only permanent discontinuations are considered as intercurrent events. This definition 
is applicable to all analyses defined in this SAP.   
The following 4 attributes describe the composite estimand that will be used to define the 
treatment effect of interest for the primary efficacy analysis: 
• Population = Study participants enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP 
• Study participant-level outcome = ASAS40 at Week 16 
• Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment prior to Week 16. A composite strategy will be implemented in which a positive 
clinical outcome is defined as achieving ASAS40 at Week 16 and not discontinuing study 
treatment through Week 16. 
• Population-level summary measure = Conditional odds ratio comparing bimekizumab to 
placebo. 
Intercurrent events will then be acknowledged as an unfavorable outcome for the composite 
estimand in considering study participants with intercurrent events as ‘non-responders’ to the 
study treatment.  
Consequently, if the date of an intercurrent event (as defined in Section 3.4) occurred prior to or 
at Week 16, study participants will be considered as “non-responders” at Week 16. 
Additionally, missing data at Week 16 that are not preceded by an intercurrent event will be 
imputed as non-responders. 
As outlined in Section 4.5, the statistical null hypothesis for the ASAS40 response at Week 16 is 
that there is no difference in the proportion of study participants with ASAS40 response between 
the bimekizumab treatment and placebo (ie, the conditional odds ratio for ASAS40 response in 
the bimekizumab treatment compared with placebo is equal to 1). The alternative hypothesis is 
that there is a difference between bimekizumab treatment and placebo. 
A logistic regression model will be used to assess the treatment effect on ASAS40 response at 
Week 16. The model will include fixed effects for treatment, and prior TNFα inhibitor exposure 
and region as stratification factors. The suitability of including these variables in the model will 
be assessed using the Hosmer-Lemeshow goodness-of-fit test.  
Also, as mentioned in Section 4.1, if the logistic regression model is unable to converge the 
stratification factors may be dropped to facilitate the model convergence.  
The SAS® PROC LOGISTIC will be used to run the logistic regression. 
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The summary table results will present the number of responders, adjusted responder rates and 
associated 95% CI for bimekizumab and placebo, the adjusted odds ratio and 95% CI for the 
comparison bimekizumab versus placebo, and the p-value that the OR=1. The treatment 
comparison will be made using the 2-sided Wald test at a significance level of α=0.05.  
8.1.3 
Secondary analyses of the primary efficacy variable 
Subgroup analyses will be performed on the primary efficacy variable on the RS.  
The variables for subgroup analyses are defined in Section 4.8.  
Unless otherwise notified, for each subgroup analysis, a logistic regression will be fitted 
involving the same terms from the primary analysis model and additional terms for the subgroup 
and the subgroup by treatment interaction. However, for the analysis by stratification variables 
(ie, prior TNFα exposure and region), the analysis model will contain the same terms from the 
primary analysis model plus the subgroup by treatment interaction only.  
The same imputation method as the one used for the primary analysis (ie, NRI) will be used to 
handle missing data. The covariates will be provided in the same order as for the primary 
analysis model with the terms for subgroup and for subgroup by treatment interaction added at 
the end of the model statement. 
For each subgroup category and each treatment group, the number of responders, and adjusted 
responder rate with associated 95% CI, and the adjusted OR (for the comparison bimekizumab 
and placebo) and the 95% CI will be provided. Results obtained for each subgroup will be 
presented in one single table. The ORs and associated 95% CIs for each subgroup category will 
also be displayed on a single forest-plot. 
8.1.4 
Supportive analyses of the primary efficacy variable 
The following sections described the different supportive analyses planned for the primary 
efficacy endpoint. Unless otherwise specified: 
• the same model as the one specified for the primary analysis will be used 
• and the same statistic results as the ones produced for the primary efficacy analysis will be 
calculated  
The adjusted odds ratios and 95% CI for the comparison of bimekizumab versus placebo 
obtained from the primary analysis and from the supportive analyses described in 
Section 8.1.4.1, Section 8.1.4.2, and Section 8.1.4.4 to 8.1.4.8 will be displayed on a forest-plot. 
8.1.4.1 
Analysis on the PPS 
The primary analysis described in Section 8.1.2 will be repeated based on the PPS to evaluate the 
effect of important protocol deviations and protocol-permitted decrease in dosing or dosing 
frequency of axSpA background medication (due to intolerance/AE/side-effects) on the analysis. 
8.1.4.2 
Analysis on the FAS 
The primary analysis described in Section 8.1.2 will be repeated on the FAS to evaluate whether 
there are differences in the efficacy analysis between randomized study participants and 
randomized study participants with a valid Baseline. This analysis will only be produced if the 
number of study participants in the RS and FAS differs.  
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8.1.4.3 
Analysis on individual components of ASAS40 
The change from Baseline in each individual component of the ASAS40 response (PGADA, 
total spinal pain score, BASFI, and BASDAI) will be analyzed at Week 16 using an analysis of 
covariance (ANCOVA) model. The analyses for the component variable BASFI will be 
described in Section 8.2.2 where analyses for secondary endpoints are described. For all four 
variables, the model will include treatment, prior TNFα inhibitor exposure and region as fixed 
effects and the respective Baseline values as covariate. These analyses will be done on the RS 
and will explore the effect of the signs and symptoms of the individual components on the 
composite endpoint.  
The following 4 attributes describe the estimand that will be used to define the treatment effect 
of interest for each of the four components for this analysis: 
• Population = Study participants enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP 
• Study participant level outcome = The change from Baseline in the ASAS component 
variable at Week 16 
• Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to any reason prior to Week 16. This estimand targets the treatment difference 
in a scenario where withdrawal from study treatment does not occur, such that outcomes for 
study participants without an IE are as observed, and outcomes for study participants with an 
IE are treated as they had completed the randomized study treatment through Week 16 but on 
placebo. In that strategy, missing data and non missing data after IE (reset as missing) will be 
imputed using reference-based MI, in which the MI model is based on data from the placebo 
group. 
• Population-level summary measure = the difference in the adjusted means between 
bimekizumab and placebo. 
Intermittent missing data will be imputed using the reference-based MI method as well. See 
Section 4.2.1.6 for technical details on how the reference-based MI method will be implemented.  
The SAS® PROC MIXED will be used to run the ANCOVA model.  
For each ANCOVA model specified in this analysis, the following statistics will be presented: 
a) For placebo and bimekizumab: the adjusted least-square means (LSM) and standard error 
(SE) 
b) For the comparison between placebo and bimekizumab: the difference between the LSM, 
the associated 95% confidence intervals for the contrasts, and the corresponding p-value. 
An additional table will present the descriptive statistics for each ASAS40 component variable at 
Week 16. Those statistics will be the mean, SE, median, minimum and maximum obtained after 
MI. 
The following supportive and additional analyses described in Section 8.1.4.4 to Section 8.1.4.8 
are planned for the primary efficacy endpoint.  
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8.1.4.4 
Analysis using modified composite estimand - MI 
A supportive analysis will evaluate the modified composite estimand (Section 4.2.1.4.2) that 
combines the clinically meaningful improvement from Baseline in ASAS40 response at Week 16 
and the intercurrent event of not discontinuing early from study treatment due to AE or lack of 
efficacy prior to Week 16.  
The same logistic regression model as the one used for the primary efficacy analysis will be used 
on the RS. The following 4 attributes describe the estimand that will be used to define the 
treatment effect of interest for this analysis: 
• Population = Study participants enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP 
• Study participant-level outcome = ASAS40 at Week 16 
• Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to AE (including death) or lack of efficacy, prior to Week 16. A composite 
strategy will be implemented in which a positive clinical outcome is defined as achieving 
ASAS40 at Week 16 and not discontinuing study treatment due to AE or lack of efficacy 
through Week 16. 
• Population-level summary measure = Conditional odds ratio comparing bimekizumab to 
placebo. 
Intercurrent events (Section 3.4) will be acknowledged as an unfavorable outcome for this 
modified composite estimand in considering study participants with intercurrent events as ‘non-
responders’ to the study treatment.  
Missing data at Week 16 that are not preceded by an intercurrent event will be imputed by 
standard MI techniques.  Refer to Section 4.2.1.2 for further details.  
8.1.4.5 
Analysis using treatment policy strategy imputation for missing data 
The treatment policy strategy will be investigated for addressing the intercurrent events. In this 
analysis, all available data at Week 16 will be considered regardless of the occurrence of 
intercurrent events. Missing data will be imputed by standard MI techniques. Refer to 
Section 4.2.1.9 for further details. This analysis will be based on the same logistic regression 
model as the one specified for the primary analysis where study participants are analyzed 
according to their randomized treatment even if they discontinued treatment prior to Week 16 
and were no longer on the randomized study treatment when the assessment was performed at 
Week 16.  
The following 4 attributes describe the estimand that will be used to define the treatment effect 
of interest for this analysis: 
• Population = Study participants enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP 
• Study participant-level outcome = ASAS40 at Week 16 
• Intercurrent event handling = There are no intercurrent events defined for this estimand. 
Discontinuation of study medication for any reason will be handled by using the data as 
observed.  
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• Population-level summary measure = Conditional odds ratio comparing ‘bimekizumab to 
‘placebo. 
8.1.4.6 
Analysis on observed cases  
An observed case (OC) analysis will additionally be conducted, where only observed data for 
study participants who are still on the randomized treatment at Week 16 are included. Study 
participants with missing data and all data after date of treatment discontinuation will be treated 
as missing and missing data will not be imputed. The same model than the one used for the 
primary efficacy analysis will be conducted on the RS. The following 4 attributes describe the 
estimand that will be used to define the treatment effect of interest for this analysis: 
• Population = Study participants enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP 
• Study participant-level outcome = ASAS40 at Week 16 
• Intercurrent event handling = A “while on randomized treatment” strategy will be 
implemented.  
• Population-level summary measure = Conditional odds ratio comparing bimekizumab to 
placebo. 
Refer to Section 4.2.1.10 for further details. 
8.1.4.7 
Tipping point analysis 
The degree of the departure from the missing at random (MAR) assumption to overturn 
conclusions from the primary analysis will be investigated in a tipping point sensitivity analysis. 
This analysis will be performed only if the primary analysis is significant at α=0.05. In this 
analysis, it will be assumed that study participants who have missing data and are randomized to 
bimekizumab have a lower probability of response compared to study participants who have 
missing data and are randomized to placebo.  
This analysis will generally follow the steps for multiple imputation described in 
Section 4.2.1.4.1. However, data for study participants after date of discontinuation of treatment 
will be changed to missing prior to imputation, but will not be changed to non-response after 
imputation, and all imputed values will be "adjusted" prior to calculating the binary response. 
For the worst-case scenario, study participants who have missing ASAS40 response (after setting 
data after date of discontinuation of study treatment for any reason as defined in Section 3.4 to 
missing) and are randomized to bimekizumab are set to non-responders and study participants 
with missing data and randomized to placebo are set to responders. If the result tips from 
statistically significant to statistically insignificant, then the delta adjustment tipping point 
analysis will be conducted where missing and imputed values for each component of the 
ASAS40 endpoint are delta-adjusted. For both analyses, the same model as used for the primary 
efficacy analysis will be conducted on the RS. More robust primary analysis results will require 
larger adjustments to tip the results from significant to not significant. 
Refer to Section 4.2.1.8 for more details on the methodology. 
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8.1.4.8 
Analyses including COVID-19 impact 
To assess the impact of the COVID-19 pandemic on the primary efficacy endpoint, the following 
sensitivity analyses will be conducted using the same analysis method as the primary analysis 
described in Section 8.1.2: 
• On the COVID-19 free set, 
• By timing of the Week 16 Visit relative to the start and end of the COVID-19 pandemic (ie, 
study participants will be categorized according to if their Week 16 Visit took place prior to, 
during or after the pandemic). See Section 3.2.2.2 for definition of pandemic periods.     
For this last analysis, the same model than the one described in Section 8.1.3 will be used. The 
ORs and associated 95% CI results of this analysis will be displayed on a forest plot. 
8.2 
Statistical analysis of the secondary efficacy variables 
8.2.1 
Derivation of secondary efficacy variables 
8.2.1.1 
Other assessment in Axial SpondyloArthritis international Society 
response criteria (ASAS20, ASAS5/6, and ASAS-PR)  
The ASAS20 response is defined as relative improvement of 20%, and an absolute improvement 
of at least 1 unit on a 0 to 10 NRS in at least 3 of the 4 following domains: 
• Patient’s Global Assessment of Disease Activity (PGADA) 
• Pain assessment (total spinal pain, question 1 from total and nocturnal spinal pain) 
• Function (represented by the Bath Ankylosing Spondylitis Functional Index (BASFI)) 
• Inflammation (represented by the mean of the Bath Ankylosing Spondylitis Disease Activity 
Index (BASDAI) questions 5 and 6) concerning morning stiffness intensity and duration) 
and absence of deterioration in the potential remaining domain. A deterioration will be defined 
as a relative worsening of at least 20% and an absolute worsening of at least 1 unit.  
The ASAS 5/6 response is defined as at least 20% improvement in 5 of 6 domains, which 
includes, in addition to the 4 domains mentioned above for ASAS20, spinal mobility (ie, lateral 
spinal flexion component of the BASMI) and hs-CRP as more objective measures.  
The ASAS-PR response is defined as a score of ≤2 units on a 0 to 10 unit scale in all 4 domains 
listed above for ASAS20. 
ASAS40 response in the TNF alpha inhibitor-naïve study participants represents the ASAS40 
response for study participants with “Prior TNFα inhibitor = No” (which are defined per actual 
information on prior use of TNFα inhibitor). For the supportive analysis based on MI, all 
randomized study participants will be included in the imputation model (since this analysis is a 
subgroup analysis of the primary endpoint), but the analysis step will only be done on the 
subgroup of TNF alpha inhibitor-naïve study participants.  
8.2.1.2 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)  
As mentioned in Section 8.1.1.4, the BASDAI consists of six 10-unit NRSs measuring the 
disease activity of AS over the past week on 5 major symptoms. To give each symptom equal 
weighting, the average of the 2 scores relating to morning stiffness is taken. The BASDAI is 
calculated as follows: 
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𝐵𝐴𝑆𝐷𝐴𝐼=
𝑄1 + 𝑄2 + 𝑄3 + 𝑄4 + (𝑄5 + 𝑄6
2
)
5
 
where Q1 – Q6 are the six questions from the BASDAI questionnaire. 
The BASDAI score is between 0 and 10, with lower scores indicating lower disease activity. 
As mentioned in Section 8.1.1.4, if 1 of the 2 morning stiffness measurements (ie, questions Q5 
and Q6) is missing, the other one will be used for the morning stiffness calculation. 
If one major symptom of the BASDAI is missing, the total score of the remaining symptoms will 
be divided by the number of symptoms assessed. If more than one major symptom is missing, the 
total BASDAI score will be set to missing. 
8.2.1.3 
Ankylosing Spondylitis Disease Activity Score major improvement 
(ASDAS-MI)  
The ASDAS-CRP consists of a number of assessments which are scored by the study participant 
and physician and multiplied by a proven formula (van der Heijde et al, 2009) as shown below: 
• 0.121 x Back pain (BASDAI Question 2 result) 
• 0.058 x Duration of morning stiffness (BASDAI Question 6 result) 
• 0.110 x Patient’s Global Assessment of Disease Activity (PGADA) 
• 0.073 x Peripheral pain/swelling (BASDAI Question 3 result) 
• 0.579 x (natural logarithm of the (hs-CRP [mg/L] + 1)) 
Back pain, PGADA, duration of morning stiffness, peripheral pain/swelling and fatigue are all 
assessed on a numerical scale (0 to 10 units) (Lukas et al, 2009). If the hs-CRP value is <2 mg/L, 
the constant value of 2 mg/L should be used in the calculation. The sum of these weighted 
components gives the ASDAS-CRP. 
For analyses with imputation of missing data, the imputed value for ASDAS-CRP will be based 
on the imputed values for the individual components. 
For observed case analyses, if any individual component score is missing, then the ASDAS-CRP 
will be set to missing. 
Disease activity categories based on ASDAS-CRP are as follows: 
• ASDAS-Inactive Disease (ASDAS-ID): ASDAS-CRP <1.3 
• ASDAS-Low Disease (ASDAS-LD): ASDAS-CRP ≥1.3 to <2.1 
• ASDAS-High Disease Activity (ASDAS-HD): ASDAS-CRP ≥2.1 to ≤3.5 
• ASDAS-very High Disease Activity (ASDAS-vHD): ASDAS-CRP >3.5 
The variables related to ASDAS improvement are defined as follows: 
• ASDAS-Clinically Important Improvement (ASDAS-CII): ASDAS-CRP reduction 
(improvement) of ≥1.1 relative to Baseline 
• ASDAS-Major Improvement (ASDAS-MI): ASDAS-CRP reduction (improvement) of ≥2.0 
relative to Baseline 
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For both ASDAS disease category and ASDAS improvement variables, multiple imputation 
methods will be used to impute the ASDAS-CRP value and then dividing into the appropriate 
category or improvement groups. 
8.2.1.4 
Nocturnal spinal pain (NSP)  
The pain in the spine at night due to AS will be measured by the study participant in answering 
question 2 of the total and nocturnal spine questionnaire “How much pain of your spine due to 
spondylitis do you have at night?”. To answer the question, the study participant will consider 
the average amount of pain in the preceding week and use a NRS ranging from 0 to 10, where 0 
represents “no pain” and 10 represents “most severe pain”.  
8.2.1.5 
Ankylosing Spondylitis Quality of Life (ASQoL)  
The ASQoL consists of 18 items which are scored by the study participant, each item with a 
score of 0=no or 1=yes. A score of "1" is given where the item is affirmed, indicating adverse 
quality of life. The ASQoL total score is based on the sum scores, ranging from 0 to 18, with 
higher scores indicating worse quality of life. 
If 3 or fewer items are missing, the missing responses will be imputed with the mean of the 
available responses from that visit to calculate a total score. If more than 3 items are missing, the 
total score will be left missing. 
8.2.1.6 
Short-Form 36-item Health Survey (SF-36) Physical Component 
Summary (PCS)  
The SF-36 (version 2, standard recall) is a 36-item generic health-related quality of life (HRQoL) 
instrument that uses a recall period of past 4 weeks. Items are grouped into the following 8 health 
domains: Physical Functioning (10 items), Role Physical (4 items), Bodily Pain (2 items), 
General Health (5 items), Vitality (4 items), Social Functioning (2 items), Role Emotional (3 
items), Mental Health (5 items). The concepts represented by these domains contribute to 
physical, mental and social aspects of HRQoL. 
 
 
In addition to domain scores, the PCS and MCS scores are calculated from the 8 domains 
(excluding the Health Transition item). Component scores appreciate the impact of each domain 
on physical and mental health status (Maruish, 2011). 
The two SF-36 component summaries (PCS and MCS) and the 8 domain scores are standardized 
with a mean of 50 and a standard deviation (SD) of 10 in the general US population (Maruish, 
2011). An individual respondent’s score that falls outside the T-score range of 45 to 55 should be 
considered outside the average range for the U.S. general population. When considering group-
level data, a score below 47 should be considered indicative of impaired functioning within that 
health domain or dimension. Similar to individual respondent data, group mean scores 47 or 
greater should be considered average or above average as compared to the general US 
population. 
For the calculation of the SF-36 domain scores and the two component summary scores, the 
scoring software QualityMetric’s Health Outcomes™ will be used. The software uses updated 
2009 U.S. population norms and applies a Full Missing Score Estimation method as follows: 
• A health domain score (except the Physical Functioning domain) will be estimated provided 
that at least one non-missing response is available within that domain  
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• For the Physical Functioning domain item response, theory will be used to develop a model 
for estimates of the missing score 
• Regression methods are then applied to estimate the PCS and MCS on the basis of the  
domain scores 
8.2.1.7 
Bath Ankylosing Spondylitis Disease Metrology Index (BASMI)  
The BASMI characterizes the spinal mobility of study participants with AS consisting of 5 
clinical measures to reflect study participant axial status: cervical rotation; tragus to wall 
distance; lateral spinal flexion; modified Schober test; intermalleolar distance. Each of the 5 
movements is scored according to the linear BASMI definition given in Table 8‒1. The mean of 
the 5 scores provides the BASMI score. The BASMI score ranges from 0 to 10. The higher the 
BASMI score the more severe the study participant’s limitation of movement due to their AS. 
Table 8‒1: 
BASMI linear definition 
Clinical Movement 
S = 0 if: 
S between 0 and 10: 
S=10 if: 
Lateral spinal flexion* 
(cm) 
A ≥ 21.1 
S = (21.1 cm – A) / 2.1 
cm 
A ≤ 0.1 
Tragus-to-wall 
distance* (cm) 
A ≤ 8 
S = (A – 8 cm) / 3 cm 
A ≥ 38 
Lumbar Flexion* 
(modified Schober) 
(cm) 
A ≥ 7.4 
S = (7.4 cm – A) /0.7 
cm 
A ≤ 0.4 
Intermalleolar distance 
(cm) 
A ≥ 124.5 
S = (124.5 cm – A) / 10 
cm 
A ≤ 24.5 
Cervical rotation 
angle* (⁰) 
A ≥ 89.3 
S = (89.3° - A) / 8.5° 
A ≤ 4.3 
S = BASMI Score, A = assessment. 
* For cervical rotation, tragus-to-wall distance, and lateral spinal flexion, the mean of the left and right measurements will be 
calculated, if both are available. Otherwise, the available measurement will be used. If multiple attempted measurements are 
obtained, calculate the mean of the attempts.  The mean of the attempts should be calculated after averaging the left and right 
measurements, where applicable.  
 From van der Heijde et al. 2008. 
For all clinical measures, values outside the ranges presented in Table 8‒2 (Maksymowych 
2006) will be flagged as invalid and treated as if they were missing values. Where two attempted 
measurements for a single clinical measure are entered at a given visit (ie, lateral lumbar flexion, 
cervical rotation, tragus-to-wall distance, and lumbar flexion) and only one attempted 
measurement is valid, the valid measurement will be used. If both attempts are invalid, the 
measure will be treated as missing. 
Table 8‒2: 
BASMI linear definition (pre-defined ranges) 
Clinical Movement 
Range* 
Lateral spinal flexion (mean right/left) 
0.75 – 25.00 cm 
Tragus-to-wall distance (mean right/left) 
9.00 – 37.50 cm 
Lumbar flexion (modified Schober) 
0.00 – 9.00 cm 
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Clinical Movement 
Range* 
Intermalleolar distance 
13.00 – 160.00 cm 
Cervical rotation (mean right/left) 
0.00 – 94.00° 
* From Maksymowych 2006 
The order of events to derive the BASMI scores is as follows: 
1. Discard individual assessment values (A) that are invalid (out of range according to the 
Table 8‒2 above) 
2. Average remaining valid left and right assessment values (A) by study participant, analysis 
visit, parameter and attempt, if more than one valid value is present 
3. Average assessment values (A) across attempts, by study participant, analysis visit and 
parameter, if more than one attempt is present with valid values 
4. From these averaged (A) values, calculate a single BASMI component score (S), by study 
participant, analysis visit and parameter  
5. Re-map early termination visits according to the specifications given in Section 3.2.3, Re-
mapping will be performed on a per-parameter basis prior to the calculation of the BASMI 
score (this method is adopted in the event that not all parameters are assessed at each visit) 
6. If 1 or 2 BASMI components scores (S) are missing for a given study participant and analysis 
visit, carry forward the most recent non-missing value for that study participant and 
component to the current analysis visit; it is allowed to carry forward a screening or Baseline 
score value (S) to a post-Baseline analysis visit 
7. If one value is available for each of the 5 component scores for a given study participant and 
analysis visit, calculate BASMI score as the average of the 5 component scores (S); 
otherwise set the BASMI score to missing for that study participant and analysis visit 
8.2.1.8 
Maastricht Ankylosing Spondylitis Enthesitis (MASES) index  
The MASES index assesses enthesitis through 13 items (bilateral costochondral 1, costochondral 
7, anterior superior iliac spine, posterior iliac spine, iliac crest and proximal insertion of the 
Achilles tendon sites, and the fifth lumbar vertebral body spinous process) (Heuft-Dorenbosch et 
al, 2003). Each item is scored as 0=yes or 1=no and then summed for a possible score of 0 to 13, 
with higher scores indicating worse enthesitis. 
If 7 or more items are available, MASES will be derived by dividing the sum score by the 
number of available assessments and multiplying the result by 13. If less than 7 items are 
available, MASES will be treated as missing. 
Analyses on MASES index will be restricted to the subset of study participants with enthesitis 
present at Baseline (defined as MASES index score>0).  
Enthesitis-free state based on MASES index is a status defined as study participants having 
achieved a MASES index score of 0 at Week 16. 
For the analysis based on multiple imputation, only randomized study participants with enthesitis 
at Baseline will be included in the imputation models. 
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8.2.2 
Analysis of secondary efficacy variables 
The secondary efficacy variables will be analyzed for all study participants in the RS as 
summarized in Table 4‒1. 
As indicated in Section 4.5, there are 11 key secondary endpoints included in the testing 
hierarchy that will be tested successively one after the other if the previous endpoint was found 
to be statistically significant.  
Three secondary endpoints (change from Baseline in BASMI at Week 16, change from Baseline 
in MASES index at Week 16 in the subgroup of study participants with enthesitis at Baseline, 
and enthesitis-free state at Week 16 based on the MASES Index in the subgroup of study 
participants with enthesitis at Baseline) will not be part of the testing hierarchy and for this 
reason the p-values produced by the statistical models will be considered nominal since these 
endpoints are not controlled for multiplicity. The following analyses will be conducted for the 
Secondary Efficacy Endpoints: 
• For the secondary binary endpoints: 
− Composite Estimand - NRI: The same composite estimand structure as the one defined in 
Section 8.1.2 for the primary efficacy analysis will be used. The same analysis model will 
be considered, and the analysis results will be presented similarly as for the primary 
efficacy analysis. The imputation strategy for handling missing data will be the same as 
for the primary endpoint, ie the NRI approach (see Section 4.2.1.1). 
−  Modified Composite - MI: A similar modified composite estimand structure as the one 
defined in Section 8.1.4.4 for the primary efficacy analysis will be used. The same 
analysis model will be considered, and the analysis results will be presented similarly as 
for the primary efficacy analysis. The imputation strategy for handling missing data will 
be the MI-MCMC/Monotone regression for the composite and non-composite binary 
endpoints as detailed in Section 4.2.1.4. 
− Observed Case: A similar analysis as the one defined in Section 4.2.1.10 for the primary 
efficacy analysis will be used. 
• For the secondary continuous endpoints: 
− Reference-Based Estimand - MI: The same hypothetical estimand (Section 4.2.1.6) 
structure as the one defined in Section 8.1.4.3 for the analysis on component variables for 
the primary efficacy endpoint will be used. The same analysis model and imputation 
strategy for handling missing data will also be considered. The analysis results will be 
presented similarly as for this analysis on the individual ASAS40 components. 
This estimand will only be implemented for the secondary continuous endpoints in the 
testing hierarchy.  
− Hypothetical Estimand - MI:   
The following 4 attributes describe the estimand that will be used to define the treatment 
effect of interest for this analysis: 
o Population = Study participants enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP 
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o Study participant level outcome = The change from Baseline in the variable at 
Week 16 
o Intercurrent event handling = An intercurrent event is defined as discontinuation 
of study treatment due to any reason prior to Week 16. A hypothetical strategy 
will be implemented in which the estimand targets the treatment difference in a 
scenario where intercurrent does not occur, such that outcomes for study 
participants without an intercurrent event are as observed, and outcomes for study 
participants with an intercurrent event are treated as though they had completed 
the randomized study treatment through Week 16. A multiple imputation (MI) 
strategy will be used to impute any missing data including observed data after the 
IE date which will be set to missing prior to running MI. 
o Population-level summary measure = the difference in the adjusted means 
between bimekizumab and placebo. 
The same analysis model as the one defined in Section 8.1.4.3 used for the analysis 
on the individual ASAS40 components will be considered. The analysis results will 
also be presented similarly. 
− Observed Case:  A similar analysis as the one defined in Section 4.2.1.10 for the primary 
efficacy analysis will be used. 
Note that the ANCOVA analysis on the change from Baseline in BASFI will be considered a 
supportive analysis for the primary endpoint since BASFI is one of the components of the 
primary endpoint.  
An overview table will combine the results of the primary analysis for the primary efficacy 
endpoint and the results of the primary analysis for each key secondary endpoint.  
Subgroup analyses will also be conducted for ASDAS-MI endpoint using NRI. The variables of 
interest will be age, gender, race, region, ASDAS status and prior TNFα inhibitor exposure. 
Exact definition of the subgroups is provided in Table 4‒4. The same methodology as the one 
used for the ASAS40 subgroup analyses will be followed. The results obtained for each 
subgroup will be combined in one single table as well as presented on a forest plot.  
Finally, to assess the impact of the COVID-19 pandemic, the primary analysis of all secondary 
efficacy endpoints included in the testing hierarchy with be analyzed on the COVID-19 free set, 
using the Reference-Based Estimand. 
8.2.3 
Additional statistical analysis of selected secondary efficacy 
variables  
For the “change from Baseline in MASES index at Week 16 in the subgroup of study 
participants with enthesitis at Baseline”, and for the “enthesitis-free state at Week 16 based on 
the MASES Index in the subgroup of study participants with enthesitis at Baseline” secondary 
efficacy variables, additional statistical tests and calculation of inferential statistics will be 
performed. As these tests are not part of the multiplicity-controlled procedure, the associated p-
values are considered nominal and are not controlled for multiplicity.  
For the enthesitis-free state responder variable, the logistic regression model described in 
Section 8.1.2 will be used for analysis. The p-values will be based on the conditional logistic 
regression model to test general association. Missing values will be imputed using the NRI. 
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For the MASES continuous variable, the Hypothetical Estimand approach used for other 
continuous variables will be applied based on the ANCOVA model describe in Section 4.2.1.7 
and Section 8.2.2. 
The results of these inferential statistics will be presented in a single table summarizing the 
estimates (OR for the binary endpoint, LSM for the continuous endpoint) with their 95% CI and 
the associated p-values. The results will be pooled with the results obtained for selected other 
efficacy variables (see Section 8.3.3).  
8.3 
Analysis of other efficacy variables 
The following sections provide the derivation of the other efficacy endpoints which have not 
been mentioned earlier in the SAP.  
8.3.1 
Derivation of other efficacy endpoints 
8.3.1.1 
Time to ASAS20/40 response 
Time to a given response (ASAS20 or ASAS40) will be defined as the time in days from the start 
date of first treatment dose until the first date when the response (respectively ASAS20, or 
ASAS40) is achieved.  
Missing ASAS response data will not be imputed. Instead, study participants with no observed 
response, will be censored at their last visit with ASAS40 response data. 
As mentioned later in Section 8.3.2, the analysis will be performed on the Double-Blind 
Treatment Period. Study participants who discontinue IMP prior to achieving a response will be 
censored at the minimum date between the date of treatment discontinuation as defined in 
Section 3.4 and the Week 16 visit date. Study participants who reach the end of the Double-Blind 
Treatment Period visit (and are still on treatment) without achieving the given response will be 
censored at the date of the end of the Double-Blind Treatment Period visit (ie, Week 16 Visit 
date).  
8.3.1.2 
ASDAS status  
The ASDAS status endpoint is derived as follows based on ASDAS-CRP endpoint previously 
defined in Section 8.2.1.1: 
• Inactive disease: when ASDAS-CRP <1.3 
• Low disease activity: when ASDAS-CRP ≥1.3 to <2.1 
• High disease activity: when ASDAS-CRP ≥2.1 to ≤3.5 
• Very high disease activity: when ASDAS-CRP >3.5 
8.3.1.3 
BASDAI50 response 
A response variable called BASDAI50 is defined as an improvement of at least 50% in the 
BASDAI compared to Baseline. See Section 8.2.1.2 for details on the BASDAI endpoint.  
8.3.1.4 
Physician’s Global Assessment of Disease Activity (PhGADA)  
PhGADA is recorded by the investigator who will assess the overall status of the study 
participant with respect to their AS signs and symptoms and functional capacity using an NRS in 
which 0= “very good, asymptomatic and no limitations of normal activities” and 10= “very poor, 
very severe symptoms which are intolerable and inability to carry out normal activities”. 
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8.3.1.5 
High-sensitivity C-Reactive Protein (hs-CRP) 
In the summary tables presenting hs-CRP values, the observed values and ratio to Baseline 
values will be displayed.  
Hs-CRP values which are below the lower limit of quantification (LLOQ) should be set to the 
midpoint between 0 and the LLOQ. The listing will show that the value was below the LLOQ.  
The LLOQ will be set according to data received by the laboratory vendor. Specifically, any 
numeric value preceded by “<” will be reset to a value equal to 0.5 * the numeric value 
following the “<” for each individual.  
Particular attention will be given to extreme CRP values. Any CRP values of ≥500mg/L will be 
set to missing prior to performing the MI procedure; the subsequently imputed CRP value will be 
included in the summary tables.  Listings will display the original result. 
8.3.1.6 
European Qol-5Dimensions 3-Level (EQ-5D-3L)  
The EQ-5D-3L health questionnaire provides a descriptive profile and a single index value for 
health status. The instrument is composed of a 5-item health status measure (mobility, self-care, 
usual activities, pain/discomfort, anxiety/depression) and a visual analogue scale (VAS). Each of 
the 5 health states is divided into 3 levels (no problem, some or moderate problems, and extreme 
problems) and is scored as 1, 2, and 3, respectively. The 5 numerical responses are averaged to 
create the ‘utility scores’. 
The change from Baseline in each of the 5 responses of the EQ-5D-3L will be analyzed 
categorically by visit. Additionally, the change from Baseline in the utility score will be 
summarized by visit using the numerical scores.  
The EQ-5D VAS records the respondent’s self-rated health status on a vertical 20 cm visual 
analogue scale, graduated from 0 to 100 (0=worst imaginable health status, 100=best imaginable 
health status). The VAS will be evaluated by changes from Baseline and actual scores over time. 
8.3.1.7 
Short Form-36 (SF-36) Mental Component Summary (MCS) and the 8 
domains scores (Physical Functioning, Role Physical, Bodily Pain, 
General Health, Vitality, Social Functioning, Role Emotional, and 
Mental Health) 
As described in Section 8.2.1.6, the SF-36 is a survey that measures 8 health domains rated by 
the study participants over the past four weeks. MCS is based on the aggregate of these 8 health 
concepts and all these 8 health domain scales are used to score the MCS. The MCS and each 
domain scores are standardized with a mean of 50 and a standard deviation of 10 in the general 
US population, and a higher score indicates better health status.   
Results for MCS as well as for each domain scores will be reported. 
8.3.1.8 
Medical Outcomes Study (MOS) sleep scale 
The MOS Sleep Scale will be used by the study participant to measure specific aspects of sleep. 
The frequency with which each sleep problem has been experienced during the previous 4 weeks 
is rated on a 5-point scale ranging from “none of the time” to “all of the time”. 
Out of the 12 sleep problems/items covered by the MOS sleep scale, only items relevant to 
derive the Sleep Disturbance and the Sleep Problems Index II subscales will be considered in this 
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study. Table 8‒3 below describes which items are used for each sleep subscale of interest, and 
which items need to be reversed scored (these are indicated with an R in brackets).  
Table 8‒3: 
MOS sleep subscales 
Subscale name 
Number of items 
Item scores 
Sleep Disturbance 
4 
1, 3 (R), 7 (R), 8 (R) 
Sleep Problems Index II 
9 
1, 3 (R), 4, 5 (R), 6 (R), 7 (R), 8 
(R), 9 (R), 12 
Note: (R) refers to a reversed item. 
The subscale scores are created by averaging the respective rescaled item scores. Scales with at 
least 1 item answered can be used to generate a scale score. Items that are missing are not taken 
into account when calculating the scale scores. Scores represent the average for all items in the 
scale that the respondent answered. 
Prior to averaging, each item score is transformed linearly to range from 0 to 100. Higher scores 
indicate more of the attribute implied by the scale name (eg, more sleep disturbance or more 
sleep problems).  
QualityMetric Health OutcomesTM Scoring Software will be used to calculate the domains of 
Sleep disturbance and Sleep problems Index II. 
8.3.1.9 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
subscale 
The FACIT-Fatigue is a 40-item measure that assesses self-reported fatigue and its impact upon 
daily activities and function within the past 7 days. The scale consists of 5 subscales (physical 
well-being, social/family well-being, emotional well-being, functional well-being, and fatigue). 
The fatigue subscale will be the only domain used in this study. It is composed of 13 items, all 
scored from 0 (Not at all) to 4 (Very much). The FACIT-Fatigue subscale score ranges from 0 to 
52 with 0 being the worst possible score and 52 being the best possible score. To obtain a score 
from 0 to 52, all negatively worded questions have to be recoded, so that responses range from 
worst (0) to the best (4) outcome. This implies that the values to all questions (except for 
 
  
The FACIT-Fatigue subscale score is then obtained by summing up the responses of all 11 
reversed items and responses of item 7 and 8 with equal weight. 
In cases where some answers are missing, a total score is re-scaled from the score of the 
answered items, so long as more than 50% of the items (ie, at least 7 of 13) were answered. 
The formula to derive the FACIT-Fatigue subscale score is then: 
𝐹𝐴𝐶𝐼𝑇−𝐹𝑎𝑡𝑖𝑔𝑢𝑒= 13 𝑥 
∑𝑆𝑐𝑜𝑟𝑒 𝑜𝑓 𝑖𝑡𝑒𝑚𝑠
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑡𝑒𝑚 𝑎𝑛𝑠𝑤𝑒𝑟𝑒𝑑  
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8.3.1.10 
Work Productivity and Activity Impairment Questionnaire–Specific 
Health Problem (WPAI-SHP)  
The WPAI-SHP is a study participant-reported questionnaire that assesses study participant’s 
employment status, work absenteeism, work impairment while working, overall work, and daily 
activity impairment attributable to a specific health problem.  
Five out of 6 items of the WPAI-SHP are regrouped into the 4 dimensions (absenteeism, 
presenteeism, work productivity and activity impairment) with scores expressed as percentage, 
where higher numbers indicate greater impairment and less productivity (ie, worse outcomes) as 
described in the WPAI-SHP scoring rules. 
The scoring rules for the WPAI-SHP are as follows: 
Question 1 is a Yes/No question.  
Questions Q5 and Q6 are measured on a 0 to 10 scale (0= no effect, 10= complete interference). 
In order to make data consistent and amenable to statistical analysis, the following counting rules 
will be applied to handle out of range and ambiguous answers of the WPAI-SHP. These rules 
will be applied prior to conducting any type of statistical analysis of the data. Due to the inter-
relation between certain questions of the WPAI-SHP, the priority order for implementing these 
specific counting rules is as in the listed order below. 
• Employment status: 
− If (Q1=missing) and (Q2>0 or Q3>0 or Q4>0), then Q1=YES. 
• Hours missed due to Ankylosing spondylitis: 
− If Q1 = NO, then Q2 = missing. 
− If (Q2 =0 or missing) and Q1 = missing, then Q2=missing. 
• Hours missed due to other reasons: 
− If Q1 = NO, then Q3 = missing. 
− If (Q3 =0 or missing) and Q1 = missing, then Q3=missing. 
• Hours actually worked: 
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− If Q1 = NO, then Q4 = missing. 
− If (Q4 =0 or missing) and Q1 = missing, then Q4=missing. 
• Work productivity: 
− If Q1 = NO, then Q5 = missing. 
− If (Q5 =0 or missing) and Q1 = missing, then Q5=missing. 
− If Q4=0, then Q5 = missing. 
In the listings, the original values will be kept and displayed. 
After implementing the missing data rules above for questions Q1 to Q5, the following four 
scores will be derived:  
• Percent work time missed due to problem from the target disease: 
𝑄2 ℎ𝑜𝑢𝑟𝑠
𝑄2 ℎ𝑜𝑢𝑟𝑠+ 𝑄4 ℎ𝑜𝑢𝑟𝑠∗100 , Q2 hours +  Q4 hours ≠0 
• Percent impairment while working due to problem from the target disease:  
𝑄5 score 
10
∗100  
• Percent overall work impairment due to problem from the target disease:  
[
𝑄2 hours
𝑄2 ℎ𝑜𝑢𝑟𝑠+ 𝑄4 ℎ𝑜𝑢𝑟𝑠+ (1 −
𝑄2 hours
𝑄2 ℎ𝑜𝑢𝑟𝑠+ 𝑄4 ℎ𝑜𝑢𝑟𝑠) ∗𝑄5 score
10
] ∗100  
• Percent activity impairment due to problem from the target disease: 
𝑄6 score 
10
∗100  
 
WPAI scores are based on 1-item (presenteeism, activity impairment), 2-items (absenteeism) and 
multiple items (overall work productivity). A score cannot be calculated if there is a missing 
response to the corresponding item. 
Because questions 2 to 6 are only relevant when the answer to question 1 is Yes, and because 
imputation of results is questionable without knowing the answer to question 1, only observed 
case analysis will be performed for this endpoint. 
8.3.1.11 
Tender joint count (TJC) and swollen joint count (SJC)  
Each of the following 44 joints will be assessed for tenderness:  
• Upper body (4) - bilateral sternoclavicular, and acromioclavicular joints. 
• Upper extremity (26) - bilateral shoulders, elbows, wrists (includes radiocarpal, carpal and 
carpometacarpal bones considered as a single unit), metacarpophalangeal (I, II, III, IV, and 
V), thumb interphalangeal, and proximal interphalangeal (II, III, IV, and V). 
• Lower extremity (14) - bilateral knees, ankles, and metatarsophalangeals (I, II, III, IV, and 
V). 
All of these 44 joints will also be assessed for swelling.  
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Each of the joints can be graded as follows by the assessor:  
• Permanently not assessable 
• Temporarily not assessable 
• Asymptomatic 
• Tender only 
• Swollen only 
• Tender and swollen 
Permanently not assessable joints will be considered missing for both tender and swollen joint 
counts at the visit at which the grading was recorded and all subsequent visits.  
For the statistical analysis, swelling and tenderness will be each graded on a 2-point scale as 
described below in Table 8‒4: 
Table 8‒4: 
Swelling and tenderness grading 
Grade 
Tenderness response (44) 
Swelling response (44) 
0 
Not tender 
None 
1 
Tenderness present 
Detectable synovial thickening 
The joint graded by the assessor will then have its grade mapped as follows: 
• The “Tender only” joints will correspond to a tenderness response of 1, and a swollen 
response of 0.  
• The “Swollen only” joints will correspond to a swollen response of 1, and a tenderness 
response of 0. 
• The “Tender and swollen” joints will correspond to a swelling and tenderness response of 1. 
In addition, injected joints will be counted as swollen and tender (ie, swelling and tenderness 
grading of 1) from the date of injection up to 1 year after injection. 
Dactylitic digits will be identified as follows and the joints will be counted as follows: 
• Fingers 2-5: Swelling Distal Interphalangeal Joint x (side), Swelling Proximal 
Interphalangeal Joint x (side), Swelling Metacarpophalangeal Joint x (side) – if they are in 
any of the gradings ‘swollen only’ or ‘tender and swelling’ or ‘injected’ then only 1 finger 
will be added to the swollen joint count 
• Toes 1-5: Swelling Interphalangeal Joint x (side), Swelling Metatarsophalangeal Joint x 
(side) – if they were in any of gradings ‘swollen’ or ‘tender and swollen’ or ‘injected’ then 
only 1 toe will be added to the swollen joint count 
The tender joint count and swollen joint count are weighted joint counts. If there are missing 
observations in the tender or swollen joint assessments (TJ and SJ, respectively), then the 
remaining observations will be assessed and weighted by the number of the assessed joints (AJ) 
as shown below: 
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𝑇𝐽𝐶= 𝑛× ∑
𝑇𝐽
𝑛
𝑖=1
∑
𝐴𝐽
𝑛
𝑖=1
 
𝑆𝐽𝐶= 𝑛×
∑
𝑆𝐽
𝑛
𝑖=1
∑
𝐴𝐽
𝑛
𝑖=1
 
Where n represents the number of total joints.  
However, if a joint is missing at Baseline, then that joint will be set to missing throughout the 
study. If more than 50% of the planned tender joint assessments (ie, more than 22) or 50% of the 
swollen joint assessments (ie, more than 22) are missing at any post-Baseline visit, then no 
imputation will be done and the total TJC or SJC will be set to missing for that visit. 
8.3.1.12 
Ankylosing Spondylitis spine MRI-activity (ASspiMRI-a) (Berlin 
modification) score  
The Berlin modification of the ASspiMRI-a is a scoring system for assessing the sacroiliac joint 
with a concentration on short-tau-inversion recovery (STIR) sequences without other fat 
saturation techniques. This scoring method quantifies active changes in 23 vertebral units (VU) 
of the spine (from C2 to S1). A VU is defined as the region between 2 virtual lines through the 
middle of each vertebra. Active inflammation is scored by grading the degree of bone marrow 
edema from 0 to 3 in 1 dimension on one or more consecutive slices that represent the highest 
level of inflammation in a particular VU. Each VU score is called a subscore. These subscores 
are combined into a total spine ASspiMRI-a score in the Berlin modification (total score), which 
can range from 0 to 69. 
The ASspiMRI-a (Berlin modification) score will only be assessed for study participants in the 
sacroiliac joint and spine MRI assessment sub-study who have both a Baseline and at least one 
post-Baseline MRI of the spine available.   
The following imputation rules will be used for calculating the total spine ASspiMRI-a (Berlin 
modification) score: 
• If all subscores are not readable or poor (N) at a visit, the total will be considered missing for 
that visit and the study participant will not be included in the analysis. 
• If one or more but not all subscores are ‘N’, then subscores = 'N' will be considered as 0 
when computing the total score. 
Note that a reviewer may consider an assessment as not readable and assign a “N” value if the 
reviewer feels unable to evaluate a scan or an area of a scan at a specific location. This could be 
related to artifacts, image quality or something else.  
If 2 independent readers are used, the analysis will use the average of the scores from the 2 
independent reviewers.  
In cases where disagreement between the two readers is large, a third adjudication reviewer will 
be required. The spine MRI adjudication trigger will occur when the difference in change scores 
(ie, change from Baseline to post-Baseline timepoint) of the two primary readers differs by >=9. 
If there are 3 readings, the analysis will use the average of the 2 closest change scores. 
As already indicated in Section 3.3, the efficacy analyses for the MRI substudy will be 
performed using two sets of study participants based on the date of the Baseline MRI relative to 
the first study medication administration: 1) all eligible substudy participants with an MRI any 
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time prior to the first study medication administration, and 2) eligible substudy participants with 
MRI performed any time from 3 weeks prior to the first dose of study drug visit up to the first 
dose of study drug visit.  
For the Week 16 visit, a time window of +/-3 weeks before or after the scheduled visit may be 
considered appropriate for mapping MRI data to the given visit. 
For the Week 52 visit, a time window of +/- 3 weeks before or after the scheduled visit may be 
considered appropriate for mapping MRI data to the given visit.  
Only study participants with non-missing Baseline and at least one post-Baseline image will be 
included in this analysis. Therefore, no MI will be performed. The analyses will be conducted on 
the observed cases.  
8.3.1.13 
Spondyloarthritis Research Consortium of Canada (SPARCC) 
sacroiliac joint (SIJ) MRI score  
The SPARCC is a scoring system for assessing the sacroiliac joint lesions based on STIR 
sequence. Each SI joint is divided into 4 quadrants (upper iliac, lower iliac, upper sacral, and 
lower sacral). The presence of increased signal on STIR in each of these 4 quadrants is scored on 
a dichotomous basis, where 1 = increased signal and 0 = normal signal. Joints that include a 
lesion exhibiting intense signal are each given an additional score of 1 per slice that 
demonstrated this feature. Similarly, each joint that included a lesion demonstrating continuous 
increased signal of depth greater than or equal to 1cm from the articular surface is also given an 
additional score of 1. The maximum score for a single coronal slice is 12. The scoring is repeated 
in each of 6 consecutive coronal slices. The total sacroiliac joint SPARCC score can range from 
0 to 72. 
Like the ASspiMRI-a (Berlin modification) score, the SPARCC score is only derived for study 
participants participating in the MRI sub-study who have both a Baseline and at least one post-
Baseline MRI. The two sets of participants to be analyzed based on the date of the Baseline MRI 
relative to the first study medication administration are as described in Section 3.3, and the rules 
for handling poor or not readable images defined in Section 8.3.1.12 also apply. If 2 independent 
readers are used, the analysis will use the average of the scores from the 2 independent 
reviewers.  
In cases where disagreement between the two readers is large, a third adjudication reviewer will 
be required. The SIJ MRI adjudication trigger will occur when the difference in change scores 
(ie, change from Baseline to post-Baseline timepoint) of the two primary readers differs by 
>=13. If there are 3 readings, the analysis will use the average of the 2 closest change scores. 
Only study participants with non-missing Baseline and post-Baseline data are included in this 
analysis. Therefore, no MI will be performed. The analyses will be conducted on the observed 
cases.  
8.3.2 
Analyses of other efficacy endpoints 
The efficacy analyses described in this section are not part of the multiplicity-controlled testing 
procedure described in Section 4.5. Other efficacy endpoints will be analyzed as summarized in 
Table 4‒1. 
For the binary variables, the following two estimand structures will be defined: 
• Composite Estimand - NRI: 
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− Population = Study participants enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP 
− Study participant-level outcome = The given variable and time point being summarized 
− Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment prior to the time point being summarized. A positive clinical outcome is 
defined as achieving the given variable at the specified time point and not having an 
intercurrent event date prior to the time point of interest.  
− Population-level summary measure = Unadjusted number and percent of responders 
Any missing data that are not preceded by an intercurrent event will be imputed based on 
NRI as well as any data after an intercurrent event, as described for the primary and 
secondary binary efficacy endpoints.  
• Modified Composite Estimand – MI: 
− Population = Study participants enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP 
− Study participant-level outcome = The given variable and time point being summarized 
− Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment due to AE or lack of efficacy, prior to the time point of interest. A composite 
strategy will be implemented in which a positive clinical outcome is defined as achieving 
the endpoint at the time point of interest and not discontinuing study treatment due to AE 
or lack of efficacy through the time point of interest. 
− Population-level summary measure = Mean proportion of responders and 95% 
confidence interval. 
An intercurrent event will be acknowledged as an unfavorable outcome for this modified 
composite estimand in considering study participants with intercurrent events as ‘non-
responders’ to the study treatment. 
Missing data that are not preceded by an intercurrent event will be imputed by standard MI 
techniques. Refer to Section 4.2.1.4 for further details.  
All binary other efficacy variables will also be summarized using OC approach as defined in 
Section 8.1.4.6. 
For all these variables, the results based on the NRI will be combined with the ones obtained on 
OC and from the MI analysis in one single table.  
In addition, a line plot by treatment group will be produced over time for some of the endpoints, 
that are part of the sequential testing procedure, based on NRI results, including the following 
binary variables: ASAS40 responder rate, ASAS40 responder rate in the TNF alpha inhibitor 
naïve study participants, ASAS20 responder rate, ASAS5/6 responder rate, ASAS-PR responder 
rate, and ASDAS-MI responder rate. 
Continuous other efficacy variables that are components of the primary endpoint will be 
analyzed using the reference-based MI estimand and procedure described in Section 8.1.4.3. 
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For the continuous and categorical other efficacy variables (not including change from Baseline 
in WPAI-SHP, ASspiMRI-a (Berlin modification) score, and SPARCC score, and EQ-5D-3L 
Utility scores), the following estimand structure will be defined: 
• Hypothetical Estimand (Section 4.2.1.7) – MI: 
− Population = Study participants enrolled according to the protocol-specified 
inclusion/exclusion criteria and randomized to IMP 
− Study participant-level outcome = The given variable and time point being summarized 
− Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
treatment prior to the time point being summarized. This estimand targets the treatment 
difference in a scenario where the intercurrent event does not occur, such that outcomes 
for study participants without an intercurrent event are as observed at the given time 
point, and outcomes for study participants with an intercurrent event are treated as though 
they had completed the randomized study treatment through the time point being 
summarized 
− Population-level summary measure = Unadjusted mean. 
The same imputation strategy for handling missing data as the one used for the secondary 
continuous efficacy endpoints as described in Section 8.2.2 will be implemented. Missing 
data for ASDAS status endpoint will also be imputed using MI, and the imputation will be 
done on the components of ASDAS-CRP prior to calculating ASDAS-CRP and categorizing 
ASDAS status. The mean proportion of responders in the multiply imputed data sets (with 
the associated 95% CI based on SE) will be displayed for each ASDAS category. 
In addition, a line plot by treatment group will be produced for some of the endpoints in the 
sequential testing hierarchy, displaying the mean change from Baseline for the following 
variables based on results obtained using MI: ASDAS-CRP, BASDAI, BASFI, Total Spinal 
Pain, Nocturnal Spinal Pain, PCS SF-36 and ASQoL. The plot will also be produced for 
ASDAS-CRP. 
All other continuous and categorical variables will be summarized using descriptive statistics for 
Baseline, absolute values and change from Baseline at each visit (except for hs-CRP endpoint for 
which ratio to Baseline will be displayed). For other continuous variables whose value at Week 
16 is part of the hierarchical testing procedure, descriptive statistics will also be provided using 
OC analysis. Categorical variables will be furthermore described using OC analysis.   
The analyses on time to ASAS20/40 response will be restricted to the Double-Blind Treatment 
Period. Each time to ASAS20/40 response will be estimated and presented using the Kaplan-
Meier product-limit method for each treatment group. The median time to response, including 
the 2-sided 95% CI, will be calculated for each treatment group. The Greenwood estimator will 
be used to estimate the variance of the survival. Comparisons of bimekizumab versus placebo 
will be analyzed using a log-rank test stratified by region and prior TNFα inhibitor exposure. The 
hazard ratio and 95% CI obtained from the Cox proportional hazards model as well as the p-
value from the log-rank test will be displayed. The time points for calculating the number at risk 
is calculated in days but expressed in weeks, with each week corresponding to 7 days. 
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8.3.3 
Additional statistical analysis of selected other efficacy variables 
Although statistical testing is not planned for other efficacy variables per protocol, statistical 
testing and inferential statistics are of interest for selected endpoints. As these tests are not part 
of the multiplicity-controlled procedure, the associated p-values are considered nominal and 
should not be used for inference. Similarly as described in Section 8.2.3, statistical tests and 
calculation of inferential statistics will be performed for the following selected other efficacy 
endpoints: 
• ASAS40 at Week 1, Week 2, Week 4, Week 8, Week 12 
• ASAS40 in the TNF alpha inhibitor-naïve study participants at Week 1, Week 2, Week 4, 
Week 8, Week 12 
• ASAS20 at Week 1, Week 2, Week 4, Week 8, Week 12 
• PGADA at Week 1, Week 2, Week 4, Week 8, Week 12, Week 16 
• Total spinal pain at Week 1, Week 2, Week 4, Week 8, Week 12, Week 16 
• Nocturnal spinal pain at Week 1, Week 2, Week 4, Week 8, Week 12 
• BASFI at Week 1, Week 2, Week 4, Week 8, Week 12  
• Mean BASDAI Q5 and Q6 score at Week 1, Week 2, Week 4, Week 8, Week 12, Week 16 
• BASDAI at Week 1, Week 2, Week 4, Week 8, Week 12,  
• BASDAI50 at Week 1, Week 2, Week 4, Week 8, Week 12, Week 16 
• CRP at Week 1, Week 2, Week 4, Week 8, Week 12, Week 16 
• ASDAS-CRP at Week 16 
• MASES at Week 16 
• Enthesitis free state at Week 16 
• TJC at Week 16 
• SJC at Week 16 
• FACIT-Fatigue at Week 16 
• WPAI at Week 16 
• ASspiMRI at Week 16 
• SPARCC at Week 16 
The same models as described in Section 8.2.3 will be run, and results will be presented in one 
single table together with the results for secondary endpoints.  
In addition, the Week 16 results from the primary analysis for the primary endpoint ASAS40, 
and key secondary endpoints in the hierarchy (ASAS20, BASDAI, BASFI, nocturnal spinal 
pain) will also be included in this table. 
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9 
PHARMACOKINETICS AND IMMUNOGENICITY 
9.1 
Pharmacokinetics  
Only study participants treated with bimekizumab will be included in the PK analyses. For the 
study participants randomized to placebo group, Baseline will be the Week 16 pre-dose sample. 
9.1.1 
Definition of ADAb Sample Status (positive, negative, missing) 
ADAb sample results will be provided as “Positive Screen” (PS) or “Negative Screen” (NS). For 
samples presenting anti-BKZ antibody levels that are PS, further confirmatory assay will be 
performed, and the result of which will be reported as either “Positive Immunodepletion” (PI) or 
“Negative Immunodepletion” (NI).  
ADAb status for each sample will be derived as following: 
• Sample values that are either NS, or PS and NI and where the BKZ concentration is less than 
the validated ADAb assay drug tolerance limit (200 μg/mL) will be defined as ADAb 
negative. 
• Sample values that are either NS, or PS and NI and where the BKZ concentration exceeds the 
validated ADAb assay drug tolerance limit will be defined as inconclusive.  
• Sample values that are PS and PI will be defined as ADAb positive (regardless of availability 
of a titer value). 
• Missing or non-evaluable samples will be defined as missing. 
PI samples will be titrated, and the ADAb titer (reciprocal dilution factor including MRD) 
reported. The PI samples will also be subject to a neutralizing assay to evaluate whether the anti-
BKZ antibody neutralizes target binding of bimekizumab (IL17AA or IL17FF or both) in-vitro 
(as described in the next section). 
9.1.2 
Definition of Cumulative ADAb Status 
The ADAb status (positive, negative or missing) will be considered in a cumulative manner at 
each time point.  
A study participant will be counted positive from the first visit at which the study participant 
achieved a positive ADAb sample result to the end of the treatment period, regardless of any 
missing/inconclusive or negative ADAb sample result.   
If a study participant has only negative ADAb samples or only one missing/inconclusive sample 
with all negative ADAb samples up to that timepoint, the study participant will be classified as 
negative. An exception remains for the Baseline Visit where only one sample could be available. 
If the sample is missing/inconclusive, then the sample will be classified as being negative for the 
cumulative ADAb status. 
Otherwise, the study participant will be classified in the missing ADAb category.  
9.1.3 
PK Sample Inclusion and Exclusion Rules 
PK samples collected at all visits except the SFU visit and meeting the following requirements 
will be included in summaries and corresponding figures. Samples not meeting the following 
requirements will be excluded from summaries and figures, and only listed: 
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• For PK samples associated with Week 2: include samples collected ≥1 week and ≤ 3 weeks 
after the first BKZ dose and before the subsequent BKZ dose. 
• For PK samples associated with Week 52 or the ET visit: include samples collected >14 days 
and <42 days after the last/previous dose received. 
• For all other visits: include samples collected >14 days after the preceding dose, <42 days 
after the preceding dose, and no later than 1 hour after the current visit dose including 
unscheduled assessments as described in Section 3.1.  
For the SFU visit, all concentrations obtained at the SFU visit will be included in the summary 
tables but will not be included in the figures. 
When multiple samples meeting the criteria above are associated with the same visit (either 
because multiple samples were collected or due to remapping or unscheduled visits), only results 
from one valid sample will be included in summaries and figures using the following rules. All 
others will be excluded and only listed: 
• For PK samples with different dates, the sample that is closest to the target visit date will be 
included.  For samples with different dates that are the same distance to the target visit date, 
the sample collected prior to IMP dosing will be included. 
• For PK samples with the same date, the first sample as provided in the raw data will be 
included. 
In addition, a PK sample could be excluded in the following situations: 
• Sample collected after the study participants received more than one dose of BKZ at a single 
visit, or multiple doses separated by a few days, 
• Sample collected after the study participants received less than a complete dose at a single 
visit, 
In each of these 2 possible scenarios, the study participants will be flagged with an appropriate 
protocol deviation, and the sample to be excluded will be identified based on the review of the 
description of the deviation. 
All excluded samples will be assigned one or more reasons for exclusion: 
• Sample collected out of window relative to current dose 
− For PK samples associated with Week 2:  includes samples collected <1 week or > 3 
weeks after the first BKZ dose.  
− For PK samples associated with visits other than week 2, 52, ET, or SFU: includes 
samples >1 hour after the current visit dose. 
• Sample collected out of window relative to previous dose 
− For PK samples associated with all visits except the Week 2 or SFU visit: includes 
samples collected <14 days or >42 days after the previous dose received. 
• More than one sample obtained at the same visit 
− Includes all samples excluded due to multiple valid samples associated with a visit. 
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• Sample collected after the study participant received more than 160 mg of study drug in 
previous 4 week period 
• Sample collected after the study participant received less than 160mg of study drug at 
previous visit  
9.1.4 
Summary of Analyses  
PK variables will be summarized by treatment group (BKZ 160 mg Q4W and Placebo / BKZ 
160 mg Q4W).  
Bimekizumab plasma concentrations will be summarized for the above treatment groups, at each 
scheduled visit at which samples were taken, using the PK-PPS analysis set and based on 
observed values. No imputation will be used for missing samples. However, if plasma 
concentration measurements are below the level of quantification (BLQ), then for calculation of 
the derived statistics, the result will be set to ½ of the lower level of quantification (LLOQ) (ie, 
1/2*0.250 = 0.125 ug/mL). Descriptive statistics including number of values, geometric mean, 
geometric mean 95% CI, geometric coefficient of variation, mean, standard deviation, median, 
minimum, and maximum if applicable will be calculated if at least 2/3 of the values of interest 
are above the LLOQ and n>=3. Otherwise, only number of values, median, minimum, and 
maximum will be presented. 
In addition, the geometric mean of bimekizumab plasma concentration (with the 95% CI) will be 
plotted versus time on linear and semi-logarithmic scales. These figures will be generated overall 
for each treatment group. 
The table summary and figures will be repeated by cumulative anti-bimekizumab antibody status 
as defined in Section 9.1.2, for the overall population. The figures will be produced separately 
for each treatment group.  
All plasma concentration data will be reported in ug/mL in the tables, figures and listings. 
Bimekizumab plasma concentrations will be listed for the SS. All concentrations will be listed as 
received prior to substitution of any BLQ values. The listing will include flags for concentrations 
that were excluded from the summary statistics and include the reason for exclusion as defined in 
Section 9.1.3.  
If more than 10% of the PK concentration results have been excluded from the table summaries, 
the PK excluded results will be listed in a separate listing. 
9.2 
Immunology (Immunogenicity) 
9.2.1 
Anti-bimekizumab antibody 
ADAb samples are analyzed when participants are on bimekizumab treatment. ADAb will be 
assessed using a three-tiered assay approach: screening assay, confirmatory assay and titration 
assay. Samples confirmed as positive within the confirmatory assay will be further evaluated for 
the presence of neutralizing anti-bimekizumab antibodies (NAb) specific to IL-17AA, IL-17FF 
or both (described in the next section). 
Screening, confirmatory and titer cut points of the respective assays will be determined by the 
bioanalytical laboratory. 
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9.2.1.1 
Definition of ADAb Sample Status (Positive, Negative, Missing) 
This will be as defined in Section 9.1.1 above. 
9.2.1.2 
Definition of Overall ADAb Status (Positive, Negative, Missing) 
A participant’s Overall ADAb Status will be derived for the following periods: 
• Overall ADAb Status in the Treatment Period: Including any visit during the treatment 
period (as defined in Section 3.2.2). Thus, this summary will exclude data obtained at the 
SFU visit and will include data obtained at Baseline. This summary will display the overall 
ADAb status up to Weeks 16, 24 and 52 by treatment group (BKZ 160 mg Q4W, Placebo / 
BKZ 160 mg Q4W). 
• Overall ADAb Status including SFU: Including any visit during the study. Thus, this 
summary will include data obtained at both the SFU visit and at Baseline. 
Study participants who rolled over to the OLE study will not have a SFU visit per study protocol. 
For these study participants, the ‘overall ADAb status including SFU’ will then be considered as 
being identical to the ‘overall ADAb status up to Week 52’. 
For each time period, the participant will be classified as: 
• Positive if the study participant has at least one positive sample up to the time point of 
interest (regardless of having missing/inconclusive data).  
• Negative if the study participant has all the samples negative or only one 
missing/inconclusive sample with negative ADAb samples up to the timepoint of interest. 
• Missing if the study participant has missed more than one ADAb result (or have more than 
one inconclusive sample) and all other available ADAb samples are negative up to the time 
point of interest.  
9.2.1.3 
Definition of ADAb Categories 
In addition, the anti-BKZ antibody status will be further classified as outlined below: 
• Pre ADAb negative – treatment emergent ADAb negative (Category 1): Includes study 
participants who are negative at Baseline and antibody negative at all sampling points 
(including SFU), one post-Baseline missing/inconclusive sample is allowed for study 
participants with pre-ADAb negative sample. This group also includes study participants 
who have a missing/inconclusive pre-treatment sample (eg, either missing/inconclusive or 
insufficient volume) at Baseline with all post-Baseline samples as ADAb negative.  
• Pre ADAb negative – treatment emergent ADAb positive (Category 2): Includes study 
participants who are ADAb negative at Baseline and ADAb positive at any sampling point 
post treatment (including SFU). This group also includes study participants who have a 
missing pre-treatment sample (either missing or insufficient volume) at Baseline with one or 
more ADAb positive post-treatment samples. 
• Pre ADAb positive – treatment emergent reduced ADAb (Category 3): Includes study 
participants who are ADAb positive at Baseline, and antibody negative at all sampling points 
post-treatment (including SFU).  
• Pre ADAb positive – treatment emergent unaffected ADAb positive (Category 4): 
Includes study participants who are positive at Baseline and are positive at any sampling 
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point post-treatment (including SFU) and all post-Baseline samples have titer values < 2.07 
times the Baseline titer (where 2.07 is Minimum Significant Ratio (MSR)) 
• Pre ADAb positive – treatment emergent ADAb boosted positive (Category 5): Includes 
study participants who are positive at Baseline and have at least one positive post-treatment 
sample (including SFU) that has titer value ≥ 2.07 times the Baseline titer (where 2.07 is 
Minimum Significant Ratio (MSR) 
Note: For any study participant who is positive at Baseline and positive at a post-Baseline 
time point, but for whom titers are not available to determine treatment unaffected or 
treatment boosted status, the study participant will be considered as treatment boosted (ie,, 
Category 5), assuming no other samples are available. 
• Inconclusive (Category 6): Includes study participants who have a positive pre-treatment 
sample and some post-treatment samples are missing/inconclusive, while other post-
treatment samples are ADAb negative. 
• Total treatment-emergent (Category 7 [Categories 2 and 5 combined]): Includes study 
participants who are pre ADAb negative – treatment emergent ADAb positive (Category 2) 
and pre ADAb positive – treatment boosted ADAb positive (Category 5).  
• Total prevalence of pre-ADAb positivity (Category 8 [Categories 3, 4, 5 and 6 
combined]): Study participants that are tested ADAb positive at Baseline. 
•  Missing (Category 9): Includes study participants who have a negative or 
missing/inconclusive pre-treatment sample at Baseline and more than one post-treatment 
samples are missing/inconclusive, while other samples are ADAb negative. Includes also 
study participants who have missing/ inconclusive pre-treatment sample at Baseline, and only 
one missing post-baseline sample with no ADAb positive. 
9.2.1.4 
ADAb status groups for Efficacy Endpoint Summaries 
For the Efficacy Endpoint by ADAb Summaries (described below), the following ADAb-
efficacy status groups will be defined: 
• ADAb positive - Defined as study participants having at least 2 ADAb positive samples up to 
the time point of interest (i.e., excluding Baseline, excluding SFU) regardless of other ADAb 
negative samples and/or missing or inconclusive samples 
• ADAb negative - Defined as study participants for whom either (1) all samples to the time 
point of interest are ADAb negative and there are no missing or inconclusive samples, (2) 
only 1 sample is ADAb positive and all other to the time point of interest (including 
Baseline) are ADAb negative or missing/inconclusive or 3) only one sample is 
missing/inconclusive and the remaining ADAb samples are negative. 
• Missing - Defined as study participants who do not fulfil the criteria for one of the 2 groups 
listed above. 
ADAb data from Baseline up to the timepoint of interest will be used to derive the ADAb-
efficacy status groups. 
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9.2.1.5 
ADAb Sample Inclusion and Exclusion Rules 
The following rules will be implemented for by-visit ADAb summaries and apply to all visits 
except Week 52, ET and SFU: 
• From Baseline through Week 24 Visit, if the ADAb sample is collected within ±14 days 
relative to the visit date at which BKZ was administered (or ±14 days from a scheduled visit 
at which BKZ dosing was not performed), the ADAb result for that sample will be associated 
with the scheduled visit and summarized accordingly.  
• After the Week 24 Visit, if the ADAb sample is collected within ±21 days relative to the visit 
date at which BKZ was administered (or ±21 days from a scheduled visit at which BKZ 
dosing was not performed), the ADAb result for that sample will be associated with the 
scheduled visit and summarized accordingly.  
• The two rules described above will include unscheduled assessments as described in 
Section 3.1 if a dose was administered at the unscheduled visit.  
Samples collected outside the relevant windows described above will be excluded from the 
ADAb by-visit summaries and will be listed only.  
For samples associated with the Week 52, ET or SFU visits, all ADAb data obtained will be 
included in the by-visit summaries.  
All other summaries of ADAb status (as described in the previous section) will use all available 
(scheduled and unscheduled) data. 
The reason for exclusion will be assigned as one or more of the following: 
• Sample collected out of window relative to current dose (or visit)  
• More than one sample obtained at the same visit 
9.2.2 
Summary of Analyses 
9.2.2.1 
Immunogenicity Summaries 
All the following analyses will be prepared on the Safety Set population by treatment group 
(BKZ 160 mg Q4W, Placebo / BKZ 160 mg Q4W), unless notified differently: 
• Summary table displaying the number and percentage of study participants with ADAb 
sample status (positive, negative, total of positive and negative, missing) at each visit, overall 
ADAb status in the treatment period, and overall ADAb status including SFU as defined 
above. If there are ≥95% of study participants included in the non-missing groups, the 
missing group will not be displayed on the table.  
• The above summary table displaying the number and percentage of study participants in each 
of the ADAb status (positive, negative, total of positive and negative, missing) will be 
repeated by region. The overall ADAb Status in the Treatment Period will be presented for 
up to and including Weeks 16, 24, 52 and SFU. 
• A summary table of the number (%) of study participants with the first occurrence of any 
ADAb positivity or treatment-emergent positivity during the study will be produced. This 
summary will include the following categories: 
− Any ADAb+: ADAb positive sample regardless of category during the treatment period 
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− Category 2: Pre ADAb negative – treatment-emergent ADAb positive 
− Category 5: Pre ADAb positive – treatment-boosted ADAb positive 
The table will summarize the number and percentage of study participants with first occurrence 
of any ADAb+ sample, and also study participants who are either treatment-emergent ADAb 
positive or treatment-boosted ADAb positive for the first time at the specified time point in the 
study and will include the cumulative number and percentage of study participants with any 
ADAb+ sample and treatment-emergent ADAb positive results at each time point. 
Treatment-emergent ADAb+ in this table will be based on ADAb category 7 (total treatment-
emergent ADAb).  
In the event that ≥ 10% of study participants are classified as category 5, the summaries will be 
further split by the following categories: 
− Category 2: Pre ADAb negative – treatment-emergent ADAb positive 
− Category 5: Pre ADAb positive – treatment-boosted ADAb positive 
• A box-plot of the ADAb titer by time of occurrence of ADAb positivity will be created for 
BKZ 160mg Q4W group, as well as for the placebo/BKZ 160mg Q4W group. The ADAb 
titer results will be presented on the log-scale. The time of occurrence is defined as the time 
in weeks from Baseline until the visit of interest when a sample is ADAb positive. Study 
participants who don’t have any positive ADAb samples post-Baseline will be excluded from 
this analysis.  
• A summary table displaying the number and percentage of study participants in each of the 9 
ADAb categories as defined above in Section 9.2.1.3 by treatment group. 
• Figure summarizing the time to achieving any ADAb positivity on a cumulative basis will be 
presented by treatment group. Similarly, figure representing the time to achieving treatment-
emergent ADAb positivity by treatment group will be plotted. Study participants will be 
considered to have an event at the time point at which an ADAb+ result (or treatment-
emergent ADAb positivity) is first achieved. Treatment-emergent ADAb+ in this plot will be 
based on ADAb category 7 (total treatment-emergent ADAb).  
In the event that >= 10% of study participants are classified as category 5, the lines will be 
further split by the following categories (thus the plot will include 3 lines per treatment 
group): 
− Category 2: Pre ADAb negative – treatment-emergent ADAb positive 
− Category 5: Pre ADAb positive – treatment-boosted ADAb positive 
9.2.2.2 
Efficacy Endpoint by ADAb Summaries 
   Several figures, tables, and listings will be created: 
• Figures will summarize efficacy response (ASAS40 and ASAS20 responders based on NRI) 
versus ADAb titer quartiles. The x-axis will display the ADAb titer quartiles at Week 16 
(categorized as negative, Q1, Q2, Q3 and Q4) and the y-axis will display percentage of 
ASAS40 (or ASAS20) responders at Week 16.  
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The plots will therefore display the percentage of ASAS40 (or ASAS20) responders as a 
function of the number of study participants within each ADAb titer categories. Study 
participants with negative ADAb results at Week 16 will be included in the ‘negative’ 
category on the x‑axis. This plot will include data from study participants only randomized to 
BKZ 160 mg Q4W.  
For each efficacy endpoint (ASAS40 and ASAS20 responders), the figure will be repeated 
using Week 24 data and then using Week 52 data, These figures will include all study study 
participants receiving BKZ and will be split by treatment group (BKZ 160 mg Q4W 
throughout, Placebo/ BKZ160 mg Q4W starting at Week 16). Thus, 2 figures per efficacy 
variable and time point will be presented.   
• Two figures will summarize efficacy response (ASAS40 responders based on NRI) over time 
for each treatment group (Placebo/BKZ 160 mg QW4 (starting at Week 16) and BKZ 
throughout) by the ADAb-efficacy status groups defined above in Section 9.2.1.4 (3 lines per 
plot). 
 
If ≥95% of study participants are included in the non-missing groups, the missing group will 
not be displayed on the figure.  
 
The first two figures will present data up to Week 24.  Two similar figures will present data 
up to Week 52. These four figures will then be repeated for the ASAS20 endpoint. For each 
figure, the ADAb-efficacy status groups will be calculated based on data up to the timepoint 
of interest.  
 
An additional figure for BKZ 160 mg Q4W group only will be generated for ASAS40 and 
ASAS20 with data up to Week 16.  
The percent of study participants in each of the ADAb-efficacy status groups considered for 
efficacy sub-group analyses will be summarized. 
• The ASAS20 and ASAS40 responder rates over time by ADAb-efficacy status groups 
defined above in Section 9.2.1.4 up to Week 16 will be presented in a tabular format with 
ASAS20 and ASAS40 results presented side by side (the analysis will be presented for BKZ 
160 mg Q4W only). The analysis will be repeated by ADAb-efficacy status groups up to 
Week 24, up to Week 52, and up to SFU Visit and presented by treatment group (BKZ 160 
mg Q4W and placebo / BKZ 160 mg Q4W).  
• Individual plots of bimekizumab concentrations, ADAb titer and ASAS40 response (based 
on NRI) will be created. All three endpoints will be plotted on the Y-axes by visit (x-axis) for 
the full treatment period, including SFU where a study participant has not progressed into the 
OLE. Plots should be labeled and grouped into the 7 pre-defined ADAb categories (described 
above in Section 9.2.1.3). For the Week 24 interim analysis, the 9 ADAb categories will be 
defined based on data up to Week 24. 
• Spaghetti plots of ADAb titer (y-axis) will be reported on the log-scale by visit (x-axis) by 
treatment group, for all study participant in the following ADAb categories: 
− Category 2: Pre ADAb negative – treatment-emergent ADAb positive 
− Category 5: Pre ADAb positive – treatment-boosted ADAb positive  
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Plots will be presented using a semi-logarithmic scale for the ADAb titers (ADAb negative 
samples will therefore be excluded from the plot). 
• All individual study participant-level ADAb results will be listed including the screening 
assay, confirmatory assay, ADAb sample status and titers if applicable. Note, that titer results 
will only be available if the confirmatory assay is positive. The listing will also include flags 
and reasons for exclusion for ADAb measurements that were excluded from the by-visit 
summaries, as well as information on whether the BKZ concentration exceed the ADAb 
assay drug tolerance limit.  
• Finally, if more than 10% of the ADAb results have been excluded from the table summaries, 
the ADAb excluded results will be listed in the same listing as the one mentioned in 
Section 9.1.4 for excluded PK results.  
9.2.3 
Neutralizing anti-bimekizumab antibodies 
NAb will be assessed using IL-17AA- and IL-17FF-specific assay methods, respectively. NAb 
results will be positive or negative to each specific NAb assay or both.  
Any NAb results derived from samples with drug concentrations higher than the drug tolerance 
limits of the NAb assays (100μg/mL) will be labeled 'inconclusive'. All inconclusive results will 
be regarded as missing. 
Participants will be assigned an overall NAb classification, inclusive of Baseline and post-
Baseline results from NAb assay: 
• NAb negative: No NAb positive samples for IL-17AA and IL-17FF at Baseline or post-
Baseline. This group will also include study participants who have only 1 missing sample 
and all other available samples during the period of interest are negative. Study participants 
who are NAb negative will be further classified as follows: 
− ADAb positive / NAb negative: ADAb positive study participants who are 1) NAb 
negative for all available ADAb positive samples or 2) with only one missing NAb 
sample and all other evaluated ADAb positive samples are NAb negative. 
− ADAb negative: if the study participant has all the samples as ADAb negative or only 
one missing/inconclusive sample with all other available samples as negative ADAb. 
Note that ADAb negative samples are not participants to the neutralizing assay. 
• NAb positive: One or more positive samples (IL-17AA positive, IL-17FF positive, or both) 
at Baseline or post-Baseline (regardless of missing samples) Study participants who are NAb 
positive will be further classified as follows: 
− Positive for IL-17AA only: one or more positive samples for IL-17AA at Baseline or 
post-Baseline. No positive samples for IL-17FF 
− Positive for IL-17FF only: one or more positive samples for IL-17 FF at Baseline or post-
Baseline. No positive samples for IL-17AA 
− Positive for both IL-17AA and IL-17FF: one or more positive samples for both IL-17AA 
and IL-17FF at Baseline or post-Baseline 
Drug tolerance limit for both the IL-17AA-specific NAb method and the IL-17FF-
specific NAb method is 100 μg/mL. 
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• NAb Missing: more than one relevant NAb samples are missing/inconclusive and other 
available NAb samples during the period of interest are negative, eg, missing or insufficient 
sample left for NAb testing. 
Summary tables and a data listing will be produced to summarize the NAb status overall in the 
study. 
The listing will be sorted by treatment group, participant identifier, and visit and, will summarize 
the following information for each participant assessed for NAbs: 
− Visit 
− Study week since first bimekizumab dose 
− laboratory sampling date and time 
− Time since previous dose (weeks) 
− The corresponding bimekizumab plasma concentration level at each visit (ug/mL) 
− Anti-bimekizumab anti-body titer at each visit 
− IL-17AA NAb status and corresponding IL-17AA signal/negative control result 
− IL-17FF NAb status and corresponding IL-17FF signal/negative control result 
The table will provide the following overall summary statistics by treatment group (based on the 
total number of participants): 
• The number and percentage of participants confirmed as anti-bimekizumab antibody positive 
and anti-bimekizumab antibody negative at any visit.  
• Number and percentage of participants who are NAb positive, NAb negative and missing at 
any visit.  
The NAb summary table will be repeated with percentages calculated on a denominator based on 
the number of ADAb positive participants at any visit in the study.  
The table summaries will display the overall NAb categories derived based on data from 
Baseline up to Weeks 16, 24, 52 and SFU by dose group (BKZ 160 mg Q4W and placebo / BKZ 
160 mg Q4W). 
For the analysis of NAb effect on pharmacokinetics, efficacy and safety of bimekizumab, the 
data from AS0011 may be pooled with other phase 3 studies for an integrated analysis and may 
be reported elsewhere. 
10 
SAFETY ANALYSES 
Safety variables will be analyzed on the SS, as well as on the MS for analyses covering the 
Maintenance Period (MP) only. 
Summaries for the MP will also include the SFU period for study participants that do not roll 
enter the OLE or discontinue early in the MP. The SFU period for study participants that 
discontinue in the DBTP will only be summarized in the Overall Period tables. 
10.1 
Extent of exposure 
Two summary tables will be created to describe the extent of exposure.  
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The first table consists of a descriptive summary of study medication duration (in days), total 
study medication duration in (subject-years), and total time at risk (in subject-years). The 
information will be presented overall (ie, for the entire treatment period (Double-Blind 
Treatment Period (DBTP) and Maintenance Period (MP) combined)) as well as by treatment 
periods.  
Study medication duration in subject-years is obtained as study medication in days divided by 
365.25. Similarly, total time at risk in subject-years is obtained as total time at risk in days 
divided by 365.25. 
A second summary will be created on the cumulative study medication duration for the overall 
period, as well as by treatment periods.  
• The following time durations categories will be considered for the overall period: >=0 weeks, 
>=16 weeks, >=24 weeks, >=48 weeks.  
• The following time durations categories will be considered for the Double-Blind Treatment 
Period:>=0 weeks, >=4 weeks, >=8 weeks, >=12 weeks.  
• The following time durations categories will be considered for the Maintenance Period:>=0 
weeks, >=16 weeks, >=24 weeks, >=36 weeks. 
A by-study participant listing of date of first and last dose and the duration of exposure will be 
performed. 
The study medication duration (in days) and the time at risk (in days) are defined depending on 
the study period of interest. See Section 10.1.1 to Section 10.1.5 for further details.  
Throughout this section, date of last clinical contact for each study participant is defined as the 
maximum of [last visit date including SFU visit, last AE start date (including imputed AE start 
dates), date of study termination or completion, last date of study drug administration]. 
10.1.1 
Duration of exposure and time at risk in the Double-Blind Treatment 
Period (DBTP) 
• The study medication duration during the DBTP will be calculated as follows: 
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) + 28 
(this formula also applies for study participants who discontinue/lost to follow-up during the 
DBTP). 
− If the date of last dose of the DBTP + 28 days extends to a date beyond the date of first 
dose of the Maintenance period, then this calculation reverts to:  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) + 1 
Note: If the date of last dose + 28 extends to a date beyond the final visit date (not including 
SFU), then this calculation reverts to:   
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡 (𝑛𝑜𝑡 𝑖𝑛𝑐𝑙𝑢𝑑𝑖𝑛𝑔 𝑆𝐹𝑈) − 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 + 1 
− For study participants who die during the DBTP, this calculation reverts to: 
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) + 1 
• The time at risk during the DBTP will be calculated as follows: 
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− For study participants who complete the final visit of the DBTP and continue to the 
Maintenance Period:  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) + 1 
− For study participants who discontinue on or prior to the final visit of the DBTP (ie, 
Week 16), use the minimum of the following:  
o Total number of days in the DBTP: 
▪ For those that discontinue prior to the Week 16 visit, use 112 days,  
▪ For those that discontinue at the Week 16 visit, use the total number of days 
based on Week 16 visit date, which can be a maximum of 115 days due to 
visit windows 
o 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑐𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝑐𝑜𝑛𝑡𝑎𝑐𝑡− 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) + 1, last clinical 
contact can be defined as last scheduled site visit. 
− For study participants who die during the DBTP, then this calculation reverts to:  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) + 1 
10.1.2 
Duration of exposure and time at risk in the Maintenance Period 
• The study medication duration during the Maintenance Period will be calculated as follows: 
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) + 28 
− If date of last dose in the Maintenance Period + 28 days extends to a date beyond the final 
visit date of the Maintenance Period (not including SFU), then this calculation reverts to:  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡 (𝑀𝑃−𝑛𝑜𝑡 𝑖𝑛𝑐𝑙𝑢𝑑𝑖𝑛𝑔 𝑆𝐹𝑈) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) + 1 
− For study participants who die during the Maintenance Period, then this calculation 
reverts to: 
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) + 1 
− For study participants who discontinue/lost to follow-up during the Maintenance Period, 
then this calculation reverts to: 
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) + 28 
• The time at risk during the Maintenance Period will be calculated as follows: 
− For study participants who complete the Maintenance Period as planned and continue 
into an open-label study (and, therefore, do not have the SFU visit in the feeder study):  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡 (𝑀𝑃) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) + 1 
− For study participants who die during the Maintenance Period, then this calculation 
reverts to:  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) + 1 
− For all other study participants, use the minimum of the following:  
o 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) − 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) + 140 + 1 
o 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑐𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝑐𝑜𝑛𝑡𝑎𝑐𝑡− 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) + 1 
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This last group could include study participants who discontinue the Maintenance Period 
early, study participants who complete the Maintenance Period as scheduled but choose not 
to continue into an open-label study, or study participants who are ongoing in the SFU period 
at the time of the interim data snapshot. 
Note that the Week 24 visit (ie, Visit 10) will be the last visit for the Week 24 interim analysis, 
and that the Week 52 visit (ie, Visit 17) will be the last visit for the Week 52 interim analysis. 
10.1.3 
Duration of exposure and time at risk in the combined Double-Blind 
Treatment and Maintenance Periods 
• The study medication duration during the combined treatment period will be calculated as 
follows: 
− For study participants who do not switch study treatments per study design: 
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒+ 28 
o If the date of last dose + 28 days extends to a date beyond the date of the final 
visit date (not including SFU), then this calculation reverts to:  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡 (𝑛𝑜𝑡 𝑖𝑛𝑐𝑙𝑢𝑑𝑖𝑛𝑔 𝑆𝐹𝑈) − 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 + 1 
o For study participants who die, then this calculation reverts to: 
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒+ 1 
− For study participants who switch study treatments per study design (ie, study 
participants initially randomized to placebo who are re-allocated to bimekizumab 
treatment): 
o During the DBTP (attributed to initially randomized treatment): 
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) + 28 
Note: If date of last dose in the Initial Period + 28 days extends to a date beyond the 
date of first dose in the Maintenance Period, then this calculation reverts to:  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝐵𝑇𝑃) + 1 
o During the Maintenance Period (attributed to the treatment initiated in the 
Maintenance Period), the study medication duration algorithm specified for the 
Maintenance Period in Section 10.1.2 applies.  
• Definitions for time at risk during the combined treatment period will be calculated as 
follows: 
− For study participants who do not switch study treatments per study design: 
o For study participants who complete the Maintenance Period as planned and 
continue into an open-label study (and, therefore, do not have the SFU visit in the 
feeder study):  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒+ 1 
o For study participants who die prior to the final visit:  
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒+ 1 
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o For all other study participants, use the minimum of the following:  
▪ 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒− 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒+ 140 + 1  
▪ 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑐𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝑐𝑜𝑛𝑡𝑎𝑐𝑡− 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 + 1 
This last group could include study participants who discontinue early, study 
participants who complete the Maintenance Period as scheduled but choose not to 
continue into an open-label study, or study participants who are ongoing in the SFU 
period at the time of the data snapshot. 
− For study participants who switch study treatments per study design: 
o During the DBTP (attributed to initially randomized treatment): 
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝑀𝑃) −1 −𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 (𝐷𝑃𝑇𝐵) + 1 
This assumes that any study participant in this category has completed the DBTP and 
doses [with a new study treatment] in the Maintenance Period. 
o During the Maintenance Period (attributed to the treatment initiated in the 
Maintenance Period), the time at risk algorithm specified for the Maintenance 
Period in Section 10.1.2 applies.  
Note that the Week 24 visit (ie, Visit 10) will be the last visit for the Week 24 interim analysis, 
and Week 52 visit (ie, Visit 17) will be the last visit for the Week 52 interim analysis. 
In addition, Week 20 visit will correspond to the last dose of the Week 24 interim analysis. and 
the Week 48 visit will correspond to the last dose of the Week 52 interim analysis. 
10.1.4 
Duration of exposure by COVID-19 pandemic period  
• If the pandemic end date is known, then the study medication exposure duration will be 
calculated as follows: 
𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑑𝑎𝑡𝑒 𝑜𝑛 𝑜𝑟 𝑎𝑓𝑡𝑒𝑟 𝑝𝑎𝑛𝑑𝑒𝑚𝑖𝑐 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒 –  𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒  
𝑜𝑛 𝑜𝑟 𝑏𝑒𝑓𝑜𝑟𝑒 𝑝𝑎𝑛𝑑𝑒𝑚𝑖𝑐 𝑒𝑛𝑑 𝑑𝑎𝑡𝑒 +  28 
• If the pandemic end date is unknown, then the study medication exposure duration will be 
calculated as follows: 
– If the first exposure date is on or after the pandemic start date, then:  
o For study participants who did not die:  
date of last exposure - date of first BKZ dose + 28 
Note: If the last exposure date + 28 extends to a date beyond the final visit date (not 
including SFU), then this calculation reverts to:   
date of last visit (not including SFU) – date of first BKZ dose +1 
o For study participants who die on or after the pandemic start date:  
date of death - date of first BKZ dose + 1 
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– If the first exposure date is before the pandemic start date and the study drug period is 
overlapping with the pandemic (ie, the study participant started or ended the treatment 
during the pandemic) then: 
o For study participants who did not die:  
date of last exposure - 11Mar2020 + 28 
Note: If the last exposure date + 28 extends to a date beyond the final visit date (not 
including SFU), then this calculation reverts to:   
date of last visit (not including SFU) – 11Mar2020 +1 
o For study participants who die:  
date of death - 11Mar2020 + 1 
10.1.5 
Time at risk in subject-years by COVID-19 pandemic period  
In this section, “study drug” refers to BKZ treatment.  
10.1.5.1 
Time at risk in the pre-COVID-19 pandemic period 
Only study participants starting study drug during the “pre-COVID-19 pandemic period” will 
have a time at risk calculated during that period. The following rules will be applied: 
• For study participants who did not discontinue medication in the “pre-COVID-19 pandemic 
period” (ie, for study participants with date of last dose of study drug on or after 
11Mar2020): 
10Mar2020 – date of first dose + 1 
• For study participants who have died on or before 10Mar2020: 
date of death – date of first dose + 1 
Note: If the date of death is later than 140 days following the last dose of BKZ, this rule does not 
apply, and the duration of exposure will follow the rule below.  
• For study participants who discontinued medication in the “pre-COVID-19 pandemic period” 
(ie, for study participants with date of last dose of study drug before 11Mar2020): 
− If the earliest date between (date of last dose + 140) and (date of last clinical contact) is 
on or after 11Mar2020, then:  
10Mar2020 – date of first dose + 1 
− If the earliest date between (date of last dose + 140) and (date of last clinical contact) is 
before 11Mar2020, then use the minimum of:  
o date of last dose + 140 – date of first dose +1 
o date of last clinical contact – date of first dose +1 
10.1.5.2 
Time at risk in the COVID-19 pandemic period 
This period is applicable for all study participants in the SS who are still considered at risk on the 
11MAR2020 (ie, those who have their first dose is on or after 11MAR2020, or for those for 
whom either dosing is continuing, or for whom the 140 day SFU period after last dose has not 
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been completed [in the case of premature treatment discontinuation or for those who do not roll 
over to the OLE]). The following rules will be applied: 
• For study participants who started IMP prior to 11MAR2020 and did not discontinue 
medication in the “during COVID-19 pandemic period” (ie, for study participants with the 
last dose of BKZ 160mg is on or after the date of the end of the pandemic +1): 
date of the end of pandemic – 11Mar2020 + 1 
• For study participants who started IMP on or after 11MAR2020 and did not discontinue 
medication in the “during COVID-19 pandemic period” (ie, for study participants with the 
last dose of BKZ 160mg is on or after the date of the end of the pandemic +1): 
date of the end of pandemic – date of first dose + 1 
• For study participants who have died on or after 11Mar2020, and on or before the pandemic 
end date: 
date of death – maximum (11MAR2020, date of first dose) + 1 
Note: If the date of death is later than 140 days following the last dose of BKZ, this rule does 
not apply. 
• For study participants who discontinued medication: 
− in the “pre-COVID-19 pandemic period” (ie, for study participants with date of last dose 
of study drug before 11Mar2020), and if the earliest date between (date of last dose + 
140) and (date of last clinical contact) is on or after 11Mar2020, then use minimum 
between:  
o date of last dose + 140 – 11Mar2020 +1 
o date of last clinical contact – 11Mar2020 + 1 
− in the “during COVID-19 pandemic period” (ie, for study participants with date of last 
dose of study drug on or after 11Mar2020, and on or before the pandemic end date),  
o For study participants who started IMP prior to 11MAR2020, and if the earliest date 
between (date of last dose + 140) and (date of last clinical contact) is after the end of 
pandemic, then use:  
date of end of pandemic – 11MAR2020 + 1 
o For study participants who started IMP on or after 11MAR2020, and if the earliest 
date between (date of last dose + 140) and (date of last clinical contact) is after the 
end of pandemic, then use:  
date of end of pandemic – date of first dose + 1 
o Else time at risk will be calculated as minimum between: 
▪ date of last dose date + 140 – maximum (11MAR2020, date of first dose) + 1 
▪ date of last clinical contact – maximum (11MAR2020, date of first dose) + 1 
10.1.5.3 
Time at risk in the post-COVID-19 pandemic period 
This period is applicable for all study participants in the SS who are still considered at risk on the 
day after the end date of the pandemic (ie, those for whom either dosing is continuing or for 
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whom the 140 day SFU period after last dose has not been completed [in the case of premature 
treatment discontinuation or for those who do not roll over to the OLE]). The following rules 
will be applied: 
• For study participants who did not discontinue medication in the “during COVID-19 
pandemic period” (ie, for study participants with date of last dose of study drug after the 
pandemic period end date), then use minimum between: 
− date of last dose + 140 – date of the end of pandemic  
− date of last clinical contact – date of the end of pandemic  
• For study participants who have died after the pandemic end date: 
date of death – date of the end of pandemic  
Note: If the date of death is later than 140 days following the last dose of BKZ, this rule does 
not apply. 
• For study participants who discontinued medication in the “during COVID-19 pandemic 
period” (ie, for study participants with date of last dose of study drug on or before the 
pandemic period end date), and if the earliest date between (date of last dose + 140) and (date 
of last clinical contact) is after the pandemic period end date, then use minimum between:  
− date of last dose + 140 – date of the end of pandemic  
− date of last clinical contact – date of the end of pandemic  
To assess the impact of the COVID-19 pandemic, the study medication duration and time at risk 
will be reported by COVID-19 pandemic period. 
10.2 
Adverse events 
Adverse events with start date prior to first administration of study medication are defined as 
pre-treatment AEs. No summaries of these events will typically be produced although they will 
be included in listings.   
Adverse events that started more than 140 days after the last administration of study medication 
are defined as post-treatment AEs. Such events will not be included in any tabulated summaries 
but will be listed. 
Treatment-emergent AEs (TEAEs) are defined as those AEs that have a start date on or 
following the first dose of study treatment through the final dose of study treatment + 140 days 
(covering the 20-week SFU period). 
All summaries will be provided by treatment group. The treatment group for each study 
participant will be defined as the treatment received at the onset of the AE. If the onset of the AE 
occurs on the day where the study participant switches treatment from the Double-Blind 
Treatment Period to the Maintenance Period and receives a new treatment, it will be attributed to 
the originally randomized study treatment. The only exception to this is if the AE fulfills the 
criteria for an anaphylactic reaction. See Section 3.7 for further details. 
AEs will be presented as “number of study participants (percentage of study participants) 
[number of events]”. In this style of output, “[number of events]” will include all cases of an AE 
including repeat occurrences in individual study participants, while “number of study 
participants” will count each study participant only once. 
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Adverse event summaries by SOC, HLT and PT will be ordered alphabetically for SOC and HLT 
within SOC and in terms of decreasing frequency for PT within HLT in the bimekizumab 
treatment group and then similarly by decreasing frequency in the placebo group. 
AE summaries by PT will be ordered in terms of decreasing frequency for PT within the 
bimekizumab treatment group, and in the event of ties, PT will be sorted alphabetically.  
Study participant time at risk represents the time a study participant is at risk for having an AE. 
The definitions for study participant time at risk (in days) are outlined in Section 10.1. These 
definitions will be used for exposure-adjusted AE summaries. 
Selected AE summaries will include the exposure adjusted incidence rate (EAIR) with associated 
95% confidence interval and the exposure adjusted event rate (EAER). 
The EAIR is defined as the number of study participants (k) with a specific AE adjusted for the 
exposure and will be scaled to 100 subject-years: 
EAIR = 100 ×
𝑘
∑
(𝑇𝐸𝑥𝑝(𝑖))
𝑛
𝑖=1
 
where n is the total number of study participants in the respective treatment group, and TExp(i) is 
the time of exposure for each study participant defined as:  
• For study participants with the specific AE of interest: years since first dose of the study 
treatment to the first occurrence for the AE of interest at the level of coding evaluated (see 
Section 10.1) 
• For study participants without the AE: the time at risk in years (see Section 10.1)  
Exact Poisson 95% confidence intervals for incidence rates are calculated using the relationship 
between the Poisson and the Chi-square distribution (Ulm, 1990; Fay and Feuer, 1997): 
𝐿𝐶𝐿=
𝜒2𝑛,𝛼/2
2
2
 
𝑈𝐶𝐿=
𝜒2(𝑛+1),1− 𝛼/2
2
2
 
where n is the number of study participants with a specific AE for the incidence rate of interest 
and is the basis for the number of the degrees of freedom for the chi-square quantile for the upper 
tail probability χ2. 
The EAER will be the number of AEs including repeat occurrences in individual study 
participants divided by the total time at risk scaled to 100 subject-years and calculated using: 
EAER = 100 ×
𝑁𝐴𝐸
∑
(𝑇𝑅𝑖𝑠𝑘(𝑖))
𝑛
𝑖=1
 
where 𝑁𝐴𝐸 is the total number of AEs, n is the total number of study participants and TRisk(i) is the 
time at risk in years for each study participant.  
No confidence interval will be computed for EAER. 
In the following sections, all tables based on “100 subject-years” will include EAIR (with 95% 
confidence interval) and EAER.  
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As previously indicated in Table 4‒3, the AE summary tables described in Section 10.2.1 and 
Section 10.2.2 will be presented: 
• on the SS for the overall period, presenting the BKZ 160 mg Total treatment column only.  
• on the SS for the Double-Blind Treatment Period for the Week 24 interim analysis only, 
presenting the Placebo and BKZ 160mg treatment columns.  
• and on the MS for the Maintenance Period for the Week 52 interim analysis only, presenting 
the BKZ 160 mg Total treatment column only.  
10.2.1 
Standard AE summaries  
The following tabular summaries will be produced: 
• Incidence of TEAEs – Overview. 
• Incidence of TEAEs per 100 subject-years by SOC, HLT, and PT. 
• Incidence of Serious TEAEs per 100 subject-years by SOC, HLT, and PT. 
• Incidence of TEAEs Leading to Study Discontinuation per 100 subject-years by SOC, HLT, 
and PT. 
• Incidence of TEAEs Leading to Study Drug Discontinuation per 100 subject-years by SOC, 
HLT, and PT  
• Incidence of TEAEs Leading to Death by SOC, HLT, and PT. 
• Incidence of TEAEs by Relationship by SOC, HLT, and PT. 
• Incidence of TEAEs by Intensity, SOC, HLT, and PT. 
• Incidence of TEAEs by decreasing frequency of PT. 
• Incidence of TEAEs Above Reporting Threshold of 5% by SOC and PT. 
• Incidence of Non-Serious TEAEs Above Reporting Threshold of 5% by Relationship SOC 
and PT. 
• Incidence of Related TEAES by SOC, HLT, and PT 
• Incidence of Related TEAES Above Reporting Threshold of 5% by SOC and PT. 
• Incidence of TEAEs per 100 subject-years by SOC, HLT, and PT and by Time of Onset 
Relative to Anti-bimekizumab Antibody Status. The table will include columns for the 
following: 
− TEAEs starting before the first ADAb positive result (includes ADAb Categories 2 and 
5) where TEAEs have occurred before the following events: 
 a) the first positive ADAb result for study participants in category 2 and 
 b) the first post-Baseline boosted ADAb titer result for study participants with titer 
results or the first post-Baseline positive ADAb result for study participants with 
positive ADAb at Baseline with no other samples with titer available for study 
participants in category 5. 
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− TEAEs starting on the same date or after the first ADAb positive result (includes ADAb 
Categories 2, 3, 4, 5 and 6) where TEAEs have occurred on or after the following events:  
a) the first positive ADAb results for study participants in categories 2, 3, 4 and 6, 
and  
b) the first post-Baseline boosted ADAb titer result for study participants with titer 
results and the first post-Baseline positive ADAb result for study participants with 
positive ADAb at Baseline with no other samples with titer available for study 
participants in category 5. 
− TEAEs for study participants who are ADAb negative at all time points (includes ADAb 
Category 1). 
Note: For TEAE by onset relative to ADAb positivity status, all available ADAb data at the 
time of IA cut-off will be utilized to derive the study participant-level ADAb status 
categories. 
The following summary tables will be produced to support results disclosure activities 
• Incidence of Serious TEAEs by Relationship SOC, HLT, and PT  
• Incidence of TEAEs Leading to Death by Relationship by SOC, HLT, and PT  
• Incidence of Non-Serious TEAEs Above Reporting Threshold of 5% (in any treatment 
group, and in any study period) by SOC and PT 
By-study participant listings on all AEs and all deaths will be provided on the enrolled set. 
Serious AEs and AEs leading to study discontinuation will also be listed on the safety set. AEs 
occurring on the day of first study drug administration will also be listed on the randomized set. 
For study participants randomized to Placebo, this will include AEs occurring at first 
administration of Bimekizumab at Week 16. A glossary listing will also be created for all 
TEAEs.  
10.2.2 
Other safety topics of interest summaries  
The safety topics of interest (or AEs with special monitoring) for the bimekizumab program are: 
• Infections (serious, fungal, opportunistic and tuberculosis) 
• Malignancies  
• Major adverse cardiac events (MACE)  
• Neutropenia 
• Suicidal Ideation and Behavior 
• Inflammatory bowel disease 
• Hypersensitivity (including anaphylactic reactions) 
• Hepatic events and drug-induced liver injury (DILI)  
The analyses produced for the TEAE of special monitoring are based on the specifications 
described in the Bimekizumab safety topic of interest document version from 26-Mar-2020. 
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Separate tables will be created to summarize each of the above AEs (except when notified) per 
100 subject-years by system organ class, high level term, and PT.  
Infections 
The summary table for fungal infection will include all TEAEs (serious and non-serious) which 
code to the High Level Group Term “Fungal infectious disorders”.  
Opportunistic infections (including tuberculosis) will be summarized in a stand-alone table and 
will include all opportunistic infection TEAEs identified as per the UCB-defined search criteria 
which were adjudicated as opportunistic infections (refer to Appendix 2 for further details on the 
process for identifying opportunistic infections).  
No dedicated table will be produced for serious infections, as there will be identified based on 
MedDRA classification (SOC “Infections and infestations”) using the “Any SAE” table specified 
in Section 10.2.1.  
Fungal infections and opportunistic infections will be listed separately.  
Malignancies 
Two tables will be created on malignancies:  
• one table will display all events in the criteria standardized MedDRA Query (SMQ)= 
“Malignant or unspecified tumors (SMQ)”,  
• and another table will display all events in the criteria SMQ= “Malignant tumors (SMQ)”. 
The SMQ search will include all TEAEs which code to a PT included in the Scope=Narrow 
group within each SMQ. 
The output tables will include two different overall incidence rows: 
• The first overall incidence row will summarize “Any Malignancy” and this row will 
summarize the incidence of all AEs flagged for inclusion in the table (using the appropriate 
SMQ depending on the table), regardless of the HLT it codes to.  
• The second overall incidence row will summarize “Any Malignancy excluding non 
melanomic skin cancers HLT” and this row will summarize the incidence of AEs flagged for 
inclusion in the table (using the appropriate SMQ depending on the table), excluding those 
which code to an HLT of “skin neoplasms malignant and unspecified (excl melanoma)”.  
All malignancy events will be listed.  
Cardiac events 
The table on cardiac events will summarize events considered as MACE by the external 
cardiovascular event adjudication committee.  
Extended MACE events will be presented in a separate table and listing. All events which are 
classified by the adjudication committee as any of the following events types will be considered 
an extended MACE event:  
• Non-Fatal Myocardial Infarction (MI)  
• Non-Fatal Stroke: hemorrhagic  
• Non-Fatal Stroke: ischemic 
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• Non-Fatal Stroke: embolic  
• Non-Fatal Stroke: undeterminable 
• Hospitalization or ER for Unstable Angina with urgent revascularization 
• Hospitalization for Heart Failure 
• Coronary Revascularization Procedures (eg, percutaneous coronary intervention, coronary 
artery bypass grafting)  
• Urgent Revascularization Procedures (ie, due to symptoms of brain ischemia or pending 
infarction) 
• Death due to Myocardial Infarction (MI 
• Death due to Stroke 
• Sudden Cardiac Death 
• Other CV Death (eg, heart failure, pulmonary embolism, cardiovascular procedure-related) 
• Cardiovascular: Undetermined Cause of Death (ie, cause of death unknown) 
A separate table and listing will present the adjudicated cardiovascular events by type. For each 
cardiovascular event type (24 total), the individual PTs which fall within each event type will be 
summarized.  
Additionally, a listing of all events identified for potential review by the cardiovascular event 
adjudication committee will be produced. This listing will indicate whether each event was 
escalated to the committee for formal review/adjudication.  
Neutropenia 
The table on neutropenia will be based on the following PTs (regardless of seriousness): 
• Autoimmune neutropenia 
• Band neutrophil count decreased 
• Cyclic neutropenia 
• Febrile neutropenia 
• Idiopathic neutropenia 
• Neutropenia 
• Neutropenic infection 
• Neutropenic sepsis 
• Neutrophil count decreased 
All neutropenia events will be listed. 
Suicidal Ideation and Behavior 
An external neuropsychiatric adjudication committee will evaluate potential neuropsychiatric 
events and determine whether any of those events were associated with suicidal ideation and 
behavior (SIB). If an event is adjudicated as SIB, further information will be provided. A table 
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and a listing for SIB events as determined by the adjudication committee will be produced as 
well as a listing for all events escalated to the committee but which were not adjudicated as a SIB 
event. 
A separate table will present the adjudicated neuropsychiatric events by type. For each 
neuropsychiatric event type (6 total), the individual PTs which fall within each event type will be 
summarized. It will include events adjudicated as SIB and events adjudicated as non-suicidal. 
Note that the event type Suicidal ideation can be classified as either SIB or non-suicidal. 
Additionally, a listing of all events identified for potential review by the neuropsychiatric 
adjudication committee will be produced. This listing will indicate whether each event was 
escalated to the committee for formal review/adjudication.  
Inflammatory bowel disease 
An external inflammatory bowel disease (IBD) adjudication committee will evaluate potential 
IBD events and will classify each one as follows: 
• Event Type Code 1: Possible IBD – Crohn’s Disease 
• Event Type Code 2: Probable IBD – Crohn’s Disease 
• Event Type Code 3: Definite IBD – Crohn’s Disease 
• Event Type Code 4: Possible IBD – Ulcerative Colitis 
• Event Type Code 5: Probable IBD – Ulcerative Colitis 
• Event Type Code 6: Definite IBD – Ulcerative Colitis 
• Event Type Code 7: Possible IBD – Unclassified 
• Event Type Code 8: Probable IBD – Unclassified 
• Event Type Code 9: Definite IBD – Unclassified 
• Event Type Code 10: Symptoms not consistent with IBD 
• Event Type Code 11: Possible Inflammatory Bowel Disease - Microscopic Colitis 
• Event Type Code 12: Probable Inflammatory Bowel Disease - Microscopic Colitis 
• Event Type Code 13: Definite Inflammatory Bowel Disease - Microscopic Colitis 
• Event Type Code 14: Possible Inflammatory Bowel Disease – no further differentiation 
possible 
• Event Type Code 15: Probable Inflammatory Bowel Disease – no further differentiation 
possible 
• Event Type Code 16: Definite Inflammatory Bowel Disease – no further differentiation 
possible 
• Event Type Code 99: Not enough information to adjudicate 
A table for adjudicated definite IBD events (event type codes 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 
14, 15 and 16) as determined by the adjudication committee will be produced. It will summarize 
events determined by the adjudication committee as definite IBD (event type codes 3, 6, 9, 13, 
and 16), probable IBD (event type codes 2, 5, 8, 12, and 15) and possible IBD (event type codes 
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1, 4, 7, 11, and 14). Definite and probable IBD will also be aggregated and summarized. This 
table will be stratified by study participants with or without a previous medical history of IBD. 
Previous medical history of IBD will be determined using the information recorded on the Extra-
Articular Assessment at Screening CRF page (“Does subject have a history of IBD”). 
A separate table will present the adjudicated gastrointestinal events by type. For each 
gastrointestinal event type (17 total), the individual PTs which fall within each event type will be 
summarized. It will include events determined by the adjudication committee as definite IBD 
probable IBD and possible IBD. It will also include events determined as Symptoms not 
consistent with IBD (event type code 10) and Not enough information to adjudicated (event type 
code 99). 
A listing of all events identified for potential review by the IBD adjudication committee will be 
produced. This listing will indicate whether each event was escalated to the committee for formal 
review/adjudication.  
A separate table and listing will present the adjudicated IBD events by type. For each IBD event 
type (event type codes 1 through 16 and 99; 17 total), the individual PTs which fall within each 
event type will be listed. 
A third listing will present the individual diagnostic criteria met for each adjudicated IBD event. 
Hypersensitivity (including anaphylactic reactions)  
The MedDRA anaphylaxis Algorithm described in Appendix 1 will be used to summarize acute 
anaphylactic events (reported on the same day as when an injection was administered or one day 
after). An AE glossary table will also be produced to summarize the MedDRA coding for these 
events. The glossary table will include the following fields: reported term, PT, LLT, HLT, and 
SOC.  
A separate table will be prepared to summarize hypersensitivity events, identified using the SMQ 
“Hypersensitivity (SMQ)”. All TEAEs which code to a PT included in the Scope=Narrow search 
will be included in this table. The analysis will be repeated for serious hypersensitivity reactions. 
An AE glossary table will also be produced to summarize the MedDRA coding for these events. 
The glossary table will include the following fields: reported term, PT, LLT, HLT, and SOC. 
No separate table will be needed for injection site reactions that will be evaluated based on the 
table on any TEAE by looking under the HLTs “Administration site reactions NEC” and 
“Injection site reactions”. 
Separate listings will be created for anaphylaxis and hypersensitivity events.  
An additional analysis will report the serious hypersensitivity events.  
Hepatic events and drug induced liver injury 
The table on hepatic events will be created based on the SMQ of “Drug related hepatic disorders 
- comprehensive search (SMQ)” excluding the two sub-SMQs “Liver neoplasms, benign (incl 
cysts and polyps) (SMQ)” and “Liver neoplasms, malignant and unspecified (SMQ)”. The SMQ 
search should include all events which code to a PT included in the Scope=Broad and/or 
Scope=Narrow, regardless of whether they have been judged as related to study medication or 
not by the investigator. Hy’s Law cases will be reported separately in a liver function test table 
(see Section 10.3) 
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Hepatic events (including DILI) will also be listed.  
Finally, the incidence of each safety topics of interest occurring in the Double-Blind Treatment 
Period will be reported in one summary table. The risk difference (bimekizumab minus placebo) 
associated to each safety event will be calculated, together with the associated 95% confidence 
interval. These results will also be displayed graphically. For each safety topic of interest, the 
risk difference (RD) will be derived as follows: 
𝑅𝐷= Number of study participants treated with bimekizumab having the safety event
Total number of study participants treated with bimekizumab
−Number of study participants treated with placebo having the safety event
Total number of study participants treated with placebo
 
The lower and upper confidence interval bounds for RD will be calculated as follows:  
𝑅𝐷−𝑍𝛼/2 ∗𝑆𝐸 (𝑅𝐷), 𝑅𝐷+ 𝑍𝛼/2 ∗𝑆𝐸 (𝑅𝐷) 
Where 𝑍𝛼/2 is the critical value from the standard normal distribution (1.96 for a 95% CI). 
10.2.3 
Extra-Articular Manifestations 
A summary table will be presented on study participants having TEAE uveitis. The table will 
include all events defined by one of the following preferred terms: “Autoimmune uveitis”, 
“Iridocyclitis”, “Iritis”, “Uveitis”. The TEAE will be summarized per 100 subject-years by 
system organ class, high level term, and PT. The analysis will be stratified by study participants 
with or without a previous medical history of uveitis at Baseline. Study participants with uveitis 
at Baseline will be identified as the ones having documented an uveitis in the” Extra-articular 
Assessments form at Baseline” form ("Does subject have a history of uveitis?”). 
The analysis will be presented on the overall period as well as on the Double-Blind period.  
10.2.4 
Impact of COVID-19 
To assess the impact of the COVID-19 pandemic on safety, additional summaries and listings 
will be presented. 
For reporting purposes, AEs will be assigned to either Pre-COVID-19, COVID-19 or post-
COVID-19 pandemic period by comparing the AE start date (based on imputed date) to the 
COVID-19 pandemic period start and end dates (Section 3.2.2.2) (AE allocated to a period if it 
starts during the period): 
The following categories of TEAE will be summarized by MedDRA SOC, HLT and PT, 
including EAIR and EAER: 
• All TEAEs by time of onset relative to COVID-19 pandemic period (prior/during/post) by 
region and overall  
• All serious TEAEs by time of onset relative to COVID-19 pandemic period 
(prior/during/post) by region and overall 
• All TEAEs leading to study discontinuation by time of onset relative to COVID-19 pandemic 
period (prior/during/post) by region and overall 
• All TEAEs leading to permanent withdrawal of study medication by time of onset relative to 
COVID-19 pandemic period (prior/during/post) by region and overall 
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• All COVID-19 related TEAEs by treatment group, region and overall 
COVID-19 related TEAEs will be identified by searching for Preferred Terms “Corona virus 
infection” and “Coronavirus test positive”. These will include confirmed or suspected COVID-
19 infections. All the above table summaries will be produced on the overall period, except for 
the summary on the COVID-19 related TEAEs that will be produced for all treatment periods.  
A separate listing of all COVID-19 related AEs will be presented, where COVID-related AEs are 
identified as described above.  
In addition, all listing of AEs will include a column for COVID-19 relatedness (as defined 
above) and the time of onset of each AE relative to the COVID-19 pandemic. 
For the purpose of calculating EAIR and EAER by COVID-19 pandemic period, the calculation 
of exposure time at risk presented in Section 10.1.5 will be used. An individual study participant 
may therefore be counted in the denominator for several COVID-19 pandemic periods dependent 
on whether the study participant is still considered at risk on the COVID-19 pandemic start and 
stop dates. In this case time at risk will be calculated separately for each period.  
10.3 
Clinical laboratory evaluations 
The list of the laboratory measurements/variables that will be evaluated in the study is specified 
in Table 10‒1 per laboratory category.  
Table 10‒1: Laboratory measurements 
Hematology 
Biochemistry 
Urinalysis 
Basophils 
Calcium 
pH 
Eosinophils 
Chloride 
Albumin (protein) 
Lymphocytes 
Magnesium 
Glucose 
Monocytes 
Potassium 
Blood 
Neutrophils 
Sodium 
Leukocyte esterase 
Hematocrit 
Glucose 
Nitrite 
Hemoglobin 
BUN 
Urine dipstick for pregnancy 
testing 
MCH 
Creatinine 
Urine drug screen 
MCHC 
AST 
 
MCV 
ALT 
 
Platelet count 
ALP 
 
RBC count 
GGT 
 
WBC count 
Total bilirubin 
 
 
LDH  
 
 
Total cholesterol 
 
 
Serum pregnancy testing 
 
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Hematology 
Biochemistry 
Urinalysis 
 
hs-CRP 
 
Hematology 
Biochemistry 
Urinalysis 
Basophils 
Calcium 
pH 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; hs-CRP=high sensitivity C-reactive protein; ET=early termination; GGT=gamma-glutamyltransferase; 
HDL=high density lipoprotein, IMP=investigational medicinal product; LDH=lactate dehydrogenase; MCH=mean 
corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; 
RBC=red blood cell; SFU=Safety Follow-Up; WBC=white blood cell. 
The laboratory analyses will mainly be prepared using data from the central laboratory, except 
for determining treatment-emergent abnormal values, potential drug-induced liver injury or 
potential Hy’s Law cases. In the latter cases, both central and local laboratory results can be used 
if the local laboratory values meet specific criteria detailed thereafter: 
• The local laboratory value should not be considered without a provided local laboratory 
range in the database on the local laboratory CRF page, 
• The local  laboratory value should have been reviewed and checked, 
• Only local laboratory results coming from the same assessment and laboratory at the exact 
same time point can be used for the determination of potential drug-induced liver injury or 
potential Hy’s law criteria, 
• Local laboratory values which are not reported in standard international (SI) units will need 
to be converted in SI units prior to inclusion in the statistical analyses, 
• An indicator will be added in the table summaries and study participant listings when local 
laboratory contributed to the displayed results.  
All laboratory summaries will be presented in SI units and will be based on observed case 
values. In the case where laboratory values are below the lower limit of quantification, then these 
will be set to the midpoint between 0 and the lower limit of quantification for the purpose of 
summarizing the data.  
The following two summary statistic tables will be created for all laboratory continuous variables 
(unless otherwise notified). These two tables will be provided on the SS for the overall period, 
presenting the Placebo/BKZ 160mg Q4W and the BKZ 160mg treatment columns. Baseline will 
correspond to the original Baseline Day 1. 
• A summary of the absolute and change from Baseline values in each laboratory variable by 
treatment group and visit.  
• A summary of the number and percentage of study participants with a given common 
terminology criteria for adverse events (CTCAE) grade (0, 1, 2, 3 or 4) based on the 
minimum/maximum post-Baseline value, by laboratory variable and treatment group. 
This analysis will be restricted to the hematology and biochemistry laboratory parameters 
only, and will include the following parameters: hemoglobin, platelet count, WBC count, 
lymphocytes, neutrophils, creatinine, sodium, potassium, calcium, magnesium, total 
cholesterol, total bilirubin, AST, AST and GGT.  
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The hs-CRP parameter will not be included in the summary statistics on absolute and change 
from Baseline values because the results are already planned to be presented as part of an 
efficacy analysis (see Section 8.3.1.5).  
As indicated in Section 3.1, for tables where data are summarized by visit only values occurring 
at scheduled visits will be included.  
A shift table of the number and percentage of study participants with a given CTCAE grade 0, 1, 
2, 3 or 4 values (as applicable) at Baseline to minimum/maximum post-Baseline CTCAE grade, 
by laboratory variable and treatment group will additionally be created for the hematology and 
biochemistry laboratory parameters only. The analysis will be performed for the following 
parameters: hemoglobin, platelet count, WBC count, lymphocytes, neutrophils, creatinine, 
sodium, potassium, calcium, magnesium, total cholesterol, total bilirubin, AST, AST and GGT.  
In addition, a summary table of the number and percentage of study participants experiencing 
markedly abnormal values by laboratory variable, treatment group and visit will be created for 
biochemistry, hematology and liver function test values.  
Markedly abnormal values are defined as those with a severity of Grade 3 and above based on 
the CTCAE criteria Version 4.03. Definitions of markedly abnormal values using the Grade 3 cut 
points are given in Table 10‒2, Table 10‒3 and Table 10‒4 in order to allow for a more thorough 
review of elevated LFTs.  
All values observed at any time while on treatment (ie, occurring at scheduled and unscheduled 
visits) will be included in this table summarizing markedly abnormal values. For this summary, 
Baseline values and values observed more than 140 days after the last administration of study 
medication are not considered. 
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Table 10‒2: Definitions of markedly abnormal biochemistry values 
Parameter name 
Unit 
Criteria 
Abnormal designation 
Creatinine 
mmol/L 
>3.0 x Baseline or  
>3.0 x ULN 
AH 
Glucose 
mmol/L 
<2.2 
>13.9 
AL 
AH 
Calcium 
mmol/L 
>3.1 
<1.75 
AH 
AL 
Magnesium 
mmol/L 
>1.23 
<0.4 
AH 
AL 
Potassium 
mmol/L 
>6.0 
<3.0 
AH 
AL 
Sodium 
mmol/L 
>155 
<130 
AH 
AL 
Cholesterol 
mmol/L 
 
>10.34 
AH 
AH=abnormal high; AL=abnormal low; dL=deciliter; L=liter; mg=milligram; mmol=millimoles; ULN=upper limit 
of normal. 
Table 10‒3: Definitions of markedly abnormal hematology values 
Parameter name 
Unit 
Criteria 
Abnormal designation 
Hemoglobin 
g/L 
<80 
>40 above ULN 
AL 
AH 
Lymphocytes Absolute 
109/L 
<0.5 
>20.0 
AL 
AH 
Neutrophils Absolute 
109/L 
<1.0 
AL 
Platelets 
109/L 
<50 
AL 
WBC/ 
Leukocytes 
109/L 
<2.0 
>100 
AL 
AH 
AH=abnormal high; AL=abnormal low; dL=deciliter; L=liter; mg=milligram; mmol=millimoles; ULN=upper limit 
of normal. 
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Table 10‒4: Definitions of markedly abnormal liver function values 
Paramter name 
Unit 
Criteria 
Abnormal designation 
Alkaline Phosphatase 
U/L 
>5.0 x ULN 
AH 
ALT 
U/L 
>5.0 x ULN 
AH 
AST 
U/L 
>5.0 x ULN 
AH 
Total Bilirubin 
umol/L 
>3.0 x ULN 
AH 
GGT 
U/L 
>5.0 x ULN 
AH 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma-glutamyltransferase 
Another table will list the count and percentage of study participants meeting the below criteria 
at any time during the study while on treatment:  
• AST: >2xULN, >3xULN, >5xULN, >10xULN, >20xULN 
• ALT: >2xULN, >3xULN, >5xULN, >10xULN, >20xULN 
• AST or ALT: >2xULN, >3xULN, >5xULN, >10xULN, >20xULN 
• Bilirubin: >1xULN, >1.5xULN 
• ALP: >2xULN 
In addition, a table will be produced to summarize potential Hy’s Law cases. The following two 
definitions will be used in that table: 
• [AST ≥3xULN or ALT ≥3xULN] and Total Bilirubin ≥2xULN 
• [AST ≥3xULN or ALT ≥3xULN] and Total Bilirubin ≥2xULN in the absence of ALP 
≥2xULN  
Neutrophil values for study participants with at least one treatment emergent markedly abnormal 
neutrophil value will be plotted over time.  
A spaghetti plot will be created for ALT values for study participants with at least one treatment 
emergent markedly abnormal ALT value. The plot will also be created for AST values.  
Results for the shift tables, the graphs and summary tables on markedly abnormal values and the 
Hy’s Law cases tables will be presented as follows: 
• on the SS for the Double-Blind Treatment Period for the Week 24 interim analysis only, 
presenting the Placebo and BKZ 160mg treatment columns,  
• on the MS for the Maintenance Period for the Week 52 interim analysis only, presenting the 
BKZ 160 mg Total treatment column only, 
• on the SS for the overall period, presenting the BKZ 160 mg Total treatment column only.  
For the two last analyses presenting data occurring during the Maintenance Period, Baseline 
Week 16 will be used as Baseline for study participants randomized to Placebo that switched to 
bimekizumab at Week 16. 
A by-study participant listing of all laboratory data (excluding urinalysis results) will be 
provided. In this listing, values that are out of normal range will be flagged (abnormal values that 
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are below the lower limit of the reference range flagged as ‘L’ (low) and abnormal values that 
are above the upper limit of the reference range flagged as ‘H’ (high)).  
In addition, the laboratory results classified as Grade 3 or Grade 4 will be listed separately. 
Urinalysis laboratory results will be listed separately, as well as all additional laboratory samples 
that may have been collected for a study participant.  
An additional listing will be created for study participants with suspected hepatic events.  
10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital signs, weight and physical findings 
The following results will be tabulated for the vital sign variables (systolic blood pressure 
(mmHg), diastolic blood pressure (mmHg), and pulse rate (beats/min)), by treatment group and 
visit: 
• A summary of the absolute and change from Baseline value  
The table will be done on the SS, will cover the overall period, and present the Placebo/BKZ 
160mg Q4W and the BKZ 160mg treatment columns.  
• A summary of the number and percentage of study participants experiencing at least one 
markedly abnormal value for a vital sign variable as defined in Table 10‒5 below. 
The table will be presented: 
− on the SS for the Double-Blind Treatment Period for the Week 24 interim analysis only, 
presenting the Placebo and BKZ 160mg treatment columns.  
− on the MS for the Maintenance Period for the Week 52 interim analysis only, presenting 
the BKZ 160 mg Total treatment column only.  
− and on the SS for the overall period, presenting the BKZ 160 mg Total treatment column 
only. 
For the two last analyses presenting TEMA data occurring during the Maintenance Period, 
Baseline Week 16 will be used as Baseline for study participants randomized to Placebo that 
switched to bimekizumab at Week 16. 
Table 10‒5: Definitions of markedly abnormal blood pressure values 
Parameter (unit) 
Markedly abnormal low 
Markedly abnormal high 
Systolic blood pressure (mmHg) 
<90 and a decrease from 
Baseline of ≥20 
>180 and an increase from 
Baseline of ≥20 
Diastolic blood pressure 
(mmHg) 
<50 and a decrease from 
Baseline of ≥15 
>105 and an increase from 
Baseline of ≥15 
At Visit 2, vital signs are planned to be assessed three times (prior to the study treatment 
administration, 30 minutes after the study treatment administration and 1 hour after the study 
treatment administration). Baseline will be defined as the last available value up to and including 
the assessment collected at Visit 2 prior to first dose.  
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At Week 16, vital signs collected before IMP belong to the double-blind treatment period, while 
vital signs collected after IMP belong to the maintenance period. 
A by-study participant listing of all vital sign results (including body temperature) with the 
details of abnormities (when applicable) will be provided (abnormal values will be flagged as 
“L” or “H” accordingly).  
Similarly, physical examination findings together with the details of abnormalities (when 
applicable) will be listed by treatment group, study participant and visit. 
Body weight will also be listed. 
10.4.2 
Electrocardiograms  
Since it is only planned to assess electrocardiogram (ECG) at the Screening Visit, the Baseline 
value will be derived based on the Screening assessment.  
The date and time of the ECG will be recorded in the eCRF together with the Investigator 
interpretation. A summary of the number and percentage of study participants with normal, 
abnormal not clinically significant, and abnormal clinically significant ECG results will be 
presented for Baseline and post-Baseline timepoints.  
A summary of the absolute and change from Baseline values in each ECG variable will also be 
created at each post-Baseline/Screening timepoints by treatment group. The following ECG 
variables will be summarized: heart rate (bpm), RR interval (ms), PR interval (ms), QRS 
duration (ms), QT interval (ms), QTcF interval (ms) and QTcB interval (ms). 
QTc outliers are defined as QTcF (or QTcB) values following dosing that are greater than 450 
ms or are increases from Baseline greater than 30 ms. QTcF and QtcB outliers will be 
summarized in a dedicated table using the following categories: 
• Values >450 ms, >480 ms, >500 ms 
• Increase from Baseline of >30 ms, increase from Baseline of >60 ms, increase from Baseline 
of >90 ms 
• Values >450 ms and increases of >30 ms. Values >500 ms and increases of >60 ms 
In this table, the number and percentage of study participants who meet the ECG outlier criteria 
at any assessment post first dose will be summarized. 
These three table summaries will cover the overall period on the SS and will present the 
Placebo/BKZ 160mg Q4W and the BKZ 160mg treatment columns. Baseline Day 1 will serve as 
Baseline.  
A by-study participant listing of all 12-lead ECG data will be provided where QTcF and QTcB 
outliers will be highlighted.  
10.4.3 
Other safety variables 
Suicidal ideation and behavior  
Suicidal ideation and behavior will be assessed using the electronic Columbia-Suicide Severity 
Rating Scale (eC-SSRS) questionnaire. The questionnaire is an assessment tool that evaluates 
suicidal ideation and behavior that may occur during the study.  
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The eC-SSRS defines 5 subtypes of suicidal ideation and behavior in addition to self-injurious 
behavior with no suicidal intent.  
Suicidal ideation is defined as an event in any of the following 5 categories: 
• Category 1 - Wish to be dead  
• Category 2 - Non-specific active suicidal thoughts  
• Category 3 - Active suicidal ideation with any methods (not plan), without intent to act  
• Category 4 - Active suicidal ideation with some intent to act, without specific plan  
• Category 5 - Active suicidal ideation with specific plan and intent  
Suicidal behavior is defined as an event in any of the following 4 categories: 
• Category 6 - Preparatory acts or behavior 
• Category 7 - Aborted attempt 
• Category 8 - Interrupted attempt 
• Category 9 - Actual attempt 
Suicidal behavior or ideation is defined as an event in any of the above 9 categories. 
Self-injurious behavior without suicidal intent is defined as an event in the category non-
suicidal self-injurious injuries. 
The incidence of study participants with suicidal ideation, suicidal behavior, suicidal behavior or 
ideation, and self-injurious behavior without suicidal intent will be summarized: 
• on the SS for the Double-Blind Treatment Period for the Week 24 interim analysis only, 
presenting the Placebo and BKZ 160mg treatment columns, 
• on the MS for the Maintenance Period for the Week 52 interim analysis only, presenting the 
BKZ 160 mg Total treatment column only, 
• and on the SS for the overall period, presenting the BKZ 160 mg Total treatment column 
only.  
A by-study participant listing of the eC-SSRS questionnaire data will be provided, as well as a 
subset listing presenting eC-SSRS data for study participants having at least one positive 
response. 
The visit name associated to the eC-SSRS data will not be transferred by the vendor since the 
way the device is designed would lead to incorrect naming of the visits. The visit date collected 
in EDC will rather be used to assign the correct visit to the eC-SSRS data, (in merging based on 
study participant number and date) as follows:  
• If the eC-SSRS assessment date is matching an eCRF scheduled visit date, then the eC-SSRS 
visit identification will be the one corresponding to eCRF visit date. 
• If the eCRF visit date directly matches the date of the eC-SSRS assessment, then the eC-
SSRS assessment will be considered in the SDTM datasets as being done on an unscheduled 
visit.  
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Among the C-SSRS assessments previously considered in the SDTM datasets as being done on 
an unscheduled visit, if the assessment is matching an eCRF visit date within a window of +/- 3 
days, then the eC-SSRS assessment will be considered as acceptable in the ADaM datasets and 
will be considered as being done on that eCRF scheduled Visit. Otherwise, the eC-SSRS 
assessment will stay recorded in an unscheduled visit.  
The following rules will be implemented in case of visit with artificially duplicated 
questionnaires caused by the technical limitations of the data capture system, like time-out 
settings with a visit resetting trigger  
• If there is a visit with one (or more) incomplete questionnaires and at least one complete 
questionnaire without discrepancies, then the incomplete questionnaire will be excluded from 
the ADaM dataset.  
• If there is a visit with one (or more) incomplete questionnaires and at least one complete 
questionnaire with discrepancies, then the incomplete questionnaire will be excluded from 
the ADaM dataset.  
• If there is a visit with one (or more) full duplicates without discrepancies, then the 
unscheduled repetition of the first completed questionnaire will be excluded from the ADaM 
dataset. 
• If there is a visit with one (or more) full duplicates with discrepancies, then the “wrong” 
questionnaire with discrepancies will be excluded from the ADaM dataset.  
•  If there is a visit with only a single incomplete questionnaire, the incomplete questionnaire 
will be included in the ADaM dataset and used for the TFL generation like a normal visit.  
Patient Health Questionnaire-9 (PHQ-9) 
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring, and measuring 
the severity of study participant’s depression. The PHQ-9 score is based on nine questions 
assessing the depression over the last two weeks. Each criteria is scored from 0 (not at all) to 3 
(nearly every day). The total score for the nine questions is added up and provide the PHQ-9 
score and can range from 0 to 27 with higher scores indicating worse state. If one of the nine 
criteria is missing, the PHQ-9 score will be set to missing. 
The following depression states are defined based on the PHQ-9 score: 
• A score of 5-9 is considered to be minimal symptoms of depression.  
• A score of 10 to 14 is considered minor depression, dysthymia, or mild major depression.  
• A score of 15 to 19 is considered to indicate moderately severe major depression. 
• A score >=20 is considered to be severe major depression.  
The percentage of study participants with PHQ-9 scores below 5, between 5 and 9, between 10 
and 14, between 15 and 19, and greater than or equal 20 will be summarized by visit and 
treatment group, as well as the change from Baseline over time. These two analyses will cover 
the overall period on the SS and will present the Placebo/BKZ 160mg Q4W and the BKZ 160mg 
treatment columns.  
Tuberculosis 
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The laboratory test results (negative, positive or indeterminate) from the TB assessment 
performed by interferon gamma release assay will be summarized by treatment group 
(Placebo/BKZ 160mg Q4W and the BKZ 160mg) for Screening and Week 44 timepoints on the 
SS, as well as listed.  
The results from the ‘Evaluation of signs and symptoms of tuberculosis’ questionnaire data will 
be also listed.  
Questionnaires 
Study participants for who the wrong user role was referenced by the site, at time of completion 
of study participant facing questionnaires will be listed on the randomized set.   
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11 
REFERENCES 
1. Maksymowych WP, Mallon C, Richardson R, et al. Development and Validation of the 
Edmonton Ankylosing Spondylitis Metrology Index. Arthritis Rheum. 2006;55:575-82. 
2. Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, Landewé R, van der Tempel H, 
Mielants H, et al. Assessment of enthesitis in ankylosing spondylitis. Ann Rheum Dis. 
2003;62:127-32. 
3. Mallinckrodt CH, Lin Q, Lipkovich I, Molenberghs G. A structured approach to choosing 
estimands and estimators in longitudinal clinical trials. Pharm Stat. 2012;11:456-61. 
4. Mallinckrodt CH. Preventing and Treating Missing Data in Longitudinal Clinical Trials: A 
Practical Guide. New York, NY: Cambridge University Press; 2013. 
5. O'Kelly, Michael, and Bohdana Ratitch. Clinical trials with missing data: A guide for 
practitioners. John Wiley & Sons, 2014 
6. Rubin, Donald B. "The calculation of posterior distributions by data augmentation: 
Comment: A noniterative sampling/importance resampling alternative to the data 
augmentation algorithm for creating a few imputations when fractions of missing information 
are modest: The SIR algorithm." Journal of the American Statistical Association 82, no. 398 
(1987): 543-546. 
7. Ulm, K., A simple method to calculate the confidence interval of a standardized mortality 
ratio. American Journal of Epidemiology, 1990; 131(12), 373-375 
 
 
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12 
APPENDICES 
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APPENDIX 1. MEDDRA ALGORITHMIC APPROACH TO 
ANAPHYLAXIS 
The SMQ Anaphylactic reaction consists of three parts:  
• A narrow search containing PTs that represent core anaphylactic reaction terms (Category A 
core anaphylactic terms)  
 
• A broad search that contains additional terms that are added to those included in the narrow 
search. These additional terms are signs and symptoms possibly indicative of anaphylactic 
reaction and categorized in B, C or D  
− Cat B 
 
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− Cat C 
 
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− Cat D 
 
• An algorithmic approach which combines a number of anaphylactic reaction symptoms in 
order to increase specificity. A case must include either (on the same day):  
− A narrow term or a term from Category A;  
− A term from Category B - (Upper Airway/Respiratory) AND a term from Category C - 
(Angioedema/Urticaria/Pruritus/Flush);  
− A term from Category D - (Cardiovascular/Hypotension) AND [a term from Category B - 
(Upper Airway/Respiratory) OR a term from Category C - (Angioedema/Urticaria/ 
Pruritus/Flush)]  
• Hypersensitivity events will be identified using the “Hypersensitivity (SMQ)”. All TEAEs 
which code to a PT included in the Scope=Narrow search will be included.  
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APPENDIX 2. UCB-DEFINED SEARCH CRITERIA FOR IDENTIFYING 
OPPORTUNISTIC INFECTIONS 
Opportunistic infections are identified in two steps:  
Step 1: Refer to column B of the spreadsheet (Opportunistic infections MedDRA v 19.xlsx) 
which identifies the Preferred Terms (PTs) to be classified as opportunistic infections using 
either a single ‘x’ or a double ‘xx’. 
TEAEs which code to a PT flagged with a single ‘x’ need to also be serious to be considered an 
opportunistic infection. 
All TEAEs which code to a PT flagged with a double ‘xx’ are considered to be an opportunistic 
infection, regardless of seriousness.  
Step 2: Refer to column C of the spreadsheet which identifies the PTs that need to be evaluated 
on a case-by-case basis by the study physician to determine whether or not it is an opportunistic 
infection. If Column C has a single ‘x’, then the corresponding preferred term should be flagged 
for case-by-case review by the study physician.  
 
 
 
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13 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
(SAP)  
13.1 
AMENDMENT 1 
Rationale for the amendment 
The major purpose of this SAP amendment was to implement changes in response to Protocol 
Amendment 4 (16FEB2021) and discussions and feedback provided at meetings between UCB 
and PAREXEL technical teams or for clarifications. The main changes are rules for handling 
missing data and guidelines on the implementation of multiple imputation and latest guidelines 
from the BKZ AE of special monitoring convention document.  
The protocol amendments derived changes include clarification of the 12-item MOS Sleep Scale 
is rated using the 5-point scale, the increase of the threshold for subgroup analyses by disease 
duration from 2 to 5 years.  
The SAP amendments can be summarized as follows: 
• Re-classification of Change from Baseline in Patient Health Questionnaire-9 (PHQ-9) 
variable from other efficacy variable to other safety variable 
• New rules for handling of missing data for the primary and key secondary efficacy variables 
• Use of latest guidelines from the BKZ AE of special monitoring convention document 
• Clarification of the 12-item MOS Sleep Scale is rated using the 5-point scale 
• The increase of the threshold for subgroup analyses by disease duration from 2 to 5 years 
• Clarification on use and multiple imputation approaches in supportive analyses 
− Observed cases 
− NRI 
• Imputation of partial start dates 
• Clarification of outputs for China and Japan submissions 
• Update in the pharmacokinetic and immunogenicity analyses 
Modifications and changes 
Global changes: 
The following changes were made throughout the SAP: 
• The use of “subject” was updated to “study participant”. 
• The list of abbreviations was updated accordingly. 
• Minor spelling, editorial, and formatting changes were made throughout the document.  
Specific changes 
In addition to the global changes, the following specific changes have been made (formats as 
missing spaces or redundant spaces are not listed, typos): 
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13.1.1 
Efficacy variables (Section 2.2.1) 
Other efficacy variable moved to the safety section: 
• Change from Baseline in Patient Health Questionnaire-9 (PHQ-9)  
Other efficacy variables: Additional detail provided as below: 
•  Change from Baseline in Ankylosing Spondylitis spine MRI-activity (ASspiMRI-a) in the 
Berlin modification score (Note that this endpoint will be analyzed for study participants in 
the MRI substudy only) 
• Change from Baseline in sacroiliac joint Spondyloarthritis Research Consortium of Canada 
(SPARCC) score (Note that this endpoint will be analyzed for study participants in the MRI 
substudy only) 
13.1.2 
Immunological variables (Section 2.2.4) 
New variable: 
• The neutralizing antidrug antibody (NAb) status  
13.1.3 
Safety variables (Section 2.2.5) 
• Secondary safety variables now focused on treatment emergent events 
New other safety variables: 
•  Change from Baseline in Patient Health Questionnaire-9 (PHQ-9)  
13.1.4 
General presentation of summaries and analyses (Section 3.1) 
New rules: 
• ADaM variables AVAL, CHG or PCHG are rounded to 12 decimal places prior to the 
comparison to the threshold 
• The summary statistics for hs-CRP should also contain arithmetic mean. 
13.1.5 
Study periods (Section 3.2.2) 
New updated study periods definition for the classification of : 
• Safety data (Screening period, 16-Week DBTP, 36-Week MP, SFU period) 
• Efficacy data (Screening period, 16-Week DBTP, 36-Week MP) 
• COVID-19 pandemic periods (Prior/during/post) 
13.1.6 
Definition of baseline variables (Section 3.3) 
New updated baseline definition: 
• When no treatment information is available, the randomization date will be used as reference 
in place of the first day of study drug administration 
• Baseline value for HLA-B27 
• Baseline value for  MRI substudy 
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13.1.7 
Treatment Discontinuation Date and Intercurrent event date 
(Section 3.4) 
• New definition of treatment discontinuation date and intercurrent event date 
13.1.8 
Protocol deviations (Section 3.5, Section 5.3) 
New category of protocol deviation: 
• Exclusion from PPS 
• COVID-19 related PD 
13.1.9 
Analysis sets (Section 3.6) 
Additional study participants to be excluded from the PPS: 
• Study participant excluded from the FAS 
New analysis sets: 
• Immunogenicity Safety Set 
• COVID-19 Free Set 
13.1.10 
Treatment assignment and treatment groups (Section 3.7) 
New category of anaphylactic reaction: 
• Events, that fulfil the hypersensitivity reaction criteria  
Efficacy analysis will be based: 
• on the RS as randomized, for the Double-Blind Treatment Period (displaying data under 
Placebo and BKZ 160mg Q4W columns), 
• on the RS as randomized/assigned treatment for the overall period (displaying data under 
Placebo/BKZ and BKZ 160mg Q4W columns). 
13.1.11 
Changes to protocol-defined analyses (Section 3.10) 
New changes from the protocol: 
• The continuous secondary efficacy endpoints which are part of the sequential testing 
procedure, as well as the components of the primary ASAS40 endpoint, will be primarily 
analyzed in implementing a reference-based imputation method. 
13.1.12 
Changes related to COVID-19 (Section 3.11, Section 5.2) 
Additional analyses including analyses by COVID-19 pandemic periods: 
• Study participant disposition (Section 5.1) 
• Details of impacted visits and effects on collection and reporting of efficacy data 
(Section 5.3) 
• Protocol deviations (Section 5.3) 
• Exposure (Section 10.1.4 and Section 10.1.5) 
• Adverse events (Section 10.2) 
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13.1.13 
Handling of missing data for efficacy analyses (Section 4.2.1) 
• New updated table 4.1 to summarize the different approaches to handle missing data for 
efficacy endpoints 
Change in missing data handling approaches for efficacy endpoints : 
• MI - MCMC/ Logistic Regression method no longer used. 
Change of primary analysis method for variables in the testing hierarchy 
• Primary analysis for binary variables performed under the composite estimand approach 
(NRI) instead of MI. 
• Primary analysis for continuous endpoints to be analyzed using the referenced-based multiple 
imputation method. 
Change of supportive analysis method for variables in the testing hierarchy 
• For binary variables, supportive analyses now include Modified Composite estimand 
approach (MI) (where IE are defined as study treatment discontinuation due to AE or Lack of 
efficacy) 
• For continuous variables (including ACR component at Week16), supportive analyses now 
performed under the Hypothetical estimand approach (MI). 
13.1.14 
Handling of missing data for AE (Section 4.2.2) 
New rules of imputation of partial start dates: 
• When the imputed stop date is prior to the imputed start date 
− For missing start day and start month 
− For missing start day only 
13.1.15 
Handling of missing data for prior and concomitant medications 
(Section 4.2.3) 
New rules of imputation of partial start dates: 
• When the imputed stop date is prior to the imputed start date 
13.1.16 
Examination of subgroups (Section 4.8) 
New categories of variable for efficacy subgroup analyses: 
• csDMARDs (Yes/No) 
• Timing of participant enrollment relative to COVID-19 pandemic periods as defined in 
Section 3.2.2.2 (Enrolled prior/during/after to the COVID-19 pandemic) 
• Timing of Week 16 Visit relative to the COVID-19 pandemic periods as defined in Section 
3.2.2.2 (Study participants who had the Week 16 Visit prior/during/after the COVID-19 
pandemic) 
13.1.17 
Study participant disposition (Section 5.1) 
New statistics: 
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• The number of study participants who completed the DBTP but discontinued prior to 
entering the MP 
• The numbers and percentages of randomized study participants entering the extension study 
• The disposition and study discontinuations reasons on the RS and MS up to Week 24  
• The number of study participants enrolled during each COVID-19 pandemic period, as well 
as the number of study participants still in the study during each COVID-19 pandemic period 
on the RS (overall and by region). 
13.1.18 
Demographics (Section 6.1) 
New categories: 
• BMI: <18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2 
• Body weight: ≤100, >100 kg 
• Body weight: <70, 70 to <95, 95 to < 115, ≥115kg 
13.1.19 
Baseline characteristics (Section 6.2) 
Additional parameter for baseline efficacy variables: 
• ASDAS-CRP 
Additional parameters for other baseline characteristics: 
• Any past biologic therapy (yes, no) 
• Current nonsteroidal anti-inflammatory drug (NSAID) drug therapies (yes/no) 
• Current oral corticosteroid use (yes, no) 
• Current Analgesic/Opioid therapies (yes, no) 
• Disease duration (<5, >= 5 years) 
13.1.20 
Medical history and concomitant diseases (Section 6.3) 
New summarized tables: 
• Pre-specified medical history coming from ‘the ‘Infection history’ CRF form 
• The extra-articular assessments at Screening and Baseline 
• Uveitis and IBD assessments at post-Entry Visit 
13.1.21 
Statistical analysis of the primary efficacy variables (Section 8.1) 
Updated the definition of intercurrent event: 
• An intercurrent event is defined as discontinuation of study treatment due to any reason 
prior to Week 16.  
Additional details: 
• The adjusted OR (for the comparison bimekizumab and placebo) and the 95% CI will be 
provided for secondary analyses of primary efficacy variable 
• Reference-based MI method is used for analysis on individual components of the ASAS 
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• A supportive analysis using modified composite estimand added 
• The worst-case scenario added for the tipping points analysis 
• Analyses including COVID-19 impact added 
13.1.22 
Statistical analysis of the secondary efficacy variables (Section 8.2) 
Additional details added for derivation: 
• BASDAI: if 1 of the 2 morning stiffness measurements (ie, questions Q5 and Q6) is missing, 
the other one will be used for the morning stiffness calculation 
• Disease activity categories based on ASDAS-CRP added  
• Re-classification of Change from Baseline in Patient Health Questionnaire-9 (PHQ-9) 
variable from other efficacy variable to other safety variable 
• SF-3 component summaries (PCS and MCS scores) and normal range 
• Updated BASMI linear definition (table 8.1, table 8.2)  
• The order of events to derive the BASMI scores 
• MASES: only randomized study participants with enthesitis at Baseline will be included in 
the multiple imputation models 
Change of analysis of secondary effect variables 
• Secondary binary endpoints performed under the composite estimand approach (NRI)  
• Secondary continuous endpoints performed under the referenced-based MI for primary 
analyses and hypothetical estimand MI method for supportive analyses in the testing 
hierarchy 
• New section for describing additional statistical analyses of selected secondary efficacy 
variables  
13.1.23 
Analysis of other efficacy variables (Section 8.3) 
Additional details added for derivation: 
• Time to a given response (ASAS20 or ASAS40) will be defined as the time in days from the 
start date of first treatment dose 
• Extra rules for calculation of hs-CRP 
• Formula to derive the FACIT-Fatigue subscale score 
• WPAI-SHP: derivation of additional four scores after implementing the missing data rules 
for questions Q1-Q5 
• Extra rules for calculation of ASspiMRI-a score and SPARCC score 
New rules for handling of missing data for the analysis of other efficacy endpoints 
Additional analyses for other efficacy endpoints:  
•  Addition of some extra analyses of efficacy endpoint with statistical testing 
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13.1.24 
Pharmacokinetics (Section 9.1) 
Additional details added for: 
• Definition of ADAb Sample Status 
• Definition of Cumulative ADAb Status 
• PK Sample Inclusion and Exclusion Rules 
• Summary of Analyses  
13.1.25 
Immunology (Section 9.2) 
Additional details added for: 
• Definition of Overall ADAb status 
• Definition of ADAb Categories 
• ADAb status groups for Efficacy Endpoint Summaries 
• ADAb Sample Inclusion and Exclusion Rules 
• Detailed immunology analyses 
• Neutralizing anti-bimekizumab antibodies 
13.1.26 
Extent of exposure (Section 10.1) 
• Now also calculated by COVID-19 pandemic period 
13.1.27 
Adverse events (Section 10.2) 
• Use of latest guidelines from the BKZ AE of special monitoring convention document 
New tables/listings for: 
• The adjudicated neuropsychiatric events by type 
• The adjudicated IBD events by type  
• The incidence of each safety topics of interest occurring in the DBTP 
• Extra-Articular Manifestations 
• Impact of COVID-19 
Additional details provided: 
• Hypersensitivity now includes injection site reactions in addition to anaphylaxis 
• Calculation of the risk difference with the upper and lower confidence interval 
13.1.28 
Clinical laboratory evaluations (Section 10.3) 
Changes the definitions of markedly abnormal values for: 
• Creatinine 
• Glucose 
• Cholesterol 
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New figures for: 
• Neutrophil values for study participants with at least one treatment emergent markedly 
abnormal neutrophil value  over time 
• ALT (or AST) values for study participants with at least one treatment emergent markedly 
abnormal value 
13.1.29 
Other safety variables (Section 10.4.3) 
New added variables: 
• Patient Health Questionnaire-9 (PHQ-9) 
• Questionnaires 
13.2 
AMENDMENT 2 
Rationale for the amendment 
The major purpose of this SAP amendment was to fix formatting issues in the SAP document 
and to add clarifications on how to analyze specific data.   
13.2.1 
Summary of Analyses (Section 9.1.4) 
Removal of PK analysis by region subgroup. 
13.2.2 
Definition of ADAb categories (Section 9.2.1.3) 
Update on the ADAb category 9 definition.  
13.2.3 
Handling of missing data for efficacy analyses (Section 4.2.1) 
Change in missing data handling approaches for efficacy endpoints : 
• LOCF will be used for the secondary continuous endpoints in case of convergence issue of 
the Reference-Based Multiple Imputation analyses. 
• Update in the rule described in Step 1c for the reference-based imputation  
New section added: 
• Section 4.2.1.11 for Last Observation Carried Forward 
• Section 4.2.1.12 for allowed ranges for continuous efficacy variables 
13.2.4 
Clinical laboratory evaluations (Section 10.3) 
Change in the use of the local laboratory results. 
13.2.5 
Other safety variables (Section 10.4.3) 
New rules for visits with incomplete eC-SSRS questionnaire or duplicated questionnaires. 
13.2.6 
Baseline characteristics (Section 6.2) 
Change in the cut-off category for disease duration and time since first diagnosis of AS, from 5 
to 2 years.  
13.2.7 
Examination of subgroups (Section 4.8) 
Change in the cut-off category for disease duration, from 5 to 2 years.  
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13.2.8 
Definition of baseline variables (Section 3.3) 
Updated baseline definition for component scores. 
 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
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Approval Signatures
Name:
AS0011-sap-amend-2
Version:
3. 0
Document Number:
CLIN-000144514
Title:
AS0011-Statistical Analysis Plan
Approved Date:
15 Nov 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 15-Nov-2021 15:23:44 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Document Author
Date of Signature: 15-Nov-2021 15:30:04 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 15-Nov-2021 15:31:24 GMT+0000
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