Clinical trial NCT03813199
Conditions: Rheumatoid Arthritis
Sponsor: Abivax S.A.
Start date: 2019-07-04; Completion date: 2021-04-27
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase IIa study aims at investigating the safety and tolerability of 2 dose-levels of ABX464 administered daily in combination with methotrexate (MTX) in patients with moderate to severe active Rheumatoid Arthritis (RA) who had an inadequate response to MTX or/and to one or more anti- tumor necrosis factor alpha (TNFα) therapies.

Detailed description:
This is a randomized, double-blind, placebo-controlled, multicenter study. The study will consist of 3 phases: a screening phase, a treatment phase, and a follow-up phase.

Approximately 60 participants with active Rheumatoid Arthritis will be randomly assigned to receive placebo, 50mg ABX464 or 100mg ABX464 during the treatment phase.

The maximum period of active treatment will be 12 weeks. The maximum duration of study participation will be 17 weeks.

Participant safety will be monitored throughout the study. In addition, several experimental and clinical endpoints will be assessed to obtain information on preliminary efficacy.

Arms: arm 1: Participants will receive one capsule of 50mg ABX464 plus one capsule of matching placebo once daily for 12 weeks

\+ methotrexate arm 2: Participants will receive two capsules of 50mg ABX464 once daily for 12 weeks

\+ methotrexate arm 3: Participants will receive two capsules of matching placebo once daily for 12 weeks

\+ methotrexate
Interventions: intervention 1: ABX464 50mg intervention 2: Matching Placebo intervention 3: ABX464 100mg intervention 4: Methotrexate
Intervention descriptions: intervention 1: ABX464 is a new anti-inflammatory drug intervention 2: placebo matching with ABX464 intervention 3: ABX464 is a new anti-inflammatory drug intervention 4: MTX ≥ 10 mg/week will be given at previous dose regimen kept stable throughout the study

Protocol documents:
Prot_000.pdf: 
PR0009-V04 
 
 
 
 
CLINICAL STUDY PROTOCOL 
ABX464-301 
 
Sponsor: 
ABIVAX 
 
5, rue de la Baume 
 
 75008 Paris 
 
FRANCE 
 
Investigational product:  
Not Available  
Product code: 
 
ABX464 
Therapeutic indication: 
 
Phase IIa randomized, double blind, placebo controlled, parallel group, 
multiple dose study on ABX464 in combination with methotrexate (MTX), in 
patients with moderate to severe active Rheumatoid Arthritis who have 
inadequate response to MTX or/and to an anti- tumor necrosis factor alpha 
(TNFα) therapy, or intolerance to anti-TNFα therapy. 
EudraCT number: 
 
2018- 004677-27 
Study code: 
 
 
ABX464-301 
 
Version number: 
 
4.0 
Release date:  
 
October 24th, 2019 
 
CONFIDENTIALITY STATEMENT 
Information and data contained herein are proprietary and confidential. 
This information should not be disclosed to any third party without the prior written consent of ABIVAX 
 
 


ABIVAX 
Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
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CLINICAL STUDY PROTOCOL 
Study code 
ABX464-301 
Investigational product 
code 
ABX464 
EudraCT number 
2018- 004677-27 
Detailed Title 
Phase IIa randomized, double blind, placebo controlled, parallel group, 
multiple dose study on ABX464 in combination with methotrexate (MTX), in 
patients with moderate to severe active Rheumatoid Arthritis who have 
inadequate response to MTX or/and to an anti- tumor necrosis factor alpha 
(TNFα) therapy, or intolerance to anti-TNFα therapy. 
Study Phase 
Phase IIa 
Coordinating Investigator 
Dr Claire DAIEN 
Département de Rhumatologie 
Hôpital Lapeyronie ; CHU de Montpellier 
34295 MONTPELLIER cedex 5 – France 
Tel: +33 (0) 4 67 33 87 10 
Sponsor 
ABIVAX 
5 rue de la Baume 
75008 Paris - France 
Tel: +33 (0) 1 53 83 08 41 
Fax: +33 (0) 1 53 83 07 48 
Date/Version 
October 24th, 2019 / Version 4.0 
 


ABIVAX 
Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
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CONTACTS 
Sponsor 
ABIVAX 
5 rue de la Baume 
75008 PARIS - France 
Dr Jean-Marc STEENS 
VP, Chief Medical Officer 
Tel: + 33 (0) 1 53 83 09 61 
Dr Paul GINESTE 
VP, Clinical Operations 
Tel: + 33 (0) 1 53 83 09 61 
 
Coordinating investigator 
Dr Claire DAIEN 
Département de Rhumatologie 
Hôpital Lapeyronie ; CHU de Montpellier 
34295 MONTPELLIER cedex 5 – France 
Tel: +33 (0) 4 67 33 87 10 
Study Conduct, Data management and 
Statistical Analysis 
Simbec-Orion 
Centre d’Affaires La Boursidière 
Bâtiment le Jura, BP 141 
92357 Le Plessis- Robinson Cedex 
France 
Pharmacokinetics  
Atlanbio (Bioanalyses) 
ZI de Brais 
1 Rue Graham Bell 
BP 40309 44605 Saint-Nazaire – France 
Pharmacovigilance 
IntuVigilance Limited 
Scotsbridge House, Scots Hill 
Rickmansworth WD3 3BB 
Hertfordshire, UK 
 
 
 


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Study code: ABX464-301 
October 24th, 2019 
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INVESTIGATOR AGREEMENT PAGE 
 
EudraCT number 
 
2018- 004677-27 
Detailed Title:  
Phase IIa randomized, double blind, placebo controlled, parallel group, 
multiple dose study on ABX464 in combination with methotrexate 
(MTX), in patients with moderate to severe active Rheumatoid Arthritis 
who have inadequate response to MTX or/and to an anti- tumor 
necrosis factor alpha (TNFα) therapy, or intolerance to anti-TNFα 
therapy. 
 
 
I have carefully read all the pages of this clinical study protocol and I agree to the following:  
• 
To conduct the study as outlined in the protocol, any mutually agreed future protocol amendments 
and with all the terms and conditions set out by ABIVAX. 
• 
Not to implement any changes in the procedures described in the protocol without the prior approval 
of the sponsor and prior to review and written approval by the Ethics Committee and/or Regulatory 
Authorities, unless instructed otherwise by the Regulatory Authorities or the wellbeing of patients is 
jeopardized. 
• 
To conduct the study in accordance with the Good Clinical Practice ICH E6 (R2) guidelines, US 21 
Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 concerning 
informed consent and IRB regulations), the European Union Clinical Trials Directive 2005/28/EC, 
the provisions of the Helsinki Declaration, and relevant legislation in force.  
• 
I am thoroughly aware of the study drug specifications and adverse events as described in the 
protocol and the current Investigator’s Brochure and any other information provided by the Sponsor. 
• 
To ensure that sub-investigator(s) and other relevant members of my staff involved in the study are 
fully aware of their responsibilities regarding this study and will conduct the study according to the 
protocol.  
 
Investigator’s Name:   
 
________________________________________ 
Investigator’s Signature:  
 
________________________________________ 
Date:   
 
 
 
________________________________________ 
 
 


ABIVAX 
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Study code: ABX464-301 
October 24th, 2019 
V4.0 
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TABLE OF CONTENTS 
 
SYNOPSIS 
9 
1. 
INTRODUCTION AND STUDY RATIONALE 
16 
1.1. 
RHEUMATOID ARTHRITIS (RA) 
16 
1.1.1. 
DISEASE 
16 
1.2. 
ABX464 RATIONALE 
18 
1.2.1. 
INVESTIGATIONAL TREATMENT DESCRIPTION 
18 
1.2.2. 
INVESTIGATIONAL PRODUCT DESCRIPTION 
18 
1.2.3. 
INVESTIGATIONAL PRODUCT MODE OF ACTION 
18 
1.2.4. 
RATIONALE FOR THE DEVELOPMENT OF ABX464 IN RHEUMATOID ARTHRITIS 
19 
1.2.5. 
PRECLINICAL DATA OF ABX464 
20 
1.3. 
RATIONALE FOR THE CLINICAL STUDY AND STUDY DESIGN 
22 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
23 
2.1. 
PRIMARY OBJECTIVE 
23 
2.2. 
SECONDARY OBJECTIVES 
23 
2.3. 
PRIMARY ENDPOINT 
23 
2.4. 
SECONDARY ENDPOINTS 
23 
3. 
INVESTIGATIONAL PLAN 
25 
3.1. 
STUDY DESIGN 
25 
3.1.1. 
DESIGN AND METHODOLOGY 
25 
3.1.2. 
DOSE LIMITING TOXICITY (DLT) 
26 
3.1.3. 
DATA SAFETY MONITORING BOARD 
26 
3.2. 
DURATION OF STUDY PARTICIPATION 
26 
4. 
STUDY POPULATION 
27 
4.1. 
NUMBER OF PATIENTS/CENTERS 
27 
4.2. 
ELIGIBILITY CRITERIA 
27 
4.2.1. 
INCLUSION CRITERIA 
27 
4.2.2. 
EXCLUSION CRITERIA 
28 
5. 
STUDY ASSESSMENTS AND PROCEDURES 
29 
5.1. 
STUDY FLOW CHART 
29 
5.2. 
STUDY CONDUCT 
29 
5.2.1. 
SCREENING VISIT (WITHIN 30 DAYS PRIOR TO BASELINE/DAY 0) 
29 
5.2.2. 
BASELINE (FIRST DOSING DAY / DAY 0) 
30 
5.2.3. 
WEEK 1 / DAY 7 (+/- 2 DAYS) - VISIT 1 
31 
5.2.4. 
WEEK 2 / DAY 14 (+/- 2 DAYS), WEEK 4 / DAY 28 (+/- 2 DAYS), WEEK 8 / DAY 56 (+/- 2 DAYS), WEEK 12 / DAY 84 (+/- 2 
DAYS) - VISITS 2, 3, 4, 5 
31 
5.2.5. 
END OF STUDY VISIT (WEEK 15 / DAY 105 ± 2 DAYS) 
32 
5.3. 
DETAIL OF THE STUDY ASSESSMENTS 
32 
5.3.1. 
PHYSICAL EXAMINATION AND VITAL SIGNS 
32 
5.3.2. 
ADVERSE EVENTS OF INTEREST 
33 
5.3.3. 
PREGNANCY 
33 
5.3.4. 
ECG 
33 
5.3.5. 
HEMATOLOGY AND BIOCHEMISTRY 
33 
5.3.6. 
PHARMACOKINETICS 
34 
5.3.7. 
DISEASE PARAMETERS 
34 
5.3.8. 
SUMMARY OF BLOOD SAMPLES 
37 
6. 
INVESTIGATIONAL PRODUCT(S) 
38 
6.1. 
DESCRIPTION OF INVESTIGATIONAL TREATMENT 
38 
6.2. 
DESCRIPTION OF INVESTIGATIONAL PRODUCT 
38 
6.2.1. 
ACTIVE INVESTIGATIONAL PRODUCT (ABX464) 
38 
6.2.2. 
PLACEBO 
38 
6.3. 
ADMINISTRATION AND DOSING 
39 
6.3.1. 
ADMINISTRATION OF THE INVESTIGATIONAL PRODUCT 
39 
6.3.2. 
GUIDELINES FOR TREATMENT POSTPONEMENT AND DOSE MODIFICATIONS 
39 
6.4. 
METHOD OF ASSIGNING PATIENTS TO TREATMENT ARMS 
39 
6.5. 
BLINDING AND BREAKING THE STUDY BLIND 
40 
6.6. 
PACKAGING 
40 
6.8. 
PRODUCT ACCOUNTABILITY 
40 
6.9. 
PRIOR AND CONCOMITANT MEDICATION 
40 
6.9.1. 
MANDATORY CONCOMITANT TREATMENT 
40 
6.9.2. 
ALLOWED CONCOMITANT MEDICATIONS 
41 
6.9.3. 
PROHIBITED CONCURRENT MEDICATIONS 
41 
6.10. 
LIFE STYLE GUIDELINES 
41 
7. 
PATIENT COMPLETION AND WITHDRAWAL 
42 
7.1. 
PATIENT COMPLETION 
42 
7.2. 
PREMATURE TRIAL DISCONTINUATION 
42 
7.3. 
STUDY DISCONTINUATION 
42 
7.4. 
SCREEN AND BASELINE FAILURES 
42 
8. 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) 
44 
8.1. 
DEFINITION OF AN AE 
44 
8.2. 
DEFINITION OF A SAE 
44 
8.2.1. 
EVENTS AND/OR OUTCOMES NOT QUALIFYING AS SAES 
45 
8.3. 
EVENTS OR OUTCOMES QUALIFYING AS AES OR SAES 
45 


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8.3.1. 
CLINICAL LABORATORY PARAMETERS 
45 
8.3.2. 
PREGNANCY REPORT 
45 
8.4. 
TIME PERIOD, AND FREQUENCY OF DETECTING AES AND SAES 
45 
8.5. 
RECORDING AES AND SAES 
46 
8.6. 
REPORTING OF SAES TO ABIVAX OR ITS DESIGNEE 
46 
8.7. 
REPORTING OF SAES TO REGULATORY AUTHORITIES 
47 
9. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
48 
9.1. 
STATISTICAL AND ANALYTICAL PLANS 
48 
9.1.1. 
PROTOCOL DEVIATIONS 
48 
9.1.2. 
DEFINITION OF STUDY ANALYSIS SETS 
48 
9.1.3. 
PATIENTS/PATIENTS DISPOSITION 
48 
9.1.4. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
48 
9.1.5. 
TREATMENT COMPLIANCE 
48 
9.2. 
PHARMACOKINETICS 
49 
9.3. 
SAFETY ANALYSES 
50 
9.4. 
CLINICAL LABORATORY EVALUATION 
50 
10. STUDY CONDUCT CONSIDERATION 
52 
10.1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
52 
10.1.1. 
GENERAL REQUIREMENTS 
52 
10.1.2. 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
52 
10.1.3. 
PATIENT INFORMED CONSENT 
52 
10.1.4. 
COMPENSATION TO PATIENTS 
53 
11. STUDY MANAGEMENT 
54 
11.1. 
REMOTE DATA ENTRY 
54 
11.2. 
DATA MANAGEMENT 
54 
11.3. 
DATA CODING 
54 
11.4. 
RANDOMIZATION 
54 
11.5. 
STUDY MONITORING 
54 
11.6. 
RECORDS RETENTION 
55 
11.7. 
QUALITY ASSURANCE AND INSPECTION BY AUTHORITIES 
55 
11.8. 
STUDY AND SITE CLOSURE 
56 
11.9. 
STUDY REPORT AND PUBLICATION 
56 
11.10. OWNERSHIP AND CONFIDENTIALITY 
56 
12. REFERENCES 
57 
13. APPENDICES 
58 
 
 


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October 24th, 2019 
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ABBREVIATIONS 
Abbreviation or Term 
Definition 
Ab 
Antibodies 
ABX 
Abivax 
Ag 
Antigens 
ACPA 
Anti-Citrullinated Peptide Antibody 
ACR 
American College of Rheumatology 
AE 
adverse event 
IA 
Intra-articular 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvate transaminase 
Anti-TNFα therapy 
Anti-tumor necrosis factor alpha therapy 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
AUC0-24 
area under the plasma concentration-versus-time curve from zero to 24 hours 
AUC0-∞ 
area under the plasma concentration-versus-time curve from zero to infinity 
AUC0-t 
area under the plasma concentration-versus-time curve from time zero to the time of the last quantifiable concentration 
Β-HCG 
Beta Human Chorionic Gonadotropin 
Bid 
bis in die (in Latin) twice a day 
BMDM 
Bone Marrow Derived Macrophages 
BMI 
Body Mass Index  
BSL 
Baseline 
CBC 
Cap Binding Complex 
CCL2 
Chemokine Ligand 2 
CDAI 
Clinical Disease Activity Index 
CFR 
Code of Federal Regulations 
CIA 
Collagen Induced Arthritis 
CI 
Confidence Interval 
Cmax 
peak plasma concentration 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CTC-AE 
Common Terminology Criteria for Adverse Events, version 5.0 
CTLA 
Cytotoxic T Lymphocyte Associated (molecule) 
CTFG 
Clinical Trial Facilitation Group 
CYP 
Cytochrome 
DAS 
Disease Activity Score 
DLT 
Dose Limiting Toxicity 
DMARD (cs/b/ts) 
Disease-Modifying Anti-Rheumatoid Drugs (conventional/biologic/targeted) 
DNA 
Deoxyribonucleic Acid 
DBP 
Diastolic Blood Pressure  
DSMB 
Data and Safety Monitoring Board 
DSS 
Dextran Sodium Sulfate 
EC 
ECG 
European Commission 
electrocardiogram 
EDC 
Electronic Data Capture 
EDTA 
ethylenediaminetetraacetic acid 
EOS 
End of Study 
ESR 
Erythrocyte Sedimentation Rate 
EULAR 
European League Against Rheumatism 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy- Fatigue 
FAS 
Full Analysis 
FIH 
First in Human 
FU 
Follow-up 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
GLP 
Good Laboratory Practice 
GM 
Geometric Mean 
GMP 
Good Manufacturing Practice 
H 
hours 
HAQ-DI 
Healthy Assessment Questionnaire-Disability Index 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HR 
heart rate 
IA 
Intra Articular 
IB 
Investigator’s Brochure 
IBD 
Inflammatory Bowel Disease 
ICF 
informed consent form  
ICH 
International Conference on Harmonization 
ID 
Identification 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IR 
Inadequate Response 
IRB 
Institutional Review Board 
IUD 
Intra-Uterine Device 
JAK 
Janus Kinase 
LDA 
Low Disease Activity 
LDH 
Lactate Dehydrogenase 
LPS 
Lipopolysaccharide 
Max 
maximum 
MC 
Methyl Cellulose 
MCP 
Metacarpophalangeal (joint) 
MCP-1 
monocyte chemo attractant protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTX 
methotrexate 
mg 
milligram 
Min 
minimum 
miR 
micro-RNA 
mL 
milliliter 
mmHg 
millimeters of mercury 
MMS 
Modified Mayo Score 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 


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October 24th, 2019 
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o.d. 
Once Daily 
PBMC 
Peripheral Blood Mononuclear Cell 
PCSA 
potentially clinically significant abnormalities 
PD 
pharmacodynamics 
PIP 
Proximal interphalangeal (joint) 
PK 
pharmacokinetics 
pMMS 
Partial Modified Mayo Score 
PP 
Per Protocol 
PT 
Preferred Term 
PtGA 
Patient Global Assessment 
PrGA 
Provider Global Assessment 
qd 
Quaque die (in Latin), once a day 
QTc 
heart-rate–corrected QT interval (time between the start of the Q wave and the end of the T wave in the heart's electrical cycle) using 
Bazett’s formula 
QTcF 
heart-rate–corrected QT interval (time between the start of the Q wave and the end of the T wave in the heart's electrical cycle) using 
Fridericia formula 
R 
Accumulation ratio 
RA 
Rheumatoid Arthritis 
RF 
Rheumatoid Factor 
RHI 
Robarts Histopathology Index 
RNA 
Ribonucleic Acid 
SAF 
Safety 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SCR 
Screening 
SD 
standard deviation 
SDAI 
Simplified Disease Activity Index 
SEM 
standard error of the mean 
SF-36 
Quality of Life Questionnaire 
SJC 
Swollen Joint Count 
SLE 
Systemic Lupus Erythematous 
SOC 
system organ class 
STAT3 
Signal Transducer and Activator of Transcription 3 
t1/2 
terminal half-life 
TB 
Tuberculosis 
TEAE 
treatment emergent adverse event 
TJC 
Tender/painful Joint Count 
tmax 
time to peak plasma concentration 
TMS 
Total Mayo Score 
TNFα 
Tumor Necrosis Factor alpha 
TREX 
Transcription/export complex 
UC 
Ulcerative Colitis 
ULN 
Upper Limit Normal 
VAS 
Visual Analog Scale 
Vd/F 
volume of distribution 
vs 
versus 
WOCBP 
Women of Child Bearing Potential 
 
 


ABIVAX 
Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
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SYNOPSIS 
Study n° ABX464-301 
Clinical Phase 
IIa 
 
 
Type of Study 
Safety, Tolerability, Efficacy Study 
Study title 
Phase IIa randomized, double blind, placebo controlled, parallel group, multiple dose study 
on ABX464 in combination with methotrexate (MTX), in patients with moderate to severe 
active Rheumatoid Arthritis who have inadequate response to MTX or/and to an anti- tumor 
necrosis factor alpha (TNFα) therapy, or intolerance to anti-TNFα therapy. 
Short title 
Phase IIa study of ABX464 in moderate to severe active Rheumatoid Arthritis patients. 
Investigators 
and study 
centers 
Approximately 20 sites in Europe will participate in this study 
Study Duration 
Recruitment period: 
Q2 2019 – Q2 2020 
Overall Study period: 
Q2 2019 – Q4 2020 
Investigational 
product 
ABX464 is a small molecule that binds the Cap Binding Complex (CBC), a protein complex 
sitting at the 5’ ends of RNAs and that is involved in cellular RNA integrity (e.g. splicing). 
ABX464 does not affect RNA biogenesis from cellular genes. ABX464 enhances the splicing 
of a long non-coding RNA to up-regulate microRNA miR-124, which functions as a potent 
endogenous anti-inflammatory mediator. ABX464 has anti-inflammatory properties in dextran 
sulfate sodium (DSS) induced colitis mice model and collagen induced arthritis mice model. 
Administration of ABX464 has demonstrated clinical efficacy in moderate to severe Ulcerative 
Colitis (UC) patients. ABX464 was safe and well tolerated in approximately 200 volunteers 
and patients in phase I and II clinical trials. 
Study Design 
and 
Methodology 
This Phase IIa study aims at investigating the safety and tolerability of 2 dose-levels of 
ABX464 administered daily in combination with methotrexate (MTX) in patients with 
moderate to severe active Rheumatoid Arthritis (RA) who had an inadequate response to 
MTX or/and to one or more anti- tumor necrosis factor alpha (TNFα) therapies. 
In addition, several experimental and clinical endpoints will be assessed to obtain information 
on preliminary efficacy in patients with moderate to severe active Rheumatoid Arthritis. 
Although no formal hypothesis will be tested, these endpoints will enable a broader 
understanding of the mechanism of action and potential for clinical efficacy of ABX464 in 
Rheumatoid Arthritis.  
The first 6 patients will be randomized to receive either ABX464 50mg (n=4) or its matching 
placebo (n=2). The Data Safety Monitoring Board (DSMB) will review the safety of these first 
6 patients dosed for at least 2 weeks. Once the DSMB recommendation is granted, the next 
patients will be randomized to receive either ABX464 50mg, ABX464 100mg or placebo. 
Then, a second DSMB meeting will be held after the next 6 patients are randomized to check 
the tolerability of the 100mg dose. Once the DSMB recommendation is granted, the next 
patients will be randomized to receive either ABX464 50mg, ABX464 100mg or placebo.  
Eligible patients will be randomized, according to a 1:1:1 ratio into 3 parallel 
intervention/treatment groups: 
 
Intervention/treatment Active Arm 
Group #1 (n=20): 100mg qd 
2 capsules of 50mg ABX464 
Group #2 (n=20): 50mg qd 
1 capsule of 50mg ABX464 + 1 capsule of matching 
placebo 
Group #3 (n=20): Placebo 
2 capsules of matching Placebo 
 
Patients will be treated for 12 weeks, followed by a follow-up period (21 days).  
The total duration of participation in the study will be approximately 15 to 19 weeks from 
screening to the last study visit (screening and baseline could occur at the same visit). 
From Day 0 onwards, randomized patients will be seen at the investigational site after 1 week 
(Day 7), 2 weeks (Day 14), 4 weeks (Day 28), 8 weeks (Day 56) and 12 weeks (Day 84) of 
treatment. 
At Week 12 (Day 84 +/- 2 days), patients willing to carry on the study treatment will be able 
to take part in an open-label study (ABX464-302). In any other case, the subjects will exit the 
study (EOS) and will be treated according to the standard of care. The ABX464-302 follow-
up study is a separate clinical study subject to health authorities and ethics committee 


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Study code: ABX464-301 
October 24th, 2019 
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Study n° ABX464-301 
Clinical Phase 
IIa 
 
 
Type of Study 
Safety, Tolerability, Efficacy Study 
approvals. 
In the present study (ABX464-301), randomization will be stratified according to a single 
factor: patients without previous exposure to anti-TNFα therapy versus patients with previous 
exposure to anti-TNFα therapy. 
Study scheme: 
 
Study 
Objectives 
Primary Objective 
The primary objective of the study is to evaluate the safety of ABX464 given at two different 
doses (100mg and 50 mg) vs placebo in combination with MTX when administered once daily 
in patients with moderate to severe active Rheumatoid Arthritis. 
Secondary Objectives 
The secondary objectives are: 
▪ 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 
8 and Week 12 on the American College of Rheumatology (ACR) 20/50/70 response 
and each of its components versus placebo; 
▪ 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 
8 and Week 12 on disease activity scores (DAS28 scores, simplified disease activity 
score [SDAI] and clinical disease activity score [CDAI]) versus placebo; 
▪ 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 
8 and Week 12 on clinical response (DAS28 EULAR good and moderate responses), 
Low Disease Activity (LDA) or remission (DAS28-ESR remission, ACR/EULAR 
remission, SDAI and CDAI remission) versus placebo; 
▪ 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 
8 and Week 12 on the Patient Reported Outcomes (PRO), Healthy Assessment 
Questionnaire – Disability Index (HAQ-DI) and Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue; 
▪ 
To evaluate the expression of miR-124 in total blood (determined by qPCR) at baseline 
and Week 8 
▪ 
To evaluate the effect of the different dose groups of ABX464 at Week 8 on miR-124 
expression in total blood versus placebo; 
▪ 
To assess the pharmacokinetics of the ABX464 and its main active metabolite N-Glu-
ABX464 after oral administration of different daily doses of ABX464 in patients with 
Rheumatoid Arthritis. 
Study 
Endpoints 
 
 
 
 
 
 
 
Primary Safety Endpoint: 
▪ 
Incidence of treatment-emergent adverse events in the ABX464 treated Patients versus 
placebo, categorized by severity 
Secondary Endpoints: 
Main Efficacy Endpoint: 
▪ 
Proportion of patients achieving a categorical ACR20 response at Week 12. 
The components of ACR20 assessment include:  
o 
C-Reactive Protein (CRP) (mg/L),  
o 
Tender/painful joint count (TJC) (28 joints),  
o 
Swollen joint count (SJC) (28 joints),  
o 
Patient assessment of joint pain (Pain-VAS),  
o 
Patient global assessment of disease (PtGA),  
o 
Physician's Global Assessment of Disease (PrGA),  


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Study code: ABX464-301 
October 24th, 2019 
V4.0 
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Study n° ABX464-301 
Clinical Phase 
IIa 
 
 
Type of Study 
Safety, Tolerability, Efficacy Study 
 
 
 
o 
Disability index of the healthy assessment questionnaire (HAQ-DI) 
 
Other secondary endpoints: 
▪ 
Change from Baseline in the following disease parameters at Week 2, Week 4, Week 8 
and Week 12: 
o 
Individual components of the ACR20 response (CRP, TJC(28), SJC(28), Pain-
VAS, PtGA, PrGA, HAQ-DI); 
o 
Erythrocyte Sedimentation Rate (ESR); 
o 
DAS28-CRP and DAS28-ESR. The components of DAS28 assessment include 
TJC(28), SJC(28), CRP/ESR, and PtGA; 
o 
SDAI score which includes TJC(28), SJC(28), CRP, PtGA, and PrGA; 
o 
CDAI score which includes TJC(28), SJC(28), PtGA, and PrGA; 
o 
FACIT-Fatigue score. 
• 
Proportion of patients achieving at Week 2, Week 4, Week 8 and Week 12: 
o 
ACR20/50/70 response  
o 
Categorical DAS28-CRP response. Proportion of patients achieving categorical 
DAS28-CRP response will be measured as moderate/good European League 
Against Rheumatism (EULAR) response at each assessment time point;  
o 
Low Disease Activity (LDA) (DAS28 ≤ 3.2) 
o 
DAS28-ESR remission (DAS28 < 2.6) 
o 
ACR/EULAR remission (TJC(28), SJC(28), CRP, and PtGA: all≤1); 
o 
SDAI remission (SDAI ≤ 3.3); 
o 
CDAI remission (CDAI ≤ 2.8). 
▪ 
Concentration of miR-124 expression in total blood (determined by qPCR) at baseline 
and Week 8 
▪ 
Change from Baseline in miR-124 expression in total blood at Week 8 
▪ 
PK parameters: 
o 
Pre-dose plasma concentration of ABX464/N-Glu at Week 2 and Week 8; 
o 
Post-dose plasma concentration of ABX464/N-Glu at 1-, 2- and 3-hours post-
dose at Baseline, Week 2 and Week 8; 
o 
Trough plasma concentration of ABX464/N-Glu at End of Study Visit 
▪ 
The number of incidences of treatment-emergent serious adverse events; 
▪ 
The number of incidences of treatment-emergent adverse events of special interest; 
▪ 
The number of incidences of adverse events leading to investigational product 
discontinuation; 
▪ 
The number of incidences of clinically significant laboratory abnormalities; 
▪ 
The number of incidences of all AE (causally related and non-related) and SAE, further 
categorized by severity. 
Main Selection 
Criteria 
 
Inclusion criteria: 
A patient will be eligible to participate in this study if ALL the following criteria are met: 
▪ 
Men or women age 18 - 75 years; 
▪ 
Patient with a confirmed and documented diagnosis of adult-onset rheumatoid arthritis, 
for at least 12 weeks, according to the revised 2010 ACR-EULAR classification criteria, 
including at least one positive criteria among the following: Rheumatoid Factor (RF), 
Anti-Citrullinated Peptide Antibody (ACPA) or bone erosion; 
▪ 
Swollen joint count (SJC) of ≥ 4 (28-joint count) and tender joint count (TJC) ≥4 (28-joint 
count) at screening; 
▪ 
Patient with a moderate to severe disease activity score DAS28 CRP ≥ 3.2 and CRP ≥ 
5 mg/L (≥ 4.76 nmol)/L) at screening; 
▪ 
Patient who had an inadequate response (IR), or failed either methotrexate (MTX) or/and 
anti-TNFα therapy (both administered for at least 12 weeks before IR) or were intolerant 
to anti- TNFα therapy.  


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Study code: ABX464-301 
October 24th, 2019 
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Study n° ABX464-301 
Clinical Phase 
IIa 
 
 
Type of Study 
Safety, Tolerability, Efficacy Study 
In addition, MTX treatment should be given at a stable dose ≥ 10 mg/week (for at least 
4 weeks prior to randomization). The maximal dose of methotrexate should not exceed 
a total of 20 mg/week.  MTX treatment should be associated with folic acid at a dose ≥ 5 
mg/week. 
For the anti-TNFα therapy, the following wash-out period will be required: 
o 
30 days prior to randomization for adalimumab and etanercept 
o 
2 months prior to randomization for infliximab, certolizumab pegol, golimumab 
▪ 
Patients with the following hematological and biochemical laboratory parameters 
obtained within 14 days prior to baseline: 
o 
Hemoglobin > 9.0 g dL-1; 
o 
Absolute neutrophil count ≥ 1000 mm-3; 
o 
Platelets ≥ 100,000 mm-3; 
o 
Total serum creatinine ≤ 1.3 x ULN (upper limit of normal); 
o 
Creatinine clearance > 50 mL min-1 by the Cockcroft-Gault equation within 60 
days prior to baseline; 
o 
Total serum bilirubin < 1.5 x ULN; 
o 
Alkaline phosphatase, AST (SGOT) and ALT (SGPT) < 1.5 x ULN; 
o 
Negative screening for TB  and HIV, HCV, HBV 
▪ 
Patients are able and willing to comply with study visits and procedures as per protocol; 
▪ 
Patients should understand, sign and date the written voluntary informed consent form 
at the screening visit prior to any protocol-specific procedures are performed; 
▪ 
Patients should be affiliated to a social security regimen (for French sites only); 
▪ 
Females and males receiving the study treatment and their partners must agree to use 
a highly effective contraceptive method during the study and for 6 months after end of 
study or early termination. Contraception should be in place at least 2 weeks prior to 
screening. Women must be surgically sterile or if of childbearing potential must use a 
highly effective contraceptive method. Women of childbearing potential (WOCBP) will 
enter the study after confirmed menstrual period and a negative pregnancy test. Highly 
effective methods of contraception include true abstinence, intrauterine device (IUD) or 
hormonal contraception aiming at inhibition of ovulation, intrauterine hormone releasing 
system, bilateral tubal ligation, vasectomized partner. True abstinence is defined when 
this is in line with the preferred and usual lifestyle of the patient. In each case of delayed 
menstrual period (over one month between menstruations) confirmation of absence of 
pregnancy is required. This recommendation also applies to WOCBP with infrequent or 
irregular menstrual cycle. Female and male patients must not be planning pregnancy 
and male patients should use condom and must not donate sperm during the trial and 
for 6 months post completion of their participation in the trial.  
Exclusion Criteria: 
The following criteria should be checked at the time of screening. If ANY exclusion 
criterion applies, the patient will not be included in the study: 
▪ 
Patient with a known positive anti-double stranded deoxyribonucleic acid (DNA [anti-
dsDNA]) and confirmed diagnosis of systemic lupus erythematosus (SLE); 
▪ 
Patients with active infection or the following history of infection(s) (the list is not 
exhaustive): 
o 
Active infection (except benign infections, according to investigator’s opinion) 
within 14 days prior to inclusion. 
o 
Serious infection, defined as an infection requiring hospitalization or IV 
infusion of anti-infective agents in the 2 months prior to inclusion. 
o 
A history of opportunistic, recurrent or chronic infections that, in the 
investigator’s opinion, could render this study detrimental to the patient. 
• 
Patients who have received or are expected to receive a live (including attenuated) 
vaccine within 3 months prior to baseline; 
▪ 
Acute, chronic or history of clinically relevant (as per investigator’s judgement) 
pulmonary, cardiovascular, hepatic, pancreatic or renal functional abnormality, 
encephalopathy, neuropathy or unstable CNS pathology such as seizure disorder, 
angina or cardiac arrhythmias, active malignancy or any other clinically significant 


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Study code: ABX464-301 
October 24th, 2019 
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Study n° ABX464-301 
Clinical Phase 
IIa 
 
 
Type of Study 
Safety, Tolerability, Efficacy Study 
medical problems as determined by physical examination and/or laboratory screening 
tests and/or medical history; 
▪ 
Acute, chronic or history of immunodeficiency or other autoimmune disease; 
▪ 
Patient previously treated with any (approved or investigational) non-anti-TNF biological 
disease-modifying antirheumatic drugs (bDMARDs), and targeted DMARDs (tDMARDS) 
prior to baseline. These treatments include: IL-6 antagonists, Janus Kinase (JAK) 
inhibitors, cytotoxic T lymphocyte-associated molecule CTLA-4Fc Chimera, rituximab; 
▪ 
Patient treated with systemic corticosteroids >10 mg/day during the 2 weeks prior to and 
at randomization; IV or IM injections of glucocorticoids 4 weeks prior to randomization 
and IA glucocorticoids 2 weeks prior to randomization; 
▪ 
Patients treated with other immunosuppressive drugs; 
▪ 
History of malignancy (other than resected cutaneous basal cell or squamous cell 
carcinoma that has been treated with no evidence of recurrence) unless it has been 
treated and a cure is achieved for at least 5 years; 
▪ 
Serious illness requiring systemic treatment and/or hospitalization within 3 weeks prior 
to baseline; 
▪ 
Pregnant or breast-feeding woman; 
▪ 
Illicit drug or alcohol abuse or dependency; 
▪ 
Use of any investigational or non-registered product within 3 months or within 5 half-lives 
preceding baseline, whichever is longer; 
▪ 
Any condition, which in the opinion of the investigator, could compromise the patient's 
safety or adherence to the study protocol. 
Medications 
Mandatory Medications: 
▪ 
ABX464 or its matching placebo administered once daily; 
▪ 
MTX ≥ 10 mg/week, at previous dose regimen kept stable throughout the study; the 
maximal dose of methotrexate should not exceed a total of 20 mg/week 
▪ 
Folic acid ≥ 5 mg/week post MTX dose, to minimize MTX toxicity. 
Potential Drug-Drug Interactions (DDIs) with methotrexate: 
ABX464 is mainly metabolized by CYP1A2 and glucuro-conjugated. Methotrexate undergoes 
hepatic and intracellular metabolism to polyglutamated forms.  
Multiple DDIs have been documented with methotrexate. In this study, potential methotrexate 
interactions on ABX464 will be sought using an on-going PK modelling approach. 
For documented DDIs with methotrexate, please refer to the Appendix 5. 
Allowed Concomitant Medications: 
▪ 
Corticosteroids at stable dose of prednisone and prednisone equivalent ≤10 mg/day 
during the study; 
▪ 
Non-steroidal anti-inflammatory drugs (NSAIDs) at stable dose during the study; 
▪ 
Antalgics including class III at stable dose during the study; 
▪ 
Other non-rheumatologic medications. 
Prohibited Concomitant Medications: 
▪ 
Any non-anti-TNFα biological or targeted DMARDs: IL-6 antagonists, JAK inhibitors, 
CTLA-4Fc Chimera, rituximab; 
▪ 
Any immunosuppressive drugs; 
▪ 
Vaccination with live components during the study and up to 8 Weeks after the last 
dosing;  
▪ 
Drugs that could interact with ABX464 should be avoided especially the CYP1A2 
substrates. The following CYP1A2 substrates with a narrow therapeutic margin are 
prohibited during the whole course of the study (rifampicin, clozapine, theophylline, 
ropinirole, warfarin, and methadone). In case of concomitant treatment with 
ondansetron, the maximal daily dose must be limited to 8 mg; 
▪ 
Use of any investigational or non-registered product within 3 months preceding baseline. 
Premature trial 
discontinuation 
Patient’s premature trial discontinuation must occur for the following reasons: 
▪ 
Investigator’s decision; 
▪ 
An Adverse Event or an intercurrent condition that preclude continuation of treatment; 


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Study code: ABX464-301 
October 24th, 2019 
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Study n° ABX464-301 
Clinical Phase 
IIa 
 
 
Type of Study 
Safety, Tolerability, Efficacy Study 
o 
Specifically, an increase ≥ 3.0 x ULN in liver transaminases (AST/SGOT and/or 
ALT/SGPT) or an increase ≥ 2.0 x ULN in Alkaline phosphatase or in total bilirubin 
requires close observation with repeating liver enzymes and serum bilirubin tests 
two times weekly and clinical investigation to understand the etiology of this 
elevation. Frequency of retesting can decrease to once a month if abnormality 
stabilizes after this initial two weeks of follow-up and if the patient is asymptomatic. 
Discontinuation of the study treatment should occur if: 
• 
 ALT or AST > 8xULN 
• 
ALT or AST >5xULN for more than 2 weeks 
• 
ALT or AST > 3xULN and total bilirubin > 2xULN or INR>1.5 
• 
ALT or AST > 3xULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
▪ 
Worsening of the RA (according to physician evaluation); 
▪ 
Major protocol violation; 
▪ 
Withdrawal of consent; 
▪ 
Administrative reasons from Sponsor. 
Patient Follow-
up  
On Day 84 +/- 2 days, patients willing to carry on the study treatment will be able to take part 
in an open-label study (ABX464-302). In any other case, the subjects will exit the study (EOS) 
and will be treated according to the standard of care. The ABX464-302 follow-up study is a 
separate clinical study subject to health authorities and ethics committee approvals. 
Data Safety 
Monitoring 
Board (DSMB)  
A Data Safety Monitoring Board with expertise and experience in the management of 
Rheumatoid Arthritis will review the safety of the trial. The DSMB will meet after the first 6 
patients (i.e. 50mg) are dosed for at least 2 Weeks to check the 50mg dose tolerability. Once 
the DSMB recommendation is granted, the next 6 patients will be randomized to receive 
either ABX464 50mg, ABX464 100mg or placebo. A second DSMB meeting will then be held 
when these 6 next  patients are treated for at least 2 weeks, to check the 100mg dose 
tolerability and grant the recommendation to resume patient’s randomization. 
In addition, from the first DSMB onwards, meetings will be held every month during the study 
period. 
Sample Size 
calculation 
The primary efficacy endpoint is the ACR20 response rate of subjects. This response rate 
will be compared in subjects who received ABX464 or placebo by likelihood ratio chi-square 
test. For the sample size assessment, the following assumptions will be made: 
• 
Response rate (ABX464): 0.65 
• 
Response rate (placebo): 0.25 
• 
Type 1 error: 10% two-sided 
• 
Group allocation rate (ABX464 100mg / ABX464 50mg / placebo): 1:1:1 
If the above assumptions and definitions hold true with a sample size of 60 subjects receiving 
two doses of ABX464 or placebo in a ratio of 1:1:1 the study has 84% power to show a 
difference in response rate between one active study group and placebo. 
Statistical 
Methods 
 
Safety: 
Analysis of safety will be performed on the safety data set consisting in all subjects who 
received at least one dose of ABX464 in the study.  
Primary safety endpoint, the rate of all treatment emergent adverse experiences, will be 
compared in subjects who received a given dose of ABX464 or placebo by likelihood ratio 
chi-square test on a 10% two-sided significance level.  
Further assessment of safety will be based on the frequency of adverse events (with and 
without regard to causality) graded according to the “CTC-AE” (Version 5.0) and also, the 
review of individual values for clinical laboratory data, vital signs and ECG focusing on the 
detection of abnormal values and PCSAs [potentially clinically significant abnormalities 
(PCSAs) determined upon investigator considerations]. 
Adverse events will be tabulated (counts and percents) by group. All adverse events will be 
listed, and the data will be tabulated by body system/organ class. Adverse event tabulations 
will include all treatment emergent adverse events, which will be further classified by severity, 
and relationship to treatment. 
Clinical laboratory parameters, vital signs, ECG will be summarized by using descriptive 
statistics (n, mean, SD, SEM, median, minimum and maximum). Number of subjects with at 


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Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
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Study n° ABX464-301 
Clinical Phase 
IIa 
 
 
Type of Study 
Safety, Tolerability, Efficacy Study 
least one abnormal value will be tabulated (counts and percents) for each parameter in 
summary shift tables by group. 
Efficacy:  
Analysis of efficacy data will be carried out in the Full Analysis Set in which subjects who 
prematurely terminate the study will be considered failures. 
The primary efficacy endpoint of the study, the ACR20 response rate, will be compared in 
subjects who received a given dose of ABX464 or placebo by likelihood ratio chi-square test 
on a 10% two-sided level. The result of the test will be interpreted in a descriptive manner 
therefore no adjustment for the multiple comparison is applied. 
In addition, descriptive statistics will be presented by treatment arm for all secondary efficacy 
variables for each measurement timepoints separately for the two study groups. 
These statistics include: 
o 
Continuous variables: mean, standard deviation, minimum and maximum, stratified 
95% confidence intervals, median and quartiles will be presented. 
o 
Categorical variables: counts, rates and stratified 95% confidence intervals for the 
rates will be calculated. 
In addition to descriptive statistics, mixed model analysis of covariance will be conducted for 
the following measurements: 
o 
The change from baseline in DAS28-CRP and DAS28-ESR 
o 
The change from baseline in the individual components of the ACR20 response 
(CRP, TJC(28), SJC(28), Pain-VAS, PtGA, PrGA, HAQ-DI) and in ESR 
o 
The change from baseline in SDAI and CDAI scores  
o 
The change from baseline in miR-124 in total blood at Week 8 
In this model, treatment will be fixed effect, subjects will be random effect, and baseline 
values of the respective measurements will be covariates. Other explanatory variables will 
also be allowed to be included in the model. In order to normalize eventual skewed 
distributions transformation of the data will also be considered. Study groups will be 
compared within this model framework. All p-values will be interpreted in a descriptive 
manner. 
 
Pharmacokinetics: 
Even though the PK characteristics of ABX464 are well documented in healthy volunteers 
and HIV-infected subjects, the RA condition deserves a population PK exploration. 
Hence, PK determinations will be performed in subjects enrolled in this study. The PK 
evaluation consists of pre-dose samples on Week 2 and Week 8, 1-, 2- and 3-h post-dose 
samples on Baseline, Week 2 and Week 8, and trough-dose sample on EOS visit. 
The following PK parameters will be derived for ABX464, NGlcABX464 for each subject: 
o 
Cmax, tmax: the maximum plasma concentration (Cmax) and the time taken to reach 
Cmax (tmax) will be obtained directly from the concentration-time data. 
o 
AUC0-τ: the area under the concentration-time curve from time zero to the time of 
dosing interval τ (12 h post-dose for ABX464 and NGlcABX464). If no concentration 
can be measured at this time point, AUC0-last (from time zero to the last quantifiable 
concentration) will be calculated. Both parameters will be presented independently. 
For both parameters, a linear trapezoidal method will be used 
 
 


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October 24th, 2019 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. Rheumatoid Arthritis (RA) 
1.1.1. Disease 
Rheumatoid arthritis (RA) is the most common auto-immune inflammatory arthritis in adults, 
characterized by a progressive functional impairment (1). RA has a significant negative impact on the 
ability to perform daily activities, including work and household tasks, and health- related quality of life, 
and it increases mortality (2,3). 
1.1.2. Management of patients 
The treatment of RA consists of an integrated approach that includes pharmacologic and non-
pharmacologic therapies, including exercise, diet, massage, counseling, stress reduction, physical 
therapy and surgery. Active participation of the patient and the family in the design and implementation 
of the therapeutic program helps boost morale and ensure compliance (4). 
Arthritis medication plays an essential role in controlling the progression and symptoms of RA (joint 
damage, pain, stiffness, inflammation and complications). The treatment will depend of the stage of the 
disease. 
The 2015 American College of Rheumatology and the 2016 EULAR guidelines recommends for the 
treatment of RA the use of methotrexate (MTX), or in case of contra-indication, the use of another 
conventional disease-modifying antirheumatic drugs (cDMARDs), including hydroxychloroquine, 
leflunomide, and sulfasalazine (5,6).  
Low-dose glucocorticoids (≤10 mg/day of prednisone or equivalent) could be added in patients with 
moderate or high RA disease activity or during RA disease flares. Analgesics, such as paracetamol or 
non-steroidal anti-inflammatory drugs (NSAIDs) might relieve symptoms such as pain and stiffness (4). 
If disease activity remains moderate or high despite DMARD monotherapy, either other csDMARD 
therapy might be used or a biologic DMARD (bDMARD), such as anti-Tumor Necrosis Factor (TNF) 
therapies (infliximab, etanercept, adalimumab, certolizumab or golimumab), non-TNF biologic DMARDs 
(abatacept, tocilizumab, sarilumab or rituximab in certain circumstances) or a Janus-Kinase (JAK) 
inhibitor (baricitinib, tofacitinib) might be used, preferentially in combination with MTX. 
If the disease activity remains moderate or high despite the use of targeted therapy (b or tsDMARD), a 
switch to another targeted therapy will be proposed, preferentially in combination with MTX (5, 6). 


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Study code: ABX464-301 
October 24th, 2019 
V4.0 
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Figure 1: Algorithm based on the 2016 EULAR recommendation on RA management (6) 


ABIVAX 
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October 24th, 2019 
V4.0 
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A failure to respond to anti-TNF therapies remains a serious concern for patients with RA. Although 
some patients experience a primary lack of drug efficacy in reducing their symptoms, others fail to 
maintain an initial response because of acquired drug resistance. Switching to another anti-TNF therapy 
is a common practice for patients who are not responsive. However, if more than one anti-TNF therapy 
has provided inadequate response and/or similar tolerability issues, switching to a different class of 
agent, with a mechanism of action unrelated to TNF inhibition, may provide a more effective option (7). 
1.2. ABX464 rationale 
1.2.1. Investigational treatment description 
ABX464 is a first in class and unique small molecule that has demonstrated an anti-HIV effects and anti-
inflammatory properties in several pre-clinical models and in patients. 
ABX464 was shown to be able to reduce the viral load in a transgenic mice model during treatment 
period. This viral load reduction was maintained after ABX464 discontinuation demonstrating a long-
lasting effect. ABX464 was also shown to be effective on all clinical HIV strains tested and did not induce 
any resistance up to 24 Weeks of treatment. Therefore, ABX464 is being developed throughout Phase 
IIa studies in patients infected by the HIV. 
Besides its antiviral indication (HIV), in-vitro assays revealed that both ABX464 and its primary 
metabolite, N-Glu-ABX464, induced a significant increase in miR-124 expression in PBMCs and up-
regulated a cytokine (IL-22) in LPS-stimulated BMDMs (Bone Marrow Derived Macrophages). 
MiR-124 is known for its anti-inflammatory effects.  Reduced levels of miR-124 in colon tissues of 
children with active UC appear to increase expression and activity of STAT3, which could promote 
inflammation and pathogenesis of UC in children [7]. In addition, IL-22 is a key cytokine in intestinal 
inflammation recovery [8]. 
These findings suggest that the modulation of miR-124 by ABX464 led to study disease specific anti-
inflammatory effects. 
1.2.2. Investigational product description  
The chemical name of ABX464 molecule is 8-chloro-N-[4-(trifluoromethoxy) phenyl]quinolin-2-amine, or 
(8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine. Its molecular weight is 338.7. 
The study drug is formulated as hard gelatin, powder-filled capsules (size 1). 
1.2.3. Investigational product Mode of Action 
HIV Indication: 
Alternative splicing is a key event for HIV replication. Successful infection and production of new 
infectious viruses requires the balanced expression of seven additional viral proteins (Rev, Tat, Nef, 
Vif, Vpr, Vpu and Env) that are produced by splicing of the primary 9 kb transcripts among which the 
Tat and the Rev factors are absolutely required for viral gene expression at the transcriptional and post-
transcriptional levels in infected cells. While most cellular unspliced RNAs are retained in the nucleus 
where they are degraded, nuclear export of the unspliced viral RNAs is facilitated by the Rev protein, 
through binding to a viral sequence called the rev responsive element (RRE). Both RNA export and RNA 
splicing are controlled by the cap binding complex (CBC) which interacts directly with either Rev or the 
transcription/export (TREX) complex, a multiprotein complex, required for transcription and export of 
bulk mRNAs. These interactions are thought to recruit Rev and TREX to a region near the 5′-terminal 
cap structure of mRNA and thereby connect the transcription and export of newly transcribed RNAs. 
ABX464 by binding directly to CBC, specifically prevent Rev-mediated splicing and export of viral RNA 
without interfering with cap binding or export of cellular transcripts. 
UC indication 
The mechanism of action of ABX464 in UC is mediated throughout the observed effect on miR-124 
observed in vitro and in patients. ABX464 in a DSS mice model has no effect on the expression profile 
of cytokines and chemokine signaling pathways in the absence of DSS exposure. Interestingly, in 
presence of dextran sodium sulfate (DSS), ABX464 compensated for most of the expression differences 


ABIVAX 
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Study code: ABX464-301 
October 24th, 2019 
V4.0 
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induced by DSS exposure, which suggests that ABX464 restores the transcriptional program modified 
by DSS in the colon. In addition, in the DSS model, ABX464 leads to reduced expression of pro-
inflammatory cytokines: IL-6 (2x), TNF (7.5x) and MCP-1 (6x). 
1.2.4. Rationale for the development of ABX464 in Rheumatoid Arthritis 
In-Vitro assays 
▪ 
Modulation of miR-124 by ABX464 
Study ABX464PHA011 performed in humans PBMCs revealed that both ABX464 and its primary 
metabolite N-Glu-ABX464 induced a significant increase in miR-124 expression. MiR-124 appears to 
regulate the expression of signal transducer and activator of transcription 3 (STAT3). MiR-124 has also 
been shown to be required for the protective role of nicotine in DSS colitis mice. 
▪ 
Bone Marrow Derived Macrophages – LPS Challenge  
Stimulation of BMDMs with LPS induced the expression of IL6, TNFα, and MCP1 (CCL2) but not that of 
IL10 (Figure 2B). The expressions of MCP1 and IL6 persisted for 48 h post LPS-stimulation, whereas 
TNF expression was down-regulated at 12 h (Figure 2B). Strikingly, ABX464-exposed BMDMs displayed 
an increased production of IL-10 at 12 and 24 h post LPS-stimulation but did not alter levels of the pro-
inflammatory cytokines IL6 and TNFα (Figure 2B).  
 
Figure 2. Effect of ABX464 on cytokine secretion (A) Bone marrow isolated cells were cultured for 6 days in the presence of GM-CSF (50ng/ml) 
to differentiate into macrophages. Cells were kept in culture for additional 3 days in the presence of ABX464 (5µM) or vehicle (DMSO) alone and for 
additional 6 hours stimulated with LPS (4µg/ml). Cells were then kept in normal medium for additional 42 hours. Cell aliquots for RNA isolation and 
supernatants were taken at time 6, 12, 24 and 48 hours. (B) Culture supernatants of the indicated cell cultures were analyzed by CBA for the content 
of MCP-1, IL-6, TNFalpha and IL-10. 
In-Vivo assays 
▪ 
Collagen induced arthritis mouse model  
The Collagen Induced Arthritis (CIA) protocol induces Arthritis in DBA1 mice.  
Collagen induced arthritis (CIA) 
 
In this model, the inflammation is characterized by persistent joint swelling and progressive destruction 
of cartilage and bone.  


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To test the protective effect of ABX464, the compound was suspended in methylcellulose (MC 0,5/100) 
and administered daily from week 12 via gavage (per os).  
In experiment 1: Named “DBA-1” 
▪ 
Mice were treated as follow (10 animals per cohort were distributed in two cages): 
▪ 
Cohort 1: 10 male mice gavage ABX464 40mg/Kg  
▪ 
Cohort 2: 9 male mice gavage MC (carrier) 
▪ 
Cohort 3: 6 female mice gavage MC (carrier) 
In experiment 2: Named “DBA-2” 
▪ 
Cohort 1: 10 male mice gavage ABX464 40mg/Kg  
▪ 
Cohort 2: 10 male mice gavage MC (carrier) 
▪ 
Cohort 3: 10 male mice gavage H2O  
In these two experiments, DBA-1 & 2, cohort 1 & 2 were repetition of sampling in two independent 
experiments. In experiment DBA-1, cohort 3 tested if females are equally sensible to induction of CIA. 
In Experiment DBA-2, cohort 3 received a water gavage per os in place of MC to test if the water 
retention of the MC modified the result. 
Mice were examined visually for the appearance of arthritis in the peripheral joints and disease severity 
was graded. Mice were considered to have arthritis when significant changes in swelling were noted in 
the digits & limb. 
The swelling was measured, and a value of inflation was measured for every limb and the average was 
made. The exact average of joint swelling week 21 is indicated for each of both independent experiment 
on the graph following for each of the animal on MC and ABX464 and the P value was notified. 
DBA-1 model  
 
 
 
DBA-2 model 
               
 
 
In this study, a specific effect of ABX464 was found on Collagen Induced Arthritis (CIA). The daily 
contribution of 40mg/Kg of ABX464 given “per-os” allowed to reduce significantly the inflammation 
noticed by joint swelling, with two independents experiments, in this model. 
1.2.5. Preclinical data of ABX464 
 
1.2.5.1. 
Non-clinical background information 
ABIVAX conducted a large pre-clinical toxicology program with ABX464. This program includes five 
different animal species (i.e. cynomolgus and marmoset monkeys, rats, beagle dogs and mini-pigs). 
joint swelling (Averages of 4 legs)
mm
DBA1-ABX464
DBA1-MC
1.6
1.8
2.0
2.2
2.4
2.6
2.8
P value 0,0236 *
joint swelling (Averages of 4 legs)
mm
DBA2-ABX464
DBA2-MC
DBA2-H2O
1.6
1.8
2.0
2.2
2.4
2.6
P value 0,0015 * *


ABIVAX 
Clinical Study Protocol 
Study code: ABX464-301 
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In the rat, 4-Week and 13-Week GLP repeated dose-studies were performed. In the 4-Week repeated 
dose-study ABX464 was overall well tolerated, transient and minor histological alterations were noted 
in the stomach for the highest dose-levels of 150 and 250 mg/kg b.i.d. The NOAEL was considered to 
be 55 mg/kg b.i.d for 28 days. In the 13-Week repeated dose-study, no adverse findings related to 
ABX464 treatment were observed up to the highest dose of 120 mg/kg o.d., the NOAEL was considered 
to be 120 mg/kg o.d. for 13 Weeks. 
In non-human primates, ABX464 oral treatment induced frequent vomiting, body weight loss and 
gastrointestinal inflammation for dose-levels of 75 mg/kg b.i.d. and above. The main target organs of 
ABX464 toxicity were found to be those of the gastro-intestinal tract. The NOAEL was considered to be 
below 75 mg/kg b.i.d. Treatment of marmoset monkeys with ABX464-N-Glu induced premature death 
at the intermediate dose of 300 mg/kg and the high dose of 1000 mg/kg. Although the death of 2/3 
animals was attributed to misgavage, additional toxicities were observed and included respiratory and 
gastro-intestinal tract signs and a decrease in spontaneous locomotor activity.  
In the dog, ABX464 oral treatment induced digestive effects, body weight losses, impaired food 
consumption and decreased red blood cell parameters for dose levels of 20 mg/kg o.d. and above. The 
NOAEL was considered to be 20 mg/kg o.d. in males and 5 mg/kg o.d. in females. 
In the minipig, in the 14-day study, ABX464 oral treatment induced a reduced food intake associated 
with body weight loss for dose levels of 10 mg/kg o.d and above, which resolved after termination of 
treatment. In the 3-month study, ABX464 at dose levels of 5, 10 and 15 mg/kg o.d. was well tolerated 
since no findings of toxicological importance were described. However, toxic effects appeared shortly 
before completion of the third month of treatment in the 26/39 Weeks study in minipigs at the same 
dose-levels. The main adverse finding was centrilobular hepatocellular degeneration/necrosis 
associated with hemorrhage, fibrosis and /or extramedullary hematopoiesis observed at dose levels of 
10 mg/kg and above. The liver lesions observed in the single animal administered 5 mg/kg o.d. were 
not considered adverse.  Based on this observation, the NOAEL was considered to be 5 mg/kg o.d. 
ABX464 was found to be non-genotoxic. Its main metabolite, the ABX464-N-Glu was not mutagenic as 
assessed by an Ames test, an in vitro and an in vivo micronucleus assay. 
Reprotoxicity assessed from fertility to postnatal development, was explored in five studies. In rabbits, 
the maternal NOAEL was considered to be 9 mg/kg o.d. and the NOAEL for the embryo-fetal 
development less than 1 mg/kg o.d. In rats, the maternal NOAEL and the NOAEL for pup development 
and survival is considered to be lower than 15 mg/kg o.d.. The F1 generation NOAEL is considered to 
be 40 mg/kg o.d. in absence of adverse effect at this dose-level. 
It is likely that ABX464 has teratogenic activity and the main target organs of ABX464 toxicity were found 
to be the gastro-intestinal tract and the liver. 
No signs of hepatotoxicity have been observed in any of the patients treated with ABX464 in the 
previously conducted or on-going clinical trials. ABIVAX and its clinical experts consider that patients 
treated with ABX464 are not at increased risk of developing a drug-induced hepatotoxicity.  
A specific liver function monitoring plan has been implemented in the current clinical study. 
Regarding the other observations made from the pre-clinical toxicology program, please refer to the 
current version of the Investigator Brochure. 
1.2.6. Previous clinical experience with ABX464 
A First In Human (FIH), Single dose, dose-escalating exploratory study evaluating ABX464 administered 
at 50, 100, 150 or 200mg to healthy male volunteers has been completed. Pharmacokinetic data 
collected in this study showed that ABX464 is substantially metabolized into the ABX464-N-glucuronide. 
ABX464’s Cmax was observed approximately 2 hours after dosing in all groups, with mean values 
ranging from 14 to 72 ng/mL. ABX464-N-glucuronide’s Cmax was about 160-fold higher. The limit of 
exposure was reached at 150 mg. No serious adverse events were reported during the study. Thirteen 
(13) patients experienced mild to moderate headache, nausea and/or vomiting. No clinically significant 
abnormal results were noted in physical examinations, laboratory test results, vital signs and ECG. 
The drug was well tolerated up to 150 mg, three out of six patients experienced vomiting at 200 mg. 
Nausea and headaches were reported in these patients. 


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A second exploratory trial (ABX464-002/ABX464-FE-001) in male healthy volunteers investigating the 
potential effects of food on pharmacokinetic parameters of ABX464 administered at single and repeated 
doses of 50 mg has been completed. No serious adverse events related to the IMP have been reported. 
The main adverse events recorded were headache, nausea and vomiting. A significant increase in 
ABX464 exposure was observed in the fed group and no significant impact on ABX464 metabolism was 
noted.  ABX464 should be taken with food. 
A first phase IIa (ABX464-003), dose escalation, placebo-controlled study to evaluate the safety, 
pharmacokinetics, and viral kinetics of ABX464 in naive patients with HIV infection has been recently 
completed. The objective of this study was to evaluate the safety of ABX-464 at ascending doses versus 
placebo in HIV-infected treatment-naive patients. Patients were randomized into successive cohorts of 
8 patients where 6 received 14 or 21 days of ABX464 and 2 placebos.  At day 0, patients received the 
first dose of ABX-464/ placebo in a once daily schedule. Safety assessments and laboratory parameters 
were recorded throughout the study. The only adverse events noted were nausea, vomiting, headache 
and upper abdominal pain. All adverse events were grade 1 or 2 and all patients completed at least 14 
days of treatment. 
A second multi-center, randomized, double-blind, placebo-controlled Phase IIa trial was conducted 
(ABX464-004). The main study objective was to compare the safety of ABX464 given at a fixed dose to 
placebo in fully controlled HIV infected patients treated with boosted protease inhibitor treatment 
(darunavir/ritonavir or darunavir/cobicistat). 50 patients received either ABX464 (50/150mg od) or its 
matching placebo according to a 3/1 ratio. The safety profile was good, and no serious adverse reactions 
were reported. 
A third study in the HIV indication (ABX464-005 / Phase Ia) was conducted at a single site in Spain. Two 
cohorts of HIV-Infected patients dosed respectively with 150mg q.d for 28 days (n=11) and 50mg q.d 
for 84 days (n=13). The safety profile is good and consistent with previous studies. No serious adverse 
reactions have been reported. 
A Proof of Concept study (ABX464-101 / phase IIa) has been carried out in 32 patients with moderate 
to severe Active Ulcerative Colitis who have failed or are intolerant to immunomodulators, Anti-TNFα or 
Corticosteroids. 
For further information, please refer to the current Investigator’s Brochure. 
1.3. Rationale for the clinical study and study design 
This study is the first in disease proof of concept study. The study population (i.e. Subjects with moderate 
to severe active Rheumatoid Arthritis who have failed, had an inadequate response to methotrexate 
(MTX) or/and anti-TNFα therapy (or were intolerant to anti-TNFα therapy) was selected since this 
population consists in subjects who are at need of alternative therapy and in whom the safety profile of 
ABX464 can be reliably assessed. 
The double-bind placebo-controlled design corresponds to a standard in this disease for which a placebo 
effect can be frequently observed. 
 
 
 


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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Primary Objective 
The primary objective of the study is to evaluate the safety of ABX464 given at two different doses 
(100mg and 50 mg) vs placebo in combination with MTX when administered once daily in patients with 
moderate to severe active Rheumatoid Arthritis. 
2.2. Secondary Objectives 
The secondary objectives are: 
▪ 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 8 and 
Week 12 on the American College of Rheumatology (ACR) 20/50/70 response and each of its 
components versus placebo; 
▪ 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 8 and 
Week 12 on disease activity scores (DAS28 scores, simplified disease activity score [SDAI] and 
clinical disease activity score [CDAI]) versus placebo; 
▪ 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 8 and 
Week 12 on clinical response (DAS28 EULAR good and moderate responses), Low Disease 
Activity (LDA) or remission (DAS28-ESR remission, ACR/EULAR remission, SDAI and CDAI 
remission) versus placebo; 
▪ 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 8 and 
Week 12 on the Patient Reported Outcome (PRO), Healthy Assessment Questionnaire – 
Disability Index (HAQ-DI); 
▪ 
To evaluate the expression of miR-124 in total blood (determined by qPCR) at baseline and 
Week 8 
▪ 
To evaluate the effects of different dose groups of ABX464 at Week 8 on miR-124 expression 
in total blood versus placebo; 
▪ 
To assess the pharmacokinetics of the ABX464 and its main active metabolite N-Glu-ABX464 
after oral administration of different daily doses of ABX464 in patients with rheumatoid Arthritis. 
2.3. Primary Endpoint 
The primary endpoint is the incidence of treatment-emergent adverse events in the ABX464 treated 
Patients versus placebo, categorized by severity. 
2.4. Secondary Endpoints 
Main Efficacy Endpoint: 
▪ 
Proportion of patients achieving a categorical ACR20 response at Week 12. 
The components of ACR20 assessment include:  
o 
C-Reactive Protein (CRP) (mg/L),  
o 
Tender/painful joint count (TJC) (28 joints),  
o 
Swollen joint count (SJC) (28 joints),  
o 
Patient assessment of joint pain (Pain-VAS),  
o 
Patient global assessment of disease (PtGA),  
o 
Physician's Global Assessment of Disease (PrGA),  
o 
HAQ-DI 
Other secondary endpoints: 
▪ 
Change from Baseline in the following disease parameters at Week 2, Week 4, Week 8 and 
Week 12: 
o 
Individual components of the ACR20 response (CRP, TJC(28), SJC(28), Pain-VAS, 
PtGA, PrGA, HAQ-DI)  
o 
Erythrocyte Sedimentation Rate (ESR); 


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o 
DAS28-CRP and DAS28-ESR. The components of DAS28 assessment include 
TJC(28), SJC(28), CRP/ESR, and PtGA; 
o 
SDAI score which includes TJC(28), SJC(28), CRP, PtGA, and PrGA; 
o 
CDAI score which includes TJC(28), SJC(28), PtGA, and PrGA; 
o 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score 
▪ 
Proportion of patients achieving at Week 2, Week 4, Week 8 and Week 12: 
o 
ACR20/50/70 response  
o 
Categorical DAS28-CRP response. Proportion of patients achieving categorical 
DAS28-CRP response will be measured as moderate/good European League Against 
Rheumatism (EULAR) response at each assessment time point;  
o 
Low Disease Activity (LDA) (DAS28 ≤ 3.2) 
o 
DAS28-ESR remission (DAS28 < 2.6) 
o 
ACR/EULAR remission (TJC(28), SJC(28), CRP, and PtGA: all≤1); 
o 
SDAI remission (SDAI ≤ 3.3); 
o 
CDAI remission (CDAI ≤ 2.8). 
▪ 
Concentration of miR-124 expression in total blood (determined by qPCR) at baseline and week 
8 
▪ 
Change from Baseline in miR-124 expression in total blood at Week 8 
▪ 
PK parameters: 
o 
Pre-dose plasma concentration of ABX464/N-Glu at Week 2 and Week 8; 
o 
Post-dose plasma concentration of ABX464/N-Glu at 1-, 2- and 3-hours post-dose at 
Baseline, Week 2 and Week 8; 
o 
Trough plasma concentration of ABX464/N-Glu at End of Study Visit 
▪ 
The number of incidences of treatment-emergent serious adverse events; 
▪ 
The number of incidences of treatment-emergent adverse events of special interest; 
▪ 
The number of incidences of adverse events leading to investigational product discontinuation; 
▪ 
The number of incidences of clinically significant laboratory abnormalities; 
▪ 
The number of incidences of all AE (causally related and non-related) and SAE, further 
categorized by severity. 


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3. INVESTIGATIONAL PLAN 
3.1. Study design 
3.1.1. Design and methodology 
This Phase IIa study aims at investigating the safety and tolerability of 2 dose-levels of ABX464 
administered daily in combination with methotrexate (MTX) in patients with moderate to severe active 
Rheumatoid Arthritis (RA) who had an inadequate response to MTX or/and to one or more anti- tumor 
necrosis factor alpha (TNFα) therapies. 
In addition, several experimental and clinical endpoints will be assessed to obtain information on 
preliminary efficacy in patients with moderate to severe active Rheumatoid Arthritis. Although no formal 
hypothesis will be tested, these endpoints will enable a broader understanding of the mechanism of 
action and potential for clinical efficacy of ABX464 in Rheumatoid Arthritis.  
The first 6 patients will be randomized to receive either ABX464 50mg (n=4) or its matching placebo 
(n=2). The Data Safety Monitoring Board (DSMB) will review the safety of these first 6 patients dosed 
for at least 2 weeks. Once the DSMB recommendation is granted, the next patients will be randomized 
to receive either ABX464 50mg, ABX464 100mg or placebo.  
Then, a second DSMB meeting will be held after the next 6 patients are randomized to check the 
tolerability of the 100mg dose. Once the DSMB recommendation is granted, the next patients will be 
randomized to receive either ABX464 50mg, ABX464 100mg or placebo. 
Eligible patients will be randomized, according to a 1:1:1 ratio into 3 parallel intervention/treatment 
groups: 
 
Intervention/treatment Active Arm 
Group #1 (n=20): 100mg qd 
2 capsules of 50mg ABX464 
Group #2 (n=20): 50mg qd 
1 capsule of 50mg ABX464 + 1 capsule of matching 
placebo 
Group #3 (n=20): Placebo 
2 capsules of matching Placebo 
 
Patients will be treated for 12 weeks, followed by a follow-up period (21 days).  
The total duration of participation in the study will be approximately 15 to 19 weeks from screening to 
the last study visit (screening and baseline could occur at the same visit). 
From Baseline / Day 0 onwards, randomized patients will be seen at the investigational site after 1 Week 
(Day 7), 2 weeks (Day 14), 4 weeks (Day 28), 8 weeks (Day 56) and 12 weeks (Day 84). 
At Week 12 (Day 84 +/- 2 days), patients willing to carry on the study treatment will be able to take part 
in an open-label study (ABX464-302). In any other case, the subjects will exit the study (EOS) and will 
be treated according to the standard of care. The ABX464-302 follow-up study is a separate clinical 
study subject to health authorities and ethics committee approvals. 
Study scheme: 
 
 
In the present study (ABX464-301), randomization will be stratified according to a single factor: patients 
without previous exposure to anti-TNFα therapy versus patients with previous exposure to anti-TNFα 


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therapy. 
3.1.2. Dose limiting toxicity (DLT) 
A dose limiting toxicity (DLT) is defined as a grade 3 or higher adverse event as defined by the Common 
Terminology Criteria for Adverse Events (CTC-AE V5.0) considered by a safety review board as 
probably or definitely related to study treatment. 
If more than 2 DLTs occur in the first 12 treated patients for at least 14 days, then the enrolment of 
additional patients in the treatment group will be stopped, otherwise the enrolment of planned patients 
will be confirmed. 
In addition, in case of a life threatening (grade 4) adverse reaction enrolment in the treatment group, all 
treatment of ongoing patients will be immediately discontinued. 
In both cases, enrolment will only be resumed upon the decision of the sponsor if the Data Safety 
Monitoring Board can conclude that the causality of the event was unrelated or unlikely related to study 
treatment. 
3.1.3. Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB), with expertise and experience in the pathology, 
and without direct involvement in the conduct of the trial, will be set up specifically to guarantee effective 
protection of patients, ensure the ethical conduct of the trial, benefit/risk ratio of the trial, and to ensure 
the independent review of the scientific results during the trial and at the end of the trial. Besides, the 
DSMB may recommend the early termination of the trial at any time if an unacceptable toxicity occurs.  
The DSMB will meet after the first 6 patients are dosed (50mg or matching placebo) for at least 2 weeks 
to check the 50mg dose tolerability. Once the DSMB recommendation is granted, the next 6 patients 
will be randomized to receive either ABX464 50mg, ABX464 100mg or placebo.   
A second DSMB meeting will then be held when these 6 next patients are treated for at least 2 weeks, 
to check the 100mg dose tolerability and grant the recommendation to resume patient’s randomization. 
In addition, from the first DSMB onwards, meetings will be held every month during the study period. 
The DSMB will also review all potential causally-related Serious Adverse Events within 7 days of the 
initial report. 
The DSMB has only a consultative role. It will inform the Sponsor who will decide whether the DSMB 
recommendation will be followed. A DSMB charter must be available upon submission of the trial (initial 
protocol) to the respective competent authorities. 
3.2. Duration of study participation 
Eligible patients will be enrolled in the present study at the screening visit within 30 days prior to the first 
dosing / randomization (screening and baseline could occur at the same visit, if all laboratory results are 
available). 
Patients will be treated for 12 Weeks.  
Patients willing to carry on the study treatment will be able to take part in an open-label study (ABX464-
302). In any other case, the subjects will exit the study (End of Study Visit) and will be treated according 
to the standard of care. The ABX464-302 follow-up study is a separate clinical study subject to health 
authorities and ethics committee approvals. 
The end of study (EOS) visit will be performed three weeks after the end of treatment period.  
Thus, the total duration of the study participation is approximately 15 to 19 Weeks. 


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4. STUDY POPULATION 
4.1. Number of Patients/Centers 
Up to 60 patients will be randomized in this study. These patients will be enrolled in approximately 20 
sites located in Europe. 
4.2. Eligibility Criteria 
4.2.1. Inclusion Criteria 
A patient will be eligible for inclusion in this study only if ALL of the following criteria apply: 
▪ 
Men or women age 18 - 75 years; 
▪ 
Patient with a confirmed and documented diagnosis of adult-onset rheumatoid arthritis, for at 
least 12 weeks, according to the revised 2010 ACR-EULAR classification criteria, including at 
least one positive criteria among the following: Rheumatoid Factor (RF), Anti-Citrullinated 
Peptide Antibody (ACPA) or bone erosion; 
▪ 
Swollen joint count of ≥ 4 (28-joint count) and tender joint count ≥4 (28-joint count) at screening; 
▪ 
Patient with a moderate to severe disease activity score DAS28 CRP of ≥ 3.2 and CRP ≥ 5 mg/L 
(≥ 4.76 nmol)/L) at screening; 
▪ 
Patient who had an inadequate response (IR), or failed either methotrexate (MTX) or/and anti-
TNFα therapy (both administered for at least 12 weeks before IR) or were intolerant to anti- 
TNFα therapy.  
In addition, MTX treatment should be given at a stable dose ≥ 10 mg/week (for at least 4 weeks 
prior to randomization). The maximal dose of methotrexate should not exceed a total of 20 mg/week.  
MTX treatment should be associated with folic acid at a dose ≥ 5 mg/week. 
For the anti-TNFα therapy, the following wash-out period will be required: 
o 
30 days prior to randomization for adalimumab and etanercept 
o 
2 months prior to randomization for infliximab, certolizumab pegol, golimumab 
▪ 
Patients with the following hematological and biochemical laboratory parameters obtained 
within 14 days prior to baseline: 
o 
Hemoglobin > 9.0 g dL-1; 
o 
Absolute neutrophil count ≥ 1000 mm-3; 
o 
Platelets ≥ 100,000 mm-3; 
o 
Total serum creatinine ≤ 1.3 x ULN (upper limit of normal); 
o 
Creatinine clearance > 50 mL min-1 by the Cockcroft-Gault equation within 60 days 
prior to baseline; 
o 
Total serum bilirubin < 1.5 x ULN; 
o 
Alkaline phosphatase, AST (SGOT) and ALT (SGPT) < 1.5 x ULN; 
o 
Negative screening for TB and HIV, HCV, HBV 
▪ 
Patients are able and willing to comply with study visits and procedures as per protocol; 
▪ 
Patients should understand, sign and date the written voluntary informed consent form at the 
screening visit prior to any protocol-specific procedures are performed; 
▪ 
Patients should be affiliated to a social security regimen (for French sites only); 
▪ 
Females and males receiving the study treatment and their partners must agree to use a highly 
effective contraceptive method during the study and for 6 months after end of study or early 
termination. Contraception should be in place at least 2 weeks prior to screening. Women must 
be surgically sterile or if of childbearing potential must use a highly effective contraceptive 
method. Women of childbearing potential (WOCBP) will enter the study after confirmed 
menstrual period and a negative pregnancy test. Highly effective methods of contraception 
include true abstinence, intrauterine device (IUD) or hormonal contraception aiming at inhibition 
of ovulation, intrauterine hormone releasing system, bilateral tubal ligation, vasectomized 
partner. True abstinence is defined when this is in line with the preferred and usual lifestyle of 
the patient. In each case of delayed menstrual period (over one month between menstruations) 


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October 24th, 2019 
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confirmation of absence of pregnancy is required. This recommendation also applies to WOCBP 
with infrequent or irregular menstrual cycle. Female and male patients must not be planning 
pregnancy and male patients should use condom and must not donate sperm during the trial 
and for 6 months post completion of their participation in the trial. 
4.2.2. Exclusion Criteria 
The following criteria should be checked at the time of screening. If ANY exclusion criterion applies, the 
patient will not be included in the study: 
▪ 
Patient with a known positive anti-double stranded deoxyribonucleic acid (DNA [anti-dsDNA]) 
and confirmed diagnosis of systemic lupus erythematosus (SLE); 
▪ 
Patients with active infection or the following history of infection(s) (the list is not exhaustive): 
o 
Active infection (except benign infections, according to investigator’s opinion) within 
14 days prior to inclusion. 
o 
Serious infection, defined as an infection requiring hospitalization or IV infusion of anti-
infective agents in the 2 months prior to inclusion. 
o 
A history of opportunistic, recurrent or chronic infections that, in the investigator’s 
opinion, could render this study detrimental to the patient. 
• 
Patients who have received or are expected to receive a live (including attenuated) vaccine 
within 3 months prior to baseline; 
▪ 
Acute, chronic or history of clinically relevant (as per investigator’s judgement) pulmonary, 
cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy 
or unstable CNS pathology such as seizure disorder, angina or cardiac arrhythmias, active 
malignancy or any other clinically significant medical problems as determined by physical 
examination and/or laboratory screening tests and/or medical history; 
▪ 
Acute, chronic or history of immunodeficiency or other autoimmune disease; 
▪ 
Patient previously treated with any (approved or investigational) non-anti-TNF biological 
disease-modifying antirheumatic drugs (bDMARDs), and targeted DMARDs (tDMARDS) prior 
to baseline. These treatments include: IL-6 antagonists, Janus Kinase (JAK) inhibitors, cytotoxic 
T lymphocyte-associated molecule CTLA-4Fc Chimera, rituximab; 
▪ 
Patient treated with systemic corticosteroids >10 mg/day during the 2 weeks prior to and at 
randomization; IV or IM injections of glucocorticoids 4 weeks prior to randomization and IA 
glucocorticoids 2 weeks prior to randomization; 
▪ 
Patients treated with other immunosuppressive drugs; 
▪ 
History of malignancy (other than resected cutaneous basal cell or squamous cell carcinoma 
that has been treated with no evidence of recurrence) unless it has been treated and a cure is 
achieved for at least 5 years; 
▪ 
Serious illness requiring systemic treatment and/or hospitalization within 3 weeks prior to 
baseline; 
▪ 
Pregnant or breast-feeding woman; 
▪ 
Illicit drug or alcohol abuse or dependency; 
▪ 
Use of any investigational or non-registered product within 3 months or within 5 half-lives 
preceding baseline, whichever is longer; 
▪ 
Any condition, which in the opinion of the investigator, could compromise the patient's safety or 
adherence to the study protocol. 
 
 


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5. STUDY ASSESSMENTS AND PROCEDURES 
5.1. Study Flow Chart 
A detailed study flow chart (with all assessments) is displayed hereafter.  
 
Screening 
Period 
 
Study Treatment Period 
Follow-up 
Period 
 
D-30 to D-1 
D0 
D7 
D14 
D28 
D56 
D84 
D105 
 
 
W0 
W1 
W2 
W4 
W8 
W12 
W15 
Time Window (time between two visits≤30 
days)  
 
 
± 2 days ± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
 
Screening 
Baseline 
V1  
V2 
V3 
V4 
V5 
EOS 
Obtained Inform Consent 
X 
 
 
 
 
 
 
 
Check of IN/EX Criteria 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Height Measurement (cm) 
X 
 
 
 
 
 
 
 
Body Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12 lead) 
X 
X 
 
 
 
 
X 
X* 
Blood Pregnancy test (WOCBP) 
X 
 
 
 
X 
X 
X 
X 
Urine Pregnancy test (WOCBP) 
 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
ABX464/placebo treatment dispensation 
 
X 
 
 
X 
X 
 
 
Hematology + Biochemistry# 
X# 
X 
X 
X 
X 
X 
X 
X 
Blood samples drug PK (pre-dose) 
 
 
 
X 
 
X 
 
X** 
Blood samples drug PK  
(1- , 2- & 3- hours post-dose) 
 
X 
 
X 
 
X 
 
 
Blood samples for Cytokines (gel tube) 
 
X 
X 
X 
X 
X 
X 
 
Blood samples for Cytokines (Truculture® tube) 
 
X 
 
 
 
X 
 
 
Blood samples for flow cytometry cells 
count*** 
 
X 
 
 
 
X 
 
 
Blood samples for CRP, ESR 
X 
X 
X 
X 
X 
X 
X 
 
Blood samples for miR-124 (Paxgene® tube) 
 
X 
 
 
 
X 
 
 
Tender Joint Count (28) 
X 
X 
 
X 
X 
X 
X 
 
Swollen Joint Count (28) 
X 
X 
 
X 
X 
X 
X 
 
Patient Global Assessment of Disease (PtGA-
VAS) 
X 
X 
 
X 
X 
X 
X 
 
Patient assessment of Joint Pain (Pain-VAS) 
 
X 
 
X 
X 
X 
X 
 
Investigator Global Assessment of Disease 
(PrGA-VAS) 
 
X 
 
X 
X 
X 
X 
 
Health Assessment Questionnaire – Disease 
Index (HAQ-DI) 
 
X 
 
X 
X 
X 
X 
 
Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue 
 
X 
 
X 
X 
X 
X 
 
Patient diary (dispensation/check) 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events recording 
X 
X 
X 
X 
X 
X 
X 
X 
Follow_up Headache Questionnaire in case 
of persistent headache (see section 5.3.2) 
 
X (throughout the study, if needed) 
Dermatologist consultation in case of skin 
effect (see section 5.3.2) 
 
X (throughout the study, if needed) 
#Tests of TB, HIV, HCV, HBV only at screening; *ECG at EOS visit in case of early termination only; **trough levels PK samples; 
***Only in French Coordinating Investigator’s Site; Two visits should not be conducted more than 30 days apart 
5.2. Study conduct 
It is the Investigator’s responsibility to ensure that all the assessments are carried out during each visit 
and that the intervals between visits/follow-ups are adhered to. 
5.2.1. Screening Visit (within 30 days prior to Baseline/Day 0) 
The patient will be informed about the general aspects of the study and will sign the informed consent 
form. The patient number will be allocated once the patient is created in the eCRF. Only when consent 
has been given may further study procedures be carried out. 
During the screening phase, the following assessments will be performed: 
▪ 
Signed informed consent form; 
▪ 
Demographic data: year of birth and gender; 


ABIVAX 
Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
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▪ 
Inclusion/exclusion criteria will be verified globally, including disease confirmation according to 
the revised 2010 ACR-EULAR classification criteria with at least one positive criteria among the 
following: Rheumatoid Factor (RF), Anti-Citrullinated Peptide Antibody (ACPA) or bone erosion; 
▪ 
Body weight and height; 
▪ 
Medical history; 
▪ 
Physical examination and vital signs; 
▪ 
12 leads ECG; 
▪ 
Hematology and Biochemistry panel; 
▪ 
Blood pregnancy test for all women of childbearing potential; 
▪ 
Blood samples for testing TB, HIV, HCV, and HBV; 
▪ 
Blood samples for acute phase reactants; 
o 
C-Reactive Protein (CRP) 
o 
Erythrocyte Sedimentation Rate (ESR) 
▪ 
Tender/painful joint count (TJC) (28); 
▪ 
Swollen joint count (SJC) (28); 
▪ 
Patient global assessment of disease (PtGA); 
▪ 
If the patient was treated by anti- TNFα therapy, confirm the adequate wash-out of the anti-
TNFα therapy has started at least and collect the reason of anti- TNFα therapy discontinuation 
(i.e. intolerance, primary or secondary resistance): 
o 
1 month prior to screening for adalimumab and etanercept 
o 
2 months prior to screening for infliximab, certolizumab pegol, golimumab 
▪ 
Record all medications received within 3 months prior to baseline and note if the medication is 
continuing; Record all RA medication without time limitation; 
▪ 
Adverse Event reporting; 
▪ 
Schedule next patient visits. 
 
NB: If patient meets all eligibility criteria, has an adequate wash-out of previous therapies and 
laboratory results are available, the baseline visit could be performed on the same day as screening 
visit.  In that case, it is not necessary to repeat twice the assessments required at both visits. The 
following additional baseline assessments have to be performed: 
▪ 
Urine Pregnancy test for all women of childbearing potential; 
▪ 
Pharmacokinetics blood samples at 1h-, 2h- and 3-hours post-dose; 
▪ 
Patient assessment of joint pain (Pain-VAS); 
▪ 
Investigator global assessment of disease (PrGA);  
▪ 
Disability index of the healthy assessment questionnaire (HAQ-DI); 
▪ 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
▪ 
Record any concomitant medications; 
▪ 
Confirm the wash-out of the anti-TNFα therapy is complete; 
▪ 
Randomization; 
▪ 
Dispense study treatment to patient and instruct how to take it (first dosing at site); 
▪ 
Dispense patient diary (for treatment compliance and adverse event recording) and instruct how 
to complete it. 
5.2.2. Baseline (First dosing day / Day 0) 
▪ 
Physical examination and vital signs; 
▪ 
Body weight; 
▪ 
12 leads ECG; 
▪ 
Hematology and Biochemistry panel; 
▪ 
Urine Pregnancy (β-HCG) test for all women of childbearing potential; 


ABIVAX 
Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
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▪ 
Pharmacokinetics blood samples at 1h-, 2h- and 3-hours post-dose; 
▪ 
Blood samples for acute phase reactants (CRP & ESR); 
▪ 
Blood (gel tubes and Truculture® tubes) samples for cytokines determination; 
▪ 
Blood samples (Paxgene® tubes) for miR-124 dosage; 
▪ 
Blood samples for flow cytometry cells count (including at least B & T lymphocytes, myeloid 
cells and macrophages) (only in the Coordinating Investigator’s site); 
▪ 
Tender/painful joint count (28) (TJC28); 
▪ 
Swollen joint count (28) (SJC28); 
▪ 
Patient global assessment of disease (PtGA); 
▪ 
Patient assessment of joint pain (Pain-VAS); 
▪ 
Investigator global assessment of disease (PrGA);  
▪ 
Disability index of the healthy assessment questionnaire (HAQ-DI); 
▪ 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue; 
▪ 
Record any concomitant medications; 
▪ 
Confirm the wash-out of the anti-TNFα therapy is complete; 
▪ 
Adverse Events reporting; 
▪ 
Randomization; 
▪ 
Dispense study treatment to patient and instruct how to take them (first dosing at site); 
▪ 
Dispense patient diary (for treatment compliance and adverse event recording) and instruct how 
to complete them; 
▪ 
Schedule next patient visits. 
5.2.3. Week 1 / Day 7 (+/- 2 days) - Visit 1 
▪ 
Physical examination and vital signs; 
▪ 
Body weight; 
▪ 
Hematology and Biochemistry; 
▪ 
Blood samples for cytokines determination 
▪ 
Record any concomitant medications; 
▪ 
Check treatment compliance on patient diary; 
▪ 
Adverse Events reporting; 
▪ 
Schedule next patient visits. 
5.2.4. Week 2 / Day 14 (+/- 2 days), Week 4 / Day 28 (+/- 2 days), Week 8 / Day 56 (+/- 2 
days), Week 12 / Day 84 (+/- 2 days) - Visits 2, 3, 4, 5  
▪ 
Physical examination and vital signs; 
▪ 
Body weight; 
▪ 
12-leads ECG (D84 only);  
▪ 
Hematology and Biochemistry panel; 
▪ 
Blood pregnancy test for all women of childbearing potential (except on Week 2); 
▪ 
Pharmacokinetics blood samples pre-dose, 1h-, 2h- and 3-hours post-dose (Week 2 / Day 14 
and Week 8 / Day 56 only); 
▪ 
Blood samples for acute phase reactants (CRP, ESR);  
▪ 
Blood samples (gel tubes) for cytokines determination; 
▪ 
Blood samples (Truculture® tubes) for cytokines determination at Week 8 only; 
▪ 
Blood samples (Paxgene® tubes) for miR-124 qPCR dosage (Week 8 only); 
▪ 
Blood samples for flow cytometry cells count (including at least B & T lymphocytes, myeloid 
cells and macrophages) (only in the French Coordinating Investigator’s site, at Week 8 only); 
▪ 
Tender/painful joint count (28) (TJC28); 


ABIVAX 
Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
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▪ 
Swollen joint count (28) (SJC28); 
▪ 
Patient global assessment of disease (PtGA); 
▪ 
Patient assessment of joint pain;  
▪ 
Investigator global assessment of disease (PrGA); 
▪ 
Disability index of the healthy assessment questionnaire (HAQ-DI); 
▪ 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue; 
▪ 
Record any concomitant medications; 
▪ 
Check treatment compliance on patient diary; 
▪ 
Adverse Events reporting; 
▪ 
Study treatment dispensation on Week 4 and Week 8 visits; 
▪ 
Schedule next patient visits (time between two visits should not exceed 30 days); 
▪ 
On Week 12 / Day 84, enrolment of patients willing to take part to the maintenance phase. 
5.2.5. End of Study Visit (Week 15 / Day 105 ± 2 days) 
This EOS visit applies to all premature discontinued patients and to patients not taking part to the 
maintenance study. Patients will perform an End of Study Visit (EOS) three weeks after last dosing. 
Patients will be treated according to the standard of care since the last day of study treatment.  
Following examinations/procedures should be performed: 
▪ 
Physical examination and vital signs; 
▪ 
Body weight; 
▪ 
Hematology and Biochemistry panel; 
▪ 
Blood pregnancy test for all women of childbearing potential;  
▪ 
Pharmacokinetics blood samples trough levels; 
▪ 
12 leads ECG (in case of premature discontinuation only); 
▪ 
Record any concomitant medications; 
▪ 
Adverse Events reporting. 
NB#1: In case of premature discontinuation occurring during the treatment phase (D1-D84), the above 
examinations should be performed as an End of Study Visit. 
5.3. Detail of the study assessments  
5.3.1. Physical Examination and Vital Signs 
A routine physical examination (including body weight) will be done at each study visit. Physical 
examinations will cover eyes, ears, nose, throat, lungs/thorax, heart/cardiovascular system, abdomen, 
skin and mucosae, nervous system, lymph nodes, musculo-skeletal system, and, if applicable, others. 
Any new clinically relevant finding compared to baseline must be documented as adverse event. 
Measurements of vital signs will be done at each visit (Blood pressure, Heart Rate, Body temperature). 
The patient should rest supine for at least 10 minutes prior to measurements. The measurements can 
be performed either in sitting or supine position of the patient. The right or left arm may be used. 
However, the position and the arm used for measurement should be kept constant throughout the trial 
for an individual patient.  
The investigator should ensure that each parameter outside the normal range is assessed for clinical 
significance. For any deviation assessed clinically significant, the investigator has to document the 
change as an AE in the CRF.  
In addition, it is at the discretion of the investigator to document any change or trend over time in vital 
signs as an AE if he considers the change to be clinically significant, even if the absolute value is within 
the alert limit or reference range. 
 


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Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
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5.3.2. Adverse Events of Interest 
Treatment with ABX464 has been associated with the occurrence of mainly mild to moderate Adverse 
Events; more specifically with headache episodes and skin lesions. To collect information regarding 
these Adverse Events of Interest, the following procedure should be applied: 
▪ 
In case of occurrence of a skin lesion (regardless of its severity), a dermatologist consultation should 
be scheduled to evaluate the type of lesion, its severity and etiology. An anonymized medical report 
shall be provided to the Sponsor. 
▪ 
In case of occurrence of a headache episode lasting more than a Week and refractory to standard 
painkillers (ibuprofen, acetaminophen, paracetamol, etc.…), a specific questionnaire will be filled in 
by the patients to better characterize the attributes of the event (Appendix #4). 
5.3.3. Pregnancy 
For all female patients of childbearing potential, a blood pregnancy test (beta human chorionic 
gonadotropin [βHCG]) will be performed at Screening, on Week 4 / Day 28, Week 8 / Day 56, Week 12 
/ Day 84 and EOS Visit. 
A urine pregnancy test will pe performed on Baseline / Day 0 in order to obtain the result before the first 
ABX464 administration. 
In case of positive pregnancy testing, detailed procedures can be found in section 8.3.2. 
5.3.4. ECG 
Electrocardiograms will be performed at Screening, Baseline / Day 0, Week 8 / Day 56 and at the EOS 
visit (in case of premature discontinuation only).  
At least a 12-lead ECG with recordings of at least 6 action potentials in lead II (paper speed 25mm/s, 
amplitude 10mm/mV) will be measured at a resting position. Prior to the recording the patient should be 
at rest for at least five minutes. Resting ECG should be performed before any examinations. 
The ECG printout will be reviewed by the Investigator and a signed and dated copy of the ECG will be 
attached to the medical file. The original ECG printouts are considered as source data and should be 
stored at site. If thermal paper is used, a copy of the original ECG must also be kept.  
All abnormal findings must be documented in the CRF. Any clinically relevant findings compared to ECG 
done at Day 0 / Baseline must be documented as adverse events. 
5.3.5. Hematology and biochemistry 
For hematology and biochemistry panels, local laboratory will be used.  
Each laboratory value that is outside of the institution’s normal range will be identified. The Investigator 
will be responsible for assessing the clinical significance of laboratory abnormalities. If the Investigator 
is uncertain about the clinical significance of a laboratory abnormality, he/she will consult with the 
Sponsor medical monitor. 
The Investigator should follow any clinically significant laboratory abnormalities until resolution. 
The Table 1 displays the clinical laboratory parameters that must be measured. 


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Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
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Table 1: Laboratory Tests 
HEMATOLOGY 
BIOCHEMISTRY 
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
WBC 
Chloride 
Neutrophils 
Calcium 
Lymphocytes 
Phosphate 
Monocytes 
Glucose  
Eosinophils 
BUN or urea  
Basophils 
Creatinine  
Platelet count 
AST / SGOT 
ESR 
ALT / SGPT 
Prothrombin time and/or INR* 
Alkaline phosphatase 
Fibrinogen* 
GLDH 
 
LDH 
 
Lipase 
 
Total cholesterol  
 
HDL cholesterol 
 
LDL cholesterol 
 
gGT 
 
Total bilirubin  
 
Total protein  
 
Albumin  
 
CRP 
 
T3, T4, TSH ( for French sites only) 
 
Troponin I & T* 
Tests of TB (Quantiferon TB Gold Plus), HIV (anti-HIV Ab), HCV (anti-HCV Ab), HBV (HBsAg, anti-HBs 
Ab), anti-HCV Ab, will be performed only at screening. * Except at Week 1 & 2  
5.3.6. Pharmacokinetics  
Blood samples will be collected in all patients for PK assessment.  
Sampling will be performed:  
▪ 
pre-dose on Week 2 / Day 14 and Week 8 / Day 56;  
▪ 
1-, 2- and 3-hours post-dose on Baseline / Day 0, Week 2 / Day 14 and Week 8 / Day 56 and  
▪ 
trough levels at the End of Study Visit (Week 15 / Day 105).  
 
The PK samples will be kept in the local laboratory, at -20°C until pick-up. 
 
Patient data will be pooled with data obtained in previous clinical studies in order to build a population 
pharmacokinetic models for ABX464 and its metabolite. 
5.3.7. Disease parameters 
• 
Laboratory disease parameters: 
o 
The acute phase reactants, CRP and ESR, will be dosed at every visit. 
o 
Blood samples (on gel tubes) for serum cytokines determination will be kept in the local 
laboratory, at -80°C (or -20°C if not possible), till the end of the study.  
o 
Blood samples (on Truculture® tubes) for determination of cytokines, produced by immune 
cells after stimulation (incubation at 37°C for 24 hours), will be kept in the local laboratory, 
at -20°C, till the end of the study. These samples will be performed only where the 
incubation procedure is feasible. 
o 
The blood samples for flow cytometry cells count (including at least B & T lymphocytes, 
myeloid cells and macrophages) will be kept in the local laboratory, at -80°C or will be 
processed immediately. 
The processes for samples preparation, storage and shipment will be fully defined in the 
laboratory manual. 


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Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
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• 
miR-124 modulation 
ABX464 up-regulates miR-124 in PBMCs, making this micro-RNA a potentially useful future biomarker 
for ABX464 treatment monitoring. Determination of miRNA level in total blood will be performed in order 
to assess treatment effect by comparing before and after treatment for this exploratory biomarker. 
Assays for miRNA determination (by qPCR method) will be conducted by a specialized central 
laboratory. 
The total blood in Paxgene® tubes will be stored at -20°C according to lab manual instructions. 
• 
Disease Activity Score (DAS) 28-CRP (DAS28-CRP) and DAS28-ESR 
The components of the DAS28 include: 
o 
tender/painful joint count (TJC) (28),  
o 
swollen joint count (SJC) (28),  
o 
CRP (in mg/L) or ESR (in mm/h), and  
o 
patient global assessment of disease (PtGA), expressed as a Visual Analog Scale (VAS) from 
0 to 100 mm 
They are calculated with the following formula: 
DAS28-CRP = 0.56 √ (TJC28) + 0.28 √ (SJC28) + 0.36 Ln [CRP(mg/L) + 1] + 0.014 PtGA(VAS100mm) + 0.96 
DAS28-ESR = 0.56 √ (TJC28) + 0.28 √ (SJC28) + 0.70 Ln [ESR(mm/h)] + 0.014 PtGA(VAS100mm) 
• 
Simplified Disease Activity Index (SDAI) 
This other composite index is defined by this equation: 
SDAI = TJC28 + SJC28 + PtGA + PrGA + CRP 
o 
PtGA is expressed as a VAS from 0 to 10 cm,  
o 
Investigator global assessment of disease (PrGA) is expressed as a VAS from 0 to 10 cm, and 
o 
CRP (mg/L). 
• 
Clinical Disease Activity Index (CDAI) 
This other composite index is defined by this equation (no acute phase reactant): 
CDAI = TJC28 + SJC28 + PtGA + PrGA  
o 
PtGA is expressed as a VAS from 0 to 10 cm, 
o 
PrGA is expressed as a VAS from 0 to 10 cm. 
• 
Categorical DAS28-CRP response 
Proportion of patients achieving categorical DAS28-CRP response will be measured as moderate/good 
European League Against Rheumatism (EULAR) response. 
 
The EULAR response criteria are defined as follows: 
DAS28 improvement → 
> 1.2 
> 0.6 and ≤ 1.2 
≤ 0.6 
Present DAS28↓ 
≤ 3.2 
good response 
moderate response 
no response 
> 3.2 and ≤ 5.1 
moderate response 
moderate response 
no response 
> 5.1 
moderate response 
no response 
no response 
• 
DAS28-ESR remission 
A remission is considered when DAS28-ESR <2.6 
• 
Low Disease Activity (LDA)  
The limit to consider a Low Disease Activity (LDA) is: DAS28-ESR ≤ 3.2 
• 
SDAI remission 


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Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
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The SDAI remission is considered achieved if the SDAI score ≤ 3.3 
• 
CDAI remission 
The CDAI remission is considered achieved if the CDAI score ≤ 2.8 
• 
ACR/EULAR remission: 
In 2011, the American College of Rheumatology (ACR) and EULAR decided to set new criteria to define 
RA remission. 
Boolean-based criteria to be used for clinical trials are:  
o 
Tender/painful Joint Count (28) 
o 
Swollen Joint Count (28) 
o 
CRP 
o 
Patient Global assessment of disease (PtGA) [VAS scale 0 – 10cm] 
All ≤ 1 
• 
Categorical ACR20/50/70 response 
The component of ACR assessment include: 
o 
tender/painful joint count (28),  
o 
swollen joint count (28),  
o 
patient assessment of joint pain,  
o 
Patient Global Assessment of Disease (PtGA) 
o 
Physician's Global Assessment of Disease (PrGA),  
o 
CRP and  
o 
Disability index of the healthy assessment questionnaire (HAQ-DI).  
Patient assessment of joint pain – VAS scale 0-10 cm 
PtGA – Patient Global Assessment of disease activity [VAS scale 0 – 10cm] 
PrGA – Physician Global Assessment of disease activity (VAS scale 0 – 10cm) 
HAQ-DI: This patient reported outcome questionnaire is usually self-administered by the patient. 
The following 8 categories are assessed by the HAQ-DI:  
1. Dressing and grooming 
2. Arising 
3. Eating 
4. Walking 
5. Hygiene 
6. Reach 
7. Grip 
8. Common daily activities 
The patients report the amount of difficulty they have in performing some of these activities. Each 
question asks on a scale ranging from 0 to 3 if the categories can be performed without any difficulty 
(scale 0) up to cannot be done at all (scale 3).  
• Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue: 
This questionnaire is a measure to assess the patient fatigue in chronic diseases, and is validated in 
RA. It includes 13 items.  
• Definition of the ACR20% response:  
o 
≥ 20% improvement in tender join counts 


ABIVAX 
Clinical Study Protocol 
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October 24th, 2019 
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o 
≥ 20% improvement swollen join counts  
o 
≥ 20% improvement in 3 of the 5 remaining ACR core set measures:  
▪ 
PtGA,  
▪ 
PrGA,  
▪ 
patient assessment of joint pain,  
▪ 
HAQ-DI,  
▪ 
CRP. 
For ACR50 and ACR70, an improvement of respectively 50 and 70% of the same parameters has to 
be observed. 
5.3.8. Summary of blood samples 
The table 2 below summarizes the volume of blood to be sampled at each study visit. 
Table 2: Blood Volume 
 
REQUIRED 
VOLUME 
COLLECTION 
TUBE 
SCR 
D-30 
BSL 
D0 
D7 
D14 
D28 
D56 
D84 
EOS 
D105 
TOTAL 
 
 
 
SCR 
BL 
V1 
V2 
V3 
V4 
V5 
EOS 
 
Hematology (Hemoglobin, 
Hematocrit, Red Cell 
Count, MCV, MCHC, 
Platelets, White cell count 
with diff.) 
0.5mL 
EDTA 
blood 
2mL EDTA 
tube 
2 
2 
2 
2 
2 
2 
2 
2 
16 
Prothrombin time/INR and 
fibrinogen  
 
2,7 mL 
plasma 
Citrate 
2,7 
2,7 
 
 
2,7 
2,7 
2,7 
2,7 
16,2 
ESR 
1mL 
EDTA 
blood 
2mL EDTA 
tube 
2 
2 
2 
2 
2 
2 
2 
 
14 
Biochemistry panel incl 
CRP, βHCG 
and thyroid function 
parameters (French sites 
only*) 
2 mL 
serum 
+ 2mL* 
2 x 5mL 
serum gel 
tube 
5 
+5* 
5 
+5* 
5 
+5* 
5 
+5* 
5 
+5* 
5 
+5* 
5 
+5* 
5 
+5* 
40 
+40* 
HBsAg, anti-HBs Ab,  
anti-HCV Ab, anti-HIV Ab 
0.75 mL 
serum 
2.5mL 
serum gel 
tube 
2,5 
 
 
 
 
 
 
 
2,5 
Quantiferon TB Gold Plus 
4 mL 
plasma 
4 x 1mL 
tube 
4 
 
 
 
 
 
 
 
4 
Cytokines determination on 
serum  
min 6 mL 
serum 
2 x 5mL 
serum gel 
tube 
 
10 
10 
10 
10 
10 
10 
10 
70 
Cytokines determination on 
total blood  
 
2 x 1 mL 
(Truculture® 
tube) 
 
2 
 
 
 
2 
 
 
4 
Samples for flow cytometry 
cells count ** 
 
4 x 6mL 
EDTA tube 
 
24** 
 
 
 
24** 
 
 
48** 
Paxgene® Tube (miR-124) 
5 mL total 
blood 
2 x 2,5 mL 
Paxgene® 
tube 
 
5 
 
 
 
5 
 
 
10 
PK samples 
1.0 mL 
serum 
2mL Li-
heparin tube 
 
6 
 
(1,2, 
3h 
post 
dose) 
 
8 
 
(pre-
dose 
& 
1,2, 
3h 
post 
dose) 
 
8 
 
(pre-
dose 
& 
1,2, 
3h 
post 
dose) 
 
2 
 
(trough 
levels) 
24 
Total per visit 
 
18,2 
+5* 
34,7 
+5* 
+24** 
19 
+5* 
27 
+5* 
21,7 
+5* 
36,7 
+5* 
+24** 
21,7 
+5* 
21,7 
+5* 
200,7 
+40* 
+ 48** 
*Only in French sites; **Only in French Coordinating Investigator Site 


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October 24th, 2019 
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INVESTIGATIONAL PRODUCT(S) 
All investigational products to be used in this study have been manufactured, packaged and labelled by 
contract manufacturers for ABIVAX, according to GMP standards and are supplied to investigators free 
of charge. 
5.4. Description of investigational treatment 
The study treatment that will be administrated to patients enrolled in this Phase IIa study consists of 
capsules containing ABX464 or its matching placebo given orally once daily for 12 weeks. 
5.5. Description of investigational Product 
5.5.1. Active investigational product (ABX464) 
The ABX464 investigational medicinal product (IMP) is a hard gelatin capsule intended for oral 
administration. 
For the proposed clinical trial, the IMP consists of size 01 capsules containing either 50mg or 100mg of 
ABX464 drug substance in the form of granulate prepared with a number of common excipients 
(microcrystalline cellulose, polyvinylpyrrolidone, magnesium stearate and colloidal silica).  
It is supplied in high-density polyethylene bottles closed with child-resistant polypropylene screw caps 
with induction seals. 
ABX464 will be manufactured by:  
DELPHARM Lille SAS 
Parc d’activité Roubaix Est 
22, rue de Toufflers 
CS 50070 
59 452 Lys-Lez-Lannoy France 
 
Packaging and labelling activities, as well as Qualified Person release of the IMP will be performed at 
the following site: 
CREAPHARM (EX-SODIA) 
Avenue Robert Schuman 
51100 REIMS Cedex 
France 
 
Storage conditions: Do not store above 30°C (86°F). Do not refrigerate or freeze. 
The capsule or combination of capsules to be used depends on the dose-level to be administered as 
per the clinical study protocol. 
5.5.2. Placebo 
The matching placebo consists of the same hard gelatin, powder-filled capsules (size 01) filled with only 
the same common excipients (microcrystalline cellulose, polyvinylpyrrolidone, magnesium stearate and 
colloidal silica) as the active IMP. It is supplied in high-density polyethylene bottles closed with child-
resistant polypropylene screw caps with induction seals. 
ABX464 matching placebo will be manufactured by: 
DELPHARM Lille SAS 
Parc d’activité Roubaix Est 
CS 50070 
59 452 Lys-Lez-Lannoy France 
 
Packaging and labelling activities, as well as Qualified Person release of the IMP will be performed at 
the following site: 


ABIVAX 
Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
Page 39 / 77 
CREAPHARM (EX-SODIA) 
Avenue Robert Schuman 
51100 REIMS Cedex 
France 
 
Storage conditions: Do not store above 30°C (86°F). Do not refrigerate or freeze. 
The capsule or combination of capsules to be used depends on the dose-level to be administered as 
per the clinical study protocol. 
5.6. Administration and Dosing 
5.6.1. Administration of the investigational product 
Following randomization, patients will be treated with a daily dose of either 50mg or 100mg ABX464 or 
will receive placebo. 
Treatment groups: 
 
Intervention/treatment Active Arm 
Group #1 (n=20): 100mg qd 
2 capsules of 50mg ABX464 
Group #2 (n=20): 50mg qd 
1 capsule of 50mg ABX464 + 1 capsule of matching placebo 
Group #3 (n=20): Placebo 
2 capsules of matching Placebo 
Patients will be orally dosed in a fed condition (regular breakfast) with a glass of water. 
On Day 84 visit, the patient will not take the ABX464-301 study medication (last day of study medication 
will be on Day 83).  
Patient enrolled in the ABX464-302 maintenance study will start the study medication on Day 84 (301 
study)/D0 (302 study), ABX464 50mg once daily, right after the study visit.  
A paper diary in which the patient should report the number of capsules taken and the intake time from 
baseline visit onwards, will be given to the patient at baseline. 
5.6.2. Guidelines for treatment postponement and dose modifications 
No intra-patient dose escalation/dose adjustment are allowed during the study.  
5.7. Method of Assigning Patients to Treatment Arms 
All patients will be assigned a unique and incremental Patient Identification (ID) number. Patient IDs will 
be unique (i.e. reallocation of the ID will not be permitted). The format will be a seven-digit number as 
follows: ABX-country/site number (4 digits) – patient number (3 digits). The latter 3-digit patient number 
will be assigned according to the patient’s order of inclusion in the center. 
Eligible patients (i.e. those who fulfil all inclusion/exclusion criteria) will be randomized according to a 
1:1:1 ratio into ABX464 100mg, ABX464 50mg or placebo treatment arms. 
Randomization will be performed via a centralized treatment allocation system that will be available 24 
hours-a-day, 7 days-a-week. 
Study treatment monthly dispensation: 
 
Bottles  
Group #1 (n=20): 100mg qd 
2 bottles of 50mg ABX464 capsules 
Group #2 (n=20): 50mg qd 
1 bottle of 50mg ABX464 capsules + 1 bottle of matching placebo 
capsules 
Group #3 (n=20): Placebo 
2 bottles of matching Placebo capsules 
 
Study treatment dispensation will be performed three times at Day 0 (30-capsule bottles; 2 bottles), at 
Day 28 (30-capsule bottles; 2 bottles), and at Day 56 (30-capsule bottles; 2 bottles). In all cases, subject 
should return his/her used and unused bottles at each study visit for a compliance check. 


ABIVAX 
Clinical Study Protocol 
Study code: ABX464-301 
October 24th, 2019 
V4.0 
Page 40 / 77 
5.8. Blinding and breaking the study blind 
Study drug will be packaged in blinded label bottles. Bottles will be numbered according to a randomized 
treatment number list. The content of the labeling is in accordance with the required references listed in 
the Good Manufacturing Practices. 
The investigator, study personnel, and study participants are blinded with respect to treatment (i.e., 
active ABX464 or placebo). Sponsor or delegate will generate the random code list and the 
corresponding treatment number list. 
Investigators may have access to unblinding only in case of medical emergency. The code breaks will 
be available 24 hours a day and 7 days a week using an Interactive Web Response System (IWRS).  
The IWRS will require an access code/password/PIN and is only available to staff members delegated 
by the PI and named on the delegation log of each site.  
The investigators and delegated members with unblinding responsibilities are responsible for testing 
their username and password prior to the treatment of subjects to ensure unblinding is possible, or for 
ensuring appropriately trained staff members are available to action code breaks when required for 
medical emergencies which may be required out of normal working hours. 
Details of any emergency unblinding shall be documented fully in the TMF and Investigator/Pharmacy 
Site File. The sponsor should be notified of the unblinding and be provided with the subject number but 
NOT the result. The details shall be included in the statistical report. 
However, as there is no antidote, it is highly unlikely that knowledge of treatment would affect the clinical 
management of the patient. In case of unblinding, the patient will be immediately withdrawn from the 
study. 
5.9. Packaging 
The IMP consists in hard gelatin, powder-filled capsules (size 01) containing either 50 mg or 100mg of 
ABX464 or placebo supplied in study specific high-density polyethylene bottles closed with child-
resistant polypropylene screw caps with induction seals. 
5.10. 
Storage 
ABX464/Placebo capsules will be shipped to the investigational site at ambient temperature. 
ABX464/Placebo capsules should not be stored above 30°C (86°F). Do not refrigerate or freeze.  
The IMP should not be used beyond the expiration date. Drug supplies are to be stored in a secure, 
limited-access location under the storage conditions required by GCP/GMP guidelines. 
5.11. 
Product Accountability 
An accurate and current accounting of the dispensing and return of IMP(s) will be maintained on an 
ongoing basis by the pharmacist and a member of the study site staff in the Accountability Log and case 
report form and will be verified by the study’s monitor. 
5.12. 
Prior and Concomitant Medication 
5.12.1.  Mandatory concomitant treatment 
▪ 
ABX464 or its matching placebo administered once daily; 
▪ 
MTX ≥ 10 mg/week, at stable dose, throughout the study; the maximal dose of methotrexate 
should not exceed a total of 20 mg/week 
▪ 
Folic acid ≥ 5 mg/week post MTX dose, to minimize MTX toxicity. 
 
Potential Drug-Drug Interactions (DDIs) with methotrexate: 
ABX464 is mainly metabolized by CYP1A2 and glucuro-conjugated. Methotrexate undergoes 
hepatic and intracellular metabolism to polyglutamated forms.  
Multiple DDIs have been documented with methotrexate. In this study, potential methotrexate 
interactions on ABX464 will be sought using an on-going PK modelling approach. 


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For documented DDIs with methotrexate, please refer to the Appendix 5. 
5.12.2. Allowed Concomitant Medications 
▪ 
Corticosteroids at stable dose of prednisone and prednisone equivalent ≤10 mg/day during the 
study; 
▪ 
Non-steroidal anti-inflammatory drugs (NSAIDs) at stable dose during the study; 
▪ 
Antalgics including class III at stable dose during the study; 
▪ 
Other non-rheumatologic medications. 
Potential other concomitant medications (not indicated for rheumatoid arthritis) should be kept at 
constant dose during the course of the study and properly reported in the medical file of the patient and 
the eCRF. 
This information should include the name of the medication (international nonproprietary name), daily 
dosage, duration, indication and the time of last intake before all PK samplings. 
5.12.3.  Prohibited concurrent medications 
The following drugs are prohibited during the course of the study:  
▪ 
Any non-anti-TNFα biological or targeted DMARDs: IL-6 antagonists, JAK inhibitors, CTLA-4Fc 
Chimera, rituximab; 
▪ 
Any immunosuppressive drugs; 
▪ 
Vaccination with live components during the study and up to 8 Weeks after the last dosing;  
▪ 
Drugs that could interact with ABX464 should be avoided especially the CYP1A2 substrates. 
The following CYP1A2 substrates with a narrow therapeutic margin are prohibited during the 
whole course of the study (rifampicin, clozapine, theophylline, ropinirole, warfarin and 
methadone). In case of concomitant treatment with ondansetron, the maximal daily dose must 
be limited to 8 mg; 
▪ 
Use of any investigational or non-registered product within 3 months preceding baseline. 
5.13. 
Life Style Guidelines 
No new non-pharmacological therapies should be started during the study period.  
Patients should avoid changing their accustomed exercise level throughout the study. They are also 
encouraged to keep their diet habits constant during the study period. 
 
 


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6. PATIENT COMPLETION AND WITHDRAWAL 
6.1. Patient Completion 
Treatment with ABX464/Placebo shall continue up to Week 12/ Day 83, except if a patient fulfils a 
premature discontinuation criterion (defined below).  
On Day 84, patient will not take ABX464-301 study medication.  
On Day 84, patients willing to carry on the study treatment will be able to take part in the long-term 
maintenance study (ABX464-302). Patient will sign the ABX464-302 specific informed consent and will 
start ABX464-302 study drug administration (50mg once daily). 
In any other case, patients will exit the study (EOS) and will be treated according to the standard of care. 
The ABX464-302 follow-up study is a separate clinical protocol subject to health authorities and ethics 
committee approvals. 
6.2. Premature trial discontinuation 
A patient can be withdrawn at any time from the study for the following reasons: 
Patient’s premature trial discontinuation could occur for the following reasons: 
▪ 
Investigator’s decision; 
▪ 
An Adverse Event or an intercurrent condition that preclude continuation of treatment; 
o 
Specifically, an increase ≥ 3.0 x ULN in liver transaminases (AST/SGOT and/or 
ALT/SGPT) or an increase ≥ 2.0 x ULN in Alkaline phosphatase or in total bilirubin 
requires close observation with repeating liver enzymes and serum bilirubin tests two 
times weekly and clinical investigation to understand the etiology of this elevation. 
Frequency of retesting can decrease to once a month if abnormality stabilizes after this 
initial two weeks of follow-up and if the patient is asymptomatic. Discontinuation of the 
study treatment should occur if: 
▪ 
 ALT or AST > 8xULN 
▪ 
ALT or AST >5xULN for more than 2 weeks 
▪ 
ALT or AST > 3xULN and total bilirubin > 2xULN or INR>1.5 
▪ 
ALT or AST > 3xULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
▪ 
Worsening of the RA (according to physician evaluation); 
▪ 
Major protocol violation; 
▪ 
Withdrawal of consent; 
▪ 
Administrative reasons from Sponsor. 
A patient who prematurely exits the study will not be replaced.  
6.3. Study Discontinuation 
All patients, regardless of the completion or premature discontinuation, should perform the End of Study 
Visit according to the study flow-chart. 
6.4. Screen and Baseline Failures 
All potential patients who have signed an informed consent and are screened for enrolment in this study 
will be listed on the patient Screening Log/Identification List. Reasons for exclusion will be recorded for 
potential patients who do not enter the study. 
A patient who does not fulfil the randomization criteria will be considered as a screen failure. All patient 
data should be entered in the eCRF including the screen failure data.  
A patient will be considered a baseline failure if the patient signs the informed consent, is eligible for 
randomization but withdraws before the baseline visit. 


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Based on the investigator evaluation and sponsor prior approval, a non-randomized patient can be re-
screened. This re-screening procedure should be documented, the patient should consent again and a 
new unique and incremental patient Identification (ID) number be allocated. 
 


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7. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) 
The investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an AE or SAE. During the study, in case of a safety evaluation, the investigator or site staff 
will be responsible for reporting AEs and SAEs, as detailed in this section of the protocol.  
During the screening period, only adverse event related to the screening procedures will be collected. 
Any disease progression will be reported in the eCRF both as an adverse event and documented in the 
efficacy section. 
7.1. Definition of an AE 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have to 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 (new or exacerbated) temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
Note: The official definition also extends to AEs occurring in the placebo arm. Because of regulatory 
requirements, events occurring during pre-and post-treatment periods will also be designated as AEs. 
Therefore, reporting of such events, AEs and SAEs, will commence when the patient is enrolled into the 
study (date of signature of the informed consent) up until 4 Weeks after the end of the treatment visits. 
The period after discontinuing study drug may be extended if there is a strong suspicion that the drug 
has not yet been eliminated. 
7.2. Definition of a SAE 
A serious adverse event (experience) or reaction is any untoward medical occurrence that, at any dose: 
a) Results in death 
NOTE: Death is an outcome of an AE, and not an AE in itself. Event which led to death should be 
recorded with fatal outcome. 
b) Is life-threatening 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
c) Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization means that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or out-patient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred, or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen after informed 
consent was given is not considered serious. 
d) Results in persistent or significant disability/incapacity,  
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) 
Is another medically important condition: This refers to an AE that may not be immediately life-
threatening or results in death or hospitalization but may jeopardize the patient or may require 


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intervention to prevent one of the outcomes listed above. Based on medical and scientific 
judgment this should usually be considered serious. 
If there is any doubt about whether or not an AE is serious, the investigator should contact the sponsor. 
7.2.1. Events and/or Outcomes Not Qualifying as SAEs 
Any hospitalization, or prolongation of hospitalization due to the circumstances listed below, will not be 
reported as SAE: 
▪ 
planned medical/surgical procedure; 
▪ 
planned medical/surgical admission (planned prior to entry into study, appropriate 
documentation required), for the disease under study; 
▪ 
Administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver respite, 
family circumstances).  
7.3. Events or Outcomes Qualifying as AEs or SAEs 
7.3.1. Clinical laboratory parameters  
Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other abnormal assessments (e.g. 
vital signs) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs 
if they meet the definitions of sections 7.1 and 7.2 respectively. Clinically significant abnormal laboratory 
findings or other abnormal assessments that are detected during the study or are present at informed 
consent and significantly worsen during the study will be reported as AEs or SAEs. Clinically significant 
abnormal laboratory findings or other abnormal assessments that are associated with the disease being 
studied and are present at the start of the study but do not worsen, will not be reported as AEs or SAEs. 
However, if these findings or assessments are judged by the investigator to be more severe than 
expected considering the patient’s condition, then they may be reported as AEs or SAEs. 
7.3.2. Pregnancy report 
Patients who become pregnant at any time will be immediately withdrawn from participation in the study. 
All appropriate withdrawal assessments may be performed at the discretion of the investigator. 
The investigator will collect pregnancy information on any woman patient or partner of a male patient, 
who becomes pregnant and their partner while participating in this study. The investigator will record 
pregnancy information on a specific pregnancy notification form and submit it to IntuVigilance Limited 
(see contact details in section 8.4) within 24 hours after knowledge of a patient's or partner’s pregnancy. 
The patient or partner will also be followed to determine the outcome of the pregnancy, be it full-term or 
prematurely terminated. Information on the status of the mother and child will be forwarded to 
IntuVigilance Limited. Follow-up will normally end 6 to 8 Weeks following the estimated delivery date. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an SAE. A spontaneous abortion is 
always considered to be an SAE and will be reported as such. 
The time period for collecting pregnancy information is identical to the time period for collecting AEs, as 
stated in Section 7.4, Time Period, Frequency, and Method of Detecting AEs and SAEs. Pregnancy 
information is collected from the signing of informed consent to 4 Weeks after the last dose. 
7.4. Time Period, and Frequency of Detecting AEs and SAEs 
All AEs and SAEs occurring from the time a patient consents to participate in the study until 4 Weeks 
after he or she has completed or discontinued the investigational product must be recorded in the 
Patient’s eCRF.  
Moreover, any occurrence of pregnancy within 6 months post stopping dosing must be reported. 
Importantly, SAEs will have to be reported, either by email or by Fax, to IntuVigilance Limited within 24 
hours of awareness of an SAE. 
 


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IntuVigilance Limited 
Scotsbridge House, Scots Hill 
Rickmansworth WD3 3BB 
Hertfordshire, UK 
 
Hotline phone: +44 800 689 4129  
Email Address: safety@intuvigilance.com  
Fax number: +44 800 915 6753  
Legislative guidance requires the investigator to also ensure that any related SAEs are reported after 
the patient finished the study if the investigator becomes aware of them. 
7.5. Recording AEs and SAEs 
Severity of AEs will be assessed according to CTC-AE Classification Version 5.0. 
Patients will be asked to report all AEs as part of the procedures performed at each study visit. The site 
personnel will document all AEs in the patient’s medical record. All AEs subsequently must be recorded 
in the appropriate eCRF sections. 
The following points must be recorded for each event: 
▪ 
A description of the event in medical terms, not as reported by the patient; 
▪ 
Date of onset (start date); 
▪ 
Date of resolution (stop date); 
▪ 
The time of onset with respect to administering the investigational product; 
▪ 
The severity of the sign/symptom or clinically significant abnormal laboratory value according to 
CTC-AE Classification Version 5.0; 
▪ 
The causal relationship between the investigational product and the occurrence of each AE. 
This will be assessed by each investigator using clinical judgment. Alternative causes, such as 
natural history of the underlying diseases, concomitant medications, other risk factors and the 
temporal relationship of the event to the investigational product will have to be considered. The 
causality of all AEs should be assessed by the investigator with the following question: Is there 
a reasonable possibility that the AE may have been caused by the investigational product? And 
answered “NO” (if not related) and “YES” (if related); 
▪ 
Action taken regarding the investigational product:  
o 
No action; 
o 
Temporary discontinuation; 
o 
Permanent discontinuation; 
o 
Patient’s outcome: 
o 
Recovered without sequelae / resolved without sequelae; 
o 
Recovered with sequelae / resolved with sequelae; 
o 
Recovering/Resolving; 
o 
On-going; 
o 
Fatal (for SAEs only). 
If in any one patient, the same AE occurs on several occasions, the AE in question must be documented 
and assessed a new each time. 
7.6. Reporting of SAEs to ABIVAX or its designee 
Throughout the study, the reporting of SAEs to the Sponsor or its designee will be done through the 
SAE forms. 
It is the investigator’s responsibility to ensure that the SAE report is submitted to IntuVigilance Limited 
within 24 hours after knowledge of the event(s).  
The study specific SAE form should be completed as thoroughly as possible, with all the available details 
of the event and signed by the investigator or designee. The investigator will assess causality between 


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the study drug and the adverse event (AE) / serious adverse event (SAE) according to the table outlined 
below: 
Related  
A clinical event, including laboratory test abnormality, occurs in a plausible 
time relationship to treatment administration, and which concurrent disease 
or other drugs or chemicals cannot explain.  
Probably related  
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the treatment, unlikely to be attributed to 
concurrent disease or other drugs or chemicals.  
Possibly related  
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the treatment, but which could also be 
explained by concurrent disease or other drugs or chemicals.  
Unlikely to be 
related  
A clinical event, including laboratory test abnormality, with a temporal 
relationship to treatment administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations.  
Unrelated  
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship with treatment administration. Typically explained by 
extraneous factors (e.g., concomitant disease, environmental factors or 
other drugs or chemicals).  
 
An assessment of causality should always be provided at the time of the initial report. If the investigator 
or designee does not have all information regarding the SAE, he/she should not wait to receive additional 
information before completing the form and notifying IntuVigilance Limited.  
Additional or follow-up information relating to the initial SAE report, will be requested, if necessary. 
Again, this information is to be completed and submitted through the SAE forms within 24 hours of 
receipt of the information.  
In the rare occasion when the facsimile equipment does not work and in the absence of, the investigator 
should notify IntuVigilance Limited by telephone within the given timeframe and send a copy of the SAE 
report form by email. 
7.7. Reporting of SAEs to Regulatory Authorities  
ABIVAX has a legal responsibility to notify, as appropriate, both the local regulatory authorities and other 
regulatory agencies about the safety of the investigational medicinal product. It is therefore important 
that the investigator notifies promptly (within 24 hours) ABIVAX or designee of any SAEs, in order for 
legal obligations and ethical responsibilities towards other patients to be met.  
In addition, the investigator or designee, will comply with the local regulatory requirements (when 
applicable) in reporting of SAEs to the ethics committee and, if required, to the relevant government 
authority. 
Safety reports on adverse events that are serious AND unexpected AND causally associated with the 
investigational product are prepared according to ABIVAX’s policy and applicable regulations and are 
forwarded to the investigators. These reports are filed with the investigator brochure or other appropriate 
study documentation. It is the Sponsor or its designee and/or investigator’s responsibility to notify the 
IRB or IEC of these reports, if applicable according to local requirements.  
 
 


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8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
A summary of the principal features of the statistical analysis of the data will be described here, in the 
statistical section of the protocol. A more technical and detailed elaboration of the principal features 
stated in the protocol will be given in the first version of the statistical analysis plan (SAP). 
Any amendments to the SAP will be clearly documented and signed prior to the final database lock 
including justifications and details of their potential impact on the interpretation of the study results. 
8.1. Statistical and Analytical Plans 
No interim analysis is planned. 
The study analysis will be performed following database lock upon the completion of the last patient or 
upon its early discontinuation whichever occurs first.  
8.1.1. Protocol deviations 
Protocol deviations will be reviewed and classed as major or minor during the blind-review meeting. 
Major protocol deviations are defined as deviations liable to bias the evaluation of the main efficacy 
endpoint. The following deviations will be considered as major (non-exhaustive list):  
▪ 
Noncompliance with the inclusion or exclusion criteria; 
▪ 
Noncompliance with the study treatment; 
▪ 
Intake of prohibited medication; 
▪ 
Noncompliance with time window. 
 
In case of major protocol deviation, the patient must not be randomized (if deviation occurs at baseline) 
or be discontinued from the study.  
8.1.2. Definition of study analysis sets 
The following datasets will be defined and used for the analyses: 
▪ 
The Safety dataset (SAF population) is defined as those patients included in the study, who 
have received at least one dose of the study treatment. 
▪ 
The Full Analysis dataset (FAS population) is defined as those patients included in the study, 
who have received at least one dose of the study treatment, and who have at least one baseline 
data. 
▪ 
The Intent-to-Treat (ITT population) is defined as those patients randomized, regardless of 
whether the patient received a dose of study treatment or completed the study. 
▪ 
The Per Protocol dataset (PP population) is defined as those patients of the FAS population 
without any major protocol deviation. 
8.1.3. Patients/Patients disposition 
The number and the percentages of patients enrolled and included in each of the populations will be 
tabulated. The reason for patient exclusions from each of the populations will also be listed. In addition, 
the number of discontinued patients with their reason for discontinuation will be tabulated. 
8.1.4. Demographic and other baseline characteristics 
Demographics and other baseline characteristics will be summarized by treatment arm. This analysis 
will be conducted on the FAS population. 
8.1.5. Treatment compliance 
Number of doses will be presented on the FAS population. 
 


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8.2. Efficacy Analysis 
Analysis of efficacy data will be carried out in the Full Analysis Set in which subjects who prematurely 
terminate the study will be considered failures. 
The primary efficacy endpoint of the study, the ACR20 response rate, will be compared in subjects who 
received a given dose of ABX464 or placebo by likelihood ratio chi-square test on a 10% two-sided level. 
The result of the test will be interpreted in a descriptive manner therefore no adjustment for multiple 
comparison is applied. 
In addition, descriptive statistics will be presented by treatment arm for all secondary efficacy variables 
for each measurement timepoints separately for the two study groups. 
These statistics include: 
▪ 
Continuous variables: mean, standard deviation, minimum and maximum, stratified 95% 
confidence intervals, median and quartiles will be presented. 
▪ 
Categorical variables: counts, rates and stratified 95% confidence intervals for the rates will be 
calculated. 
 
In addition to descriptive statistics, mixed model analysis of covariance will be conducted for the 
following measurements: 
▪ 
The change from baseline in DAS28-CRP and DAS28-ESR 
▪ 
The change from baseline in the individual components of the ACR20 response (CRP, TJC(28), 
SJC(28), Pain-VAS, PtGA, PrGA, HAQ-DI) and in ESR 
▪ 
The change from baseline in SDAI and CDAI scores 
▪ 
The change from baseline in miR-124 in total blood at Week 8 
 
In this model, treatments and stratum will be fixed effects, subjects will be random effect, and baseline 
values of the respective measurements will be covariates. Other explanatory variables will also be 
allowed to be included in the model. In order to normalize eventual skewed distributions transformation 
of the data will also be considered. Study groups will be compared within this model framework. All p-
values will be interpreted in a descriptive manner. 
8.3. Pharmacokinetics 
Population PK data analysis will be performed via three steps: 
• 
Data preparation and exploratory: The analysis dataset will be created and formatted according to 
MONOLIX or NONMEM requirement using SAS®. An exploratory analysis by visual inspection of 
PK profiles/dose normalized PK profiles in natural and semi-log scale will be performed in order to 
anticipate the type of PK model (number of compartments, linear or saturable elimination, etc) 
• 
 Population PK model development: A PopPK model consists of four basic components: 
o 
The structural PK model, which defines the PK parameters and describes the plasma 
concentration-time profiles of ABX464 and its metabolite. 
o 
The inter-individual variability model component, which describes the inter-individual 
variability of PK parameters in the population 
o 
The residual error model component, which describes the underlying distribution of the error 
in the measured concentrations. 
o 
The covariate model component, which describes the influence of covariates such as 
demographic data on PK parameters. 
The search for the final model will follow the following strategy: 
o 
Selection of the simplest structural model, which predicts the plasma concentration as a 
function of time and dose, based on smallest objective function and by the pattern in the 
residual plots. The best estimation method, the most appropriate inter-individual variability 
(IIV) models, and the residual error model, are identified. The resulting model is called BASE 
model. 
o 
Test of influence of selected covariates. 


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o 
Refinement of inter-individual variability model and residual error models 
• 
Model validation: Goodness of fit plots will be assessed for each important step of model building. 
For the final model, a visual predictive check (an evaluation graph based on simulation) will be 
provided. 
Data will be prepared using SAS version 9.2. Population analysis will be performed using MONOLIX 
version 2018 R1 or NONMEM version 7.2. Graphs will be provided using SAS. 
8.4. Safety Analyses 
Adverse events will be coded using the standard dictionary (MedDRA) down to the lower level term 
(LLT). 
An overall summary table will be presented (Any adverse event, any treatment emergent adverse event 
(TEAE), any serious adverse event (SAE), death, any grade 3 or higher adverse events from baseline 
to the end of Study. This analysis will be conducted on SAF population. 
Two periods will be defined for TEAE: 
▪ 
Any adverse event which occurs or worsens from first dosing to Day 84; 
▪ 
Any adverse event which occurs after Day 84. 
Adverse events will be described by primary system organ class and preferred term. Numbers and 
percentage of patients, and number of occurrences of adverse event will be presented for: 
▪ 
TEAE; 
▪ 
Serious TEAE; 
▪ 
TEAE leading to drug discontinuation; 
▪ 
TEAE of grade 3 or 4; 
▪ 
TEAE for which relationship with the study drug is recorded as possible or probable. 
Analysis of safety will be performed on the safety data set consisting all subjects who received at least 
one dose of ABX464 in the study.  
Primary safety endpoint, the rate of all treatment emergent adverse experiences, will be compared in 
subjects who received a given dose of ABX464 or placebo by likelihood ratio chi-square test on a 10% 
two-sided significance level. 
Further assessment of safety will be based on the frequency of adverse events (with and without regard 
to causality) graded according to the CTC-AE Classification and also, the review of individual values for 
clinical laboratory data, vital signs and ECG focusing on the detection of abnormal values and PCSAs 
[potentially clinically significant abnormalities (PCSAs) determined upon investigator considerations]. 
Adverse events will be tabulated (counts and percentages) by group. All adverse events will be listed, 
and the data will be tabulated by body system/organ class. Adverse event tabulations will include all 
treatment emergent adverse events, which will be further classified by severity, and relationship to 
treatment and dose level. 
Clinical laboratory parameters, vital signs, ECG will be summarized by using descriptive statistics (n, 
mean, SD, SEM, median, minimum and maximum). Number of patients with at least one abnormal value 
will be tabulated (counts and percentages) for each parameter in summary shift tables, by group and 
dose. 
8.5. Clinical laboratory evaluation 
Descriptive statistics for laboratory parameters will be computed at each scheduled assessment. If 
relevant for some parameter, change from baseline will also be tabulated. 
In addition, shift tables from baseline will be presented. 
8.6. Determination of sample size 
The primary efficacy endpoint is the rate of subjects meeting the ACR20. This response rate will be 
compared in subjects who received a given dose of ABX464 or placebo by likelihood ratio chi-square 


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test. The result of the test will be interpreted in a descriptive manner therefore no adjustment for multiple 
comparison is applied. 
For the sample size assessment, the following assumptions will be made: 
▪ 
Response rate (ABX464): 0.65 
▪ 
Response rate (placebo): 0.25 
According to literature the ACR20 response rate for ABX464 + MTX treated subjects is expected to be 
between 50% and 65% while that in the placebo + MTX group is assumed to be approximately 25 to 
30% (Xeljanz® Summary of Product Characteristics; ORAL Standard Investigators - N Engl J Med 2012; 
367:508-519 August 9, 2012 (8).  
▪ 
Type 1 error: 10% two-sided 
▪ 
Group allocation rate (ABX464 / placebo): 1:1:1 
If the above assumptions and definitions hold true with a sample size of 60 subjects receiving two doses 
of ABX464 or placebo in a ratio of 1:1:1 the study has 84% power to show a difference in response rate 
between one active study group and placebo.  
Subjects who terminates the study prematurely will be considered failures therefore no adjustment for 
drop-outs is needed. 
Primary safety endpoint is the rate of all treatment emergent adverse experiences. The above sample 
size is sufficient to detect an increase in general treatment emergent adverse experience rate from 10% 
to 50% with 89% power by likelihood ratio chi-square test on a 10%, two-sided significance level. 
If approximately 20 subjects receive ABX464 the study has 88% chance to detect at least 1 specific 
treatment emergent AE if the underlying rate of occurrence is 1:10.  
When the underlying rate of occurrence is around 1:20 the sample size of 40 subjects receiving active 
treatment is sufficient to observe at least 1 such an event with a probability of 87% in the active treatment 
group. 
 
 


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9. STUDY CONDUCT CONSIDERATION 
9.1. 
Regulatory and Ethical Considerations 
9.1.1. General Requirements 
The study will be conducted in compliance with the study protocol, ABIVAX / SIMBEC ORION Standard 
Operating Procedures and in accordance with any local regulatory requirements, to ensure adherence 
to Good Clinical Practice (GCP) as described in the following documents: 
▪ 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice (ICH E6 (R2)).. 
▪ 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
▪ 
Directive 2001/20/EC on the approximation of the laws, regulations and administrative 
provisions of the Member States relating to the implementation of good clinical practice in the 
conduct of clinical studies on medicinal products for human use and its guidance. 
▪ 
Declaration of Helsinki and its amendments. 
▪ 
EudraLex GMP guidelines Annex 13 related to shipment, storage and handling of investigational 
products. 
Upon signing the protocol, the investigator agrees to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
Written informed consents will be obtained for each patient before he or she can participate in the study.  
ABIVAX will obtain favorable opinion/approval to conduct the study from the appropriate regulatory 
agencies in accordance with any applicable country-specific regulatory requirements prior to a site 
initiating the study in that country. 
9.1.2. Independent Ethics Committee/Institutional Review Board 
Prior to the start of the study, the study protocol and amendments if applicable as well as other 
appropriate study-related documents will be submitted to an independent Institutional Review Board 
(IRB) or independent Ethics Committee (IEC), respectively. 
For each center it will be individually specified, who (investigator or sponsor) will be responsible for 
informing the IRB or IEC, respectively of any protocol amendments or new relevant information that 
require an ethical reconsideration of the study protocol. 
If the investigator is responsible for obtaining approval, he/she should also obtain a statement from the 
IRB or IEC, respectively that it is organized and operates according to GCP and applicable laws and 
regulations. 
9.1.3. Patient Informed Consent 
It is the responsibility of the investigator to give each patient full and adequate verbal and written 
information regarding the aims, methods, anticipated benefits and potential hazards. The patient must 
be informed that participation is voluntary, and that they are free to withdraw from the study at any time 
without any disadvantages for their subsequent care. Although a patient is not obliged to give her/his 
reason(s) for withdrawing prematurely from the trial, the investigator should make a reasonable effort to 
ascertain the reason(s), while fully respecting the patient's rights. Written consent (signed and dated by 
the patient and the investigator) must be obtained prior to admission. The patient must be provided with 
a copy of the patient information and informed consent.  
The data collected in this study will be processed anonymously at ABIVAX. Patients should be informed 
about the purpose of the planned computer data processing and the publication of the data (e.g. at 
scientific meetings). The patient must give consent to the computer processing and to the publishing of 
anonymous data.  
The patient must be informed of and consent in writing that personal data relating to the trial may be 
patient to audits by Health Authorities and the sponsor. However, personal data will be kept strictly 
confidential and will not be made publicly available. 


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9.1.4. Compensation to Patients 
Insurance coverage will be provided for all patients enrolled in the study from the time of the patient’s 
inclusion in the study (i.e. date of signing the ICF). The insurance coverage will be provided by the 
Sponsor and will be in line with GCP guidance and legal requirements, but also in accordance with local 
regulations. A confirmation of insurance and corresponding insurance conditions should be archived in 
the Investigator File. 
Besides, due to the cumbersome procedures related to the study (number of visits, pharmacokinetics 
samples) patients could be financially compensated by the Sponsor in accordance with the national 
regulations and the approval of the Ethics Committees. 


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10. STUDY MANAGEMENT 
10.1. 
Remote Data Entry 
An electronic case report form (eCRF) will be used to record all data required by the protocol. Remote 
Data Entry (RDE) will be used for data collection, i.e. the Patient’s information pertaining to the study, 
will be entered into the eCRF via a computer at the investigational site. 
Prior to the start of the study, the investigator will complete a "Investigator site staff signature and task 
delegation log" form, showing the signatures and initials of any person who is authorized to make or 
change entries in the eCRF and any person authorized to electronically sign the eCRF. 
The eCRF used for this study is validated and fulfils the GCP ICH E6 (R2) requirements, European and 
FDA (21 CFR Part 11) regulations.  
Training sessions will be held for all the participants who will use this tool (e.g. investigators, ABIVAX 
staff and contract research organization [CRO] staff, including project managers, CRAs and data 
managers). 
Several supports are available to help all users with this tool including eCRF User Guide and five days 
a Week / working hours helpdesk (support line). 
All of the information will be recorded through transcription from source documents into the eCRF by an 
authorized person.  
The investigator is responsible for the management and accuracy of the information in the eCRF. At 
each monitoring visit, the patient medical files should be at the clinical research associates’ (CRA) 
disposal for review. 
10.2. Data management 
Data management will be outsourced to a Contract Research Organization (CRO). The data managers 
will issue electronic edit checks via EDC, and modification of the data will be permitted by the investigator 
to achieve accuracy with source documents and eliminate all inconsistencies in the data.  
The data will be reviewed for completeness and logical consistency. Automated validation programs will 
identify missing data, out of range data and other data inconsistencies at the time of entry. 
All new/updated information will be reviewed and verified by the appointed monitor.  
10.3. Data coding 
Adverse events, concomitant diseases, medical/surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medication will be coded using the WHO-
DRUG dictionary. 
10.4. Randomization 
Randomization will be centrally managed. It will be performed via a centralized treatment allocation 
system that will be available 24 hours-a-day, 7 days-a-week. Randomization will be stratified according 
to previous exposure to anti-TNFα therapy. The bottle numbers to be used for a specific patient will be 
assigned according to a pre-defined randomization list.  
10.5. Study Monitoring 
The study will be conducted in accordance with the related topic of the ICH E6 (R2) GCP guidelines. 
The appointed monitor will contact the site prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and ABIVAX 
requirements. Throughout the study, the monitor will arrange visits to the study center at appropriate 
intervals to assess the progress of the study and review the completed eCRFs.  
During the monitoring visits, the monitor will: 
▪ 
Ensure that the safety and the rights of patients are being protected; 
▪ 
Check that the data are authentic, accurate, and complete and discuss any inconsistencies; 


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▪ 
Ensure that all study materials are correctly stored and dispensed with particular emphasis to 
the investigational product; 
▪ 
Verify that the site staff and facilities continue to be adequate for the proper conduct of the study; 
▪ 
Ensure that the study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements; 
▪ 
Help resolve any problems that may have arisen. 
In line with ICH E6 (R2) GCP guidelines, monitoring will include verification of data entered in the CRF 
against the original patient records. Therefore, for the purpose of monitoring review, direct access to all 
study-related site and source documents is mandatory. Data items for which the eCRF will serve as the 
source document will be identified, agreed upon and documented. The investigator must also ensure 
provision of sufficient time, space and qualified personnel for the monitoring visits. 
10.6. Records Retention 
Following closure of the study, the investigator or the head of the medical institution (where applicable) 
must maintain all site study records, except for those required by local regulations to be maintained by 
someone else, in a safe and secure location. The records must be maintained to allow easy and timely 
retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent 
review of data in conjunction with assessment of the facility, supporting systems, and staff. 
ABIVAX will inform the investigator/institution of the required time period for retaining these records in 
order to be compliant with all applicable regulatory requirements. The minimum retention time will meet 
the strictest standard applicable to that study site, as dictated by ICH E6 (R2) Section 4.9, any 
institutional requirements or local laws and regulations, or ABIVAX standards/procedures; otherwise, by 
default the retention period will be 15 years. 
The investigator must notify ABIVAX of any changes in the archival arrangements, including, but not 
limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event 
the investigator leaves the site. In addition, the investigator should seek the written approval of the 
Sponsor prior to disposing any of the archived records. 
10.7. Quality Assurance and Inspection by Authorities 
To ensure compliance with GCP and all applicable regulatory requirements, ABIVAX may conduct 
quality assurance audits. Regulatory agencies may also conduct a regulatory inspection of this study. 
Such audits/inspections can occur at any time during or after completion of the study. By signing the 
protocol agreement page, the investigator agrees to permit drug regulatory agencies and ABIVAX 
audits. If an audit or inspection occurs, the investigator and institution will allow the auditor/inspector 
direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues. Items of particular interest in case of an 
audit are, but not limited to, the following: 
▪ 
IRB/IEC and regulatory authority approvals; 
▪ 
Informed consent forms of the patients; 
▪ 
Approved study protocol and amendments and investigator brochure; 
▪ 
Treatment accountability; 
▪ 
Safety reporting; 
▪ 
Study file; 
▪ 
Study personnel; 
▪ 
Log of monitoring visits and monitoring process; 
▪ 
Medical records and other source documents; 
▪ 
Site facilities; 
▪ 
Reports to the IRB/IEC and the sponsor; 
▪ 
Record retention. 
 
 


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10.8. Study and Site Closure 
If the study is terminated prematurely or suspended for any reason, the investigator/institution should 
promptly inform the study patients and should assure appropriate therapy and follow-up for the patients 
ABIVAX reserves the right to temporarily suspend or prematurely discontinue this study, at any time for 
reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter 
studies, this can occur at one or more or at all sites. If such action is required, the Sponsor will discuss 
this with the investigator or the head of the medical institution (where applicable), including the reasons 
for taking such action, at that time. Advance notification will be provided to the site(s) when feasible, on 
the impending action prior to it taking effect. 
All investigators and/or medical institutions conducting the study will be informed in writing should the 
Sponsor decide to suspend or prematurely discontinue the study for safety reasons. The regulatory 
authorities will also be informed of the suspension or premature discontinuation of the study and the 
reason(s) for the action. If required by local regulations, the investigator must inform the IRB/IEC 
promptly and provide the reason for the suspension or premature discontinuation. 
Upon premature discontinuation of the study, the monitor will conduct site closure activities with the 
investigator or site staff, as appropriate, in accordance with applicable regulations, GCP, and ABIVAX 
procedures. All data must be returned to ABIVAX. Arrangements will be made for any unused 
investigational product based on the relevant ABIVAX procedures for the study. 
10.9. Study report and Publication 
Upon conclusion of the study, an integrated clinical and statistical study report will be written by the 
Sponsor in consultation with the Coordinating Investigator. This report will be based on the items 
detailed in this study protocol. When the clinical study report is completed, ABIVAX will provide the 
investigators with a full summary of the study results. The investigators are encouraged to share the 
summary results with the patients, as appropriate. 
The first resulting publication will be a full publication of all data from all participating sites, coordinated 
by ABIVAX. Any secondary publications by the investigators (abstracts in journals, oral presentations 
etc.) will reference the original publication and will require pre-submission review by the Sponsor. Note 
that the Sponsor is entitled to delay any proposed secondary publication, in order to obtain patent 
protection, if required. 
The Coordinating Investigator as well as other members of the study committee will be authors on the 
first publication. The principal investigator of the trial will be the first author. Authorship for other 
investigators will be assigned on the basis of their recruitment contribution, as well as intellectual and 
administrative input. Ranking will be according to the number of patients randomized as well as 
contribution to the study conduct and preparation of final manuscript.  
10.10. Ownership and Confidentiality 
All information provided by ABIVAX and all data and information generated by the sites, as parts of the 
study (excluding the patients’ medical records) are property of ABIVAX.  
All potential investigators must be aware of and agree in writing (confidentiality agreement) to the 
confidential nature of the information pertaining to this study. Furthermore, all information provided by 
ABIVAX and all data and information generated by the sites during the study must be kept confidential 
by the investigator and other site staff and may not be used for any purpose other than conducting this 
study. 


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11. REFERENCES  
1. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the 
prevalence of arthritis and other rheumatic conditions in the United States: part I. Arthritis Rheum. 
2008;58:15–25. 
2. Pincus T, Callahan LF, SaleWG, Brooks AL, Payne LE, Vaughn WK. Severe functional declines, 
work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine 
years. Arthritis Rheum. 1984;27:864–72. 
3. Salaffi F, Sarzi-Puttini P, Girolimetti R, Atzeni F, Gasparini S, Grassi W. Health-related quality 
of life in fibromyalgia patients: a comparison with rheumatoid arthritis patients and the general 
population using the SF-36 health survey. Clin Exp Rheumatol. 2009;27(Supp56):S67–74. 
4.  National Institute for Health and Care Excellence (NICE) guideline. Rheumatoid arthritis in 
adults: management. www.nice.org.uk/guidance/ng100. July 2018. 
5.  Singh JA, Saag KG, Bridges Jr L, et al. 2015 American College of Rheumatology guideline for 
the treatment of rheumatoid arthritis. Arthritis Rheum. 2016;68 (vol.1):1-26. 
6.  Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of 
rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 
update. Ann. Rheum. Dis. 2017;76:960-977 
7.  Emery P. Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response 
to anti-TNF treatment. Rheumatology 2012;51:v22-v30 
8. Ronald F. van Vollenhoven et al. for the ORAL Standard Investigators. Tofacitinib or Adalimumab 
versus Placebo in Rheumatoid Arthritis. N Engl J Med 2012; 367:508-519 August 9, 2012 
 
 
 


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12. APPENDICES 
Appendix 1: CYPIA2 substrates (in bold: prohibited concomitant medications) 
 
Amitriptyline, Clomipramine, Imipramine, Agomelatine, Fluvoxamine, Clozapine, Olanzapine, 
Haloperidol, Ropivacaine, Theophylline, Zolmitriptan, Tamoxifen, Erlotinib, Cyclobenzaprine, 
Mexiletine, Naproxen, Ondansetron, Phenacetin, Paracetamol, Propranolol, Tacrine, Tizanidine, 
Verapamil, Warfarin, Zileuton, Ropinirole, Methadone, Rifampicin 
 
 
 


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Appendix 2: HAQ-DI 
 
 
 
 
Copyright © 1980 James F. Fries, M.D. - Stanford, CA, U.S.A. - All Rights Reserved 
 


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Copyright © 1980 James F. Fries, M.D. - Stanford, CA, U.S.A. - All Rights Reserved 
 
 
 


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Appendix 3: Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
 
FACIT Fatigue Scale (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
HI7 
I feel fatigued
 ........................................................................................................................  
0 
1 
2 
3 
4 
HI12 
I feel weak all over
 ........................................................................................................................  
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”)
 ........................................................................................................................  
0 
1 
2 
3 
4 
An2 
I feel tired
 ........................................................................................................................  
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired
 ........................................................................................................................  
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired
 ........................................................................................................................  
0 
1 
2 
3 
4 
An5 
I have energy
 ........................................................................................................................  
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities
 ........................................................................................................................  
0 
1 
2 
3 
4 
An8 
I need to sleep during the day
 ........................................................................................................................  
0 
1 
2 
3 
4 
An12 
I am too tired to eat
 ........................................................................................................................  
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities
 ........................................................................................................................  
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want to do
 ........................................................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am tired
 ........................................................................................................................  
0 
1 
2 
3 
4 
 
 
 


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Appendix 4: Follow_up Headache Questionnaire 
 
 


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Appendix 5: Methotrexate SmPC 
 
SUMMARY OF PRODUCT CHARACTERISTICS 
 
1. NAME OF THE MEDICINAL PRODUCT 
Metoject 50 mg/ml solution for injection, pre-filled syringe 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
1 ml of solution contains 50 mg methotrexate (as methotrexate disodium). 
1 pre-filled syringe of 0.15 ml contains 7.5 mg methotrexate. 
1 pre-filled syringe of 0.20 ml contains 10 mg methotrexate. 
1 pre-filled syringe of 0.25 ml contains 12.5 mg methotrexate. 
1 pre-filled syringe of 0.30 ml contains 15 mg methotrexate. 
1 pre-filled syringe of 0.35 ml contains 17.5 mg methotrexate. 
1 pre-filled syringe of 0.40 ml contains 20 mg methotrexate. 
1 pre-filled syringe of 0.45 ml contains 22.5 mg methotrexate. 
1 pre-filled syringe of 0.50 ml contains 25 mg methotrexate. 
1 pre-filled syringe of 0.55 ml contains 27.5 mg methotrexate. 
1 pre-filled syringe of 0.60 ml contains 30 mg methotrexate 
For the full list of excipients, see section 6.1. 
3. PHARMACEUTICAL FORM 
Solution for injection, pre-filled syringe. 
Clear, yellow-brown solution. 
4. CLINICAL PARTICULARS 
4.1 Therapeutic indications 
Metoject is indicated for the treatment of 
− active rheumatoid arthritis in adult patients, 
− polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal 
anti-inflammatory drugs (NSAIDs) has been inadequate, 
− severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy 
such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients, 
− mild to moderate Crohn’s disease either alone or in combination with corticosteroids in adult 
patients refractory or intolerant to thiopurines. 
4.2 Posology and method of administration 
Metoject should only be prescribed by physicians who are familiar with the various characteristics of 
the medicinal product and its mode of action. The administration should routinely be done by health 
professionals. If the clinical situation permits the treating physician can, in selected cases, delegate the 
subcutaneous administration to the patient her/himself. In these cases, detailed administration 
instructions from the physician are obligate. Metoject is injected once weekly. 
The patient is to be explicitly informed about the fact of administration once weekly. It is advisable to 
determine a fixed, appropriate weekday as day of injection. 
Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural 
effusions). 
Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some 
cases, discontinuation of methotrexate administration (see section 5.2 and 4.4). 
Dosage in adult patients with rheumatoid arthritis 
The recommended initial dose is 7.5 mg of methotrexate once weekly, administered either 


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subcutaneously, intramuscularly or intravenously. Depending on the individual activity of the disease 
and tolerability by the patient, the initial dose may be increased gradually by 2.5 mg per week. A 
weekly dose of 25 mg should in general not be exceeded. However, doses exceeding 20 mg/week are 
associated with significant increase in toxicity, especially bone marrow suppression. Response to 
treatment can be expected after approximately 4 – 8 weeks. Upon achieving the therapeutically desired 
result, the dose should be reduced gradually to the lowest possible effective maintenance dose. 
Dosage in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic 
arthritis 
The recommended dose is 10 – 15 mg/m² body surface area (BSA)/once weekly. In therapy-refractory 
cases the weekly dosage may be increased up to 20 mg/m² body surface area/once weekly. However, 
an increased monitoring frequency is indicated if the dose is increased. 
Due to limited data availability about intravenous use in children and adolescents, parenteral 
administration is limited to subcutaneous and intramuscular injection. 
Patients with JIA should always be referred to a rheumatology specialist in the treatment of 
children/adolescents. 
Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety is 
available for this population (see section 4.4). 
Dosage in patients with psoriasis vulgaris and psoriatic arthritis 
It is recommended that a test dose of 5 – 10 mg should be administered parenterally, one week prior to 
therapy to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg of 
methotrexate once weekly, administered either subcutaneously, intramuscularly or intravenously. The 
dose is to be increased gradually but should not, in general, exceed a weekly dose of 25 mg of 
methotrexate. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, 
especially bone marrow suppression. Response to treatment can generally be expected after 
approximately 2 – 6 weeks. Upon achieving the therapeutically desired result, the dose should be 
reduced gradually to the lowest possible effective maintenance dose. 
Dosage in patients with Crohn’s disease 
• Induction treatment: 
25 mg/week administered either subcutaneously, intravenously or intramuscularly. 
Response to treatment can be expected after approximately 8 to 12 weeks. 
• Maintenance treatment: 
15 mg/week administered either subcutaneously, intravenously or intramuscularly. 
There is not sufficient experience in the paediatric population to recommend Metoject for the 
treatment of Crohn’s disease in this population. 
Maximum weekly dose 
The dose should be increased as necessary but should in general not exceed the maximum 
recommended weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically 
justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will 
markedly increase. 
Patients with renal impairment 
Metoject should be used with caution in patients with impaired renal function. The dose should be 
adjusted as follows: 
Creatinine clearance (ml/min) Dose 
≥ 60  
 
 
 
100 % 
30 – 59  
 
 
50 % 
< 30  
 
 
 
Metoject must not be used 
See section 4.3. 
 
Patients with hepatic impairment 


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Methotrexate should be administered with great caution, if at all, to patients with significant current or 
previous liver disease, especially if due to alcohol. If bilirubin is  5 mg/dl (85.5 μmol/l), methotrexate 
is contraindicated. 
For the full list of contraindications, see section 4.3. 
Use in elderly patients 
Dose reduction should be considered in elderly patients due to reduced liver and kidney function as 
well as lower folate reserves which occur with increased age. 
Use in patient with a third distribution space (pleural effusions, ascitis) 
As the half-life of methotrexate can be prolonged to 4 times the normal length in patients who possess 
a third distribution space dose reduction or, in some cases, discontinuation of methotrexate 
administration may be required (see section 5.2 and 4.4). 
Method of administration 
The medicinal product is for single use only. 
Metoject can be given by intramuscular, intravenous or subcutaneous route (in children and 
adolescents only subcutaneous or intramuscular). 
The overall duration of the treatment is decided by the physician. 
Note: 
If changing the oral application to parenteral administration a reduction of the dose may be required 
due to the variable bioavailability of methotrexate after oral administration. 
Folic acid supplementation may be considered according to current treatment guidelines. 
4.3 Contraindications 
Metoject is contraindicated in the case of 
− hypersensitivity to the active substance or to any of the excipients listed in section 6.1, 
− severe liver impairment (see section 4.2), 
− alcohol abuse, 
− severe renal impairment (creatinine clearance less than 30 ml/min., see section 4.2 and section 4.4), 
− pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or 
significant anaemia, 
− serious, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency 
syndromes, 
− ulcers of the oral cavity and known active gastrointestinal ulcer disease, 
− pregnancy and breast-feeding (see section 4.6), 
− concurrent vaccination with live vaccines. 
4.4 Special warnings and precautions for use 
Patients must be clearly informed that the therapy has to be administered once a week, not every day. 
Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic 
effects or adverse reactions may be detected and evaluated with minimal delay. Therefore, 
methotrexate should be only administered by, or under the supervision of physicians whose knowledge 
and experience includes the use of antimetabolite therapy. Because of the possibility of severe or even 
fatal toxic reactions, the patient should be fully informed by the physician of the risks involved and the 
recommended safety measures. 
Recommended examinations and safety measures 
Before beginning or reinstituting methotrexate therapy after a rest period 
Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum 
albumin, chest x-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis. 
During therapy (at least once a month during the first six months and every three months thereafter) 


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An increased monitoring frequency should be considered also when the dose is increased. 
1.  
Examination of the mouth and throat for mucosal changes 
2.  
Complete blood count with differential blood count and platelets. Haemopoietic suppression 
caused by methotrexate may occur abruptly and with apparently safe doses. Any profound drop 
in whitecell or platelet counts indicates immediate withdrawal of the medicinal product and 
appropriate supportive therapy. Patients should be advised to report all signs and symptoms 
suggestive of infection. Patients taking simultaneous administration of haematotoxic medicinal 
products (e.g. leflunomide) should be monitored closely with blood count and platelets. 
3.  
Liver function tests: Particular attention should be given to the appearance of liver toxicity. 
Treatment should not be instituted or should be discontinued if any abnormality of liver function 
tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to 
normal within two weeks after which treatment may be recommenced at the discretion of the 
physician. There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in 
rheumatological indications. 
For psoriasis patients the need of a liver biopsy prior to and during therapy is controversial. 
Further research is needed to establish whether serial liver chemistry tests or propeptide of type 
III collagen can detect hepatotoxicity sufficiently. The evaluation should be performed case by 
case and differentiate between patients with no risk factors and patients with risk factors such as 
excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver 
disease, family history of inheritable liver disease, diabetes mellitus, obesity, and history of 
significant exposure to hepatotoxic drugs or chemicals and prolonged methotrexate treatment or 
cumulative doses of 1.5 g or more. 
Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or 
three times of the upper limit of normal have been reported by patients at a frequency of 13 – 20 
%. In the case of a constant increase in liver-related enzymes, a reduction of the dose or 
discontinuation of therapy should be taken into consideration. 
Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should 
not be taken during treatment with methotrexate unless clearly necessary and the consumption 
of alcohol should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver 
enzymes should be exercised in patients taking other hepatotoxic medicinal products 
concomitantly (e.g. leflunomide). 
The same should be taken into account with the simultaneous administration of haematotoxic 
medicinal products (e.g. leflunomide). 
4.  
Renal function should be monitored by renal function tests and urinalysis (see sections 4.2 and 
4.3). 
As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be 
expected in the case of renal impairment, which may result in severe undesirable effects. 
Where renal function may be compromised (e.g. in the elderly), monitoring should take place 
more frequently. This applies in particular when medicinal products are administered 
concomitantly that affect the elimination of methotrexate, cause kidney damage (e.g. non-
steroidal anti-inflammatory medicinal products) or that can potentially lead to impairment of 
blood formation. Dehydration may also intensify the toxicity of methotrexate. 
5.  
Assessment of respiratory system: Alertness for symptoms of lung function impairment and, if 
necessary lung function test. Pulmonary affection requires a quick diagnosis and discontinuation 
of methotrexate. Pulmonary symptoms (especially a dry, non-productive cough) or a non-
specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially 
dangerous lesion and require interruption of treatment and careful investigation. Acute or 
chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths 
have been reported. 
Although clinically variable, the typical patient with methotrexate-induced lung disease presents 
with fever, cough, dyspnoea, hypoxemia, and an infiltrate on chest X-ray, infection needs to be 


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excluded. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate 
therapy. This lesion can occur at all doses. 
In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in 
rheumatologic and related indications. This event may also be associated with vasculitis and 
other comorbidities. Prompt investigations should be considered when pulmonary alveolar 
haemorrhage is suspected to confirm the diagnosis. 
6.  
Methotrexate may, due to its effect on the immune system, impair the response to vaccination 
results and affect the result of immunological tests. Particular caution is also needed in the 
presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) for 
reasons of eventual activation. Vaccination using live vaccines must not be carried out under 
methotrexate therapy. 
Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy 
must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the 
initiation of cytotoxic therapy. 
Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been 
reported to cause an acute megaloblastic pancytopenia in rare instances. 
Radiation-induced dermatitis and sunburn can reappear under methotrexate therapy (recall-reaction). 
Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of 
methotrexate. 
Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural 
effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction 
or, in some cases, discontinuation of methotrexate administration. Pleural effusions and ascites should 
be drained prior to initiation of methotrexate treatment (see section 5.2). 
Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise 
haemorrhagic enteritis and death from intestinal perforation may occur. 
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may 
decrease the effectiveness of methotrexate. 
For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling 
psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis 
has been established by biopsy and/or after dermatological consultation. 
Encephalopathy/leukoencephalopathy have been reported in oncologic patients receiving methotrexate 
therapy and cannot be excluded for methotrexate therapy in non-oncologic indications. 
Fertility and reproduction 
Fertility 
Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in 
humans, during and for a short period after cessation of therapy, and to cause impaired fertility, 
affecting spermatogenesis and oogenesis during the period of its administration – effects that appear to 
be reversible on discontinuing therapy. 
Teratogenicity – Reproductive risk 
Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible 
risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed 
with female patients of childbearing potential (see section 4.6). The absence of pregnancy must be 
confirmed before Metoject is used. If women of a sexually mature age are treated, effective 
contraception must be performed during treatment and for at least six months after. 
For contraception advice for men see section 4.6. 
Sodium 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 
“sodium-free”. 


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Paediatric population 
Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are 
available for this population (see section 4.2). 
4.5 Interaction with other medicinal products and other forms of interaction 
Nitrous oxide 
The use of nitrous oxide potentiates the effect of methotrexate on folate, yielding increased toxicity 
such as severe unpredictable myelosuppression and stomatitis. Whilst this effect can be reduced by 
administering calcium folinate, the concomitant use should be avoided. 
Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products 
The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol 
consumption and when other hepatotoxic medicinal products are taken at the same time (see section 
4.4). 
Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide) should be 
monitored with special care. The same should be taken into account with the simultaneous 
administration of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids, 
sulfasalazine). The incidence of pancytopenia and hepatotoxicity can be increased when leflunomide is 
combined with methotrexate. 
Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of 
hepatotoxicity. 
Oral antibiotics 
Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics 
can interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of 
the bacterial metabolism. 
Antibiotics 
Antibiotics, like penicillines, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in 
individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of 
methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur. 
Medicinal products with high plasma protein binding 
Methotrexate is plasma protein bound and may be displaced by other protein bound medicinal 
products such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, 
tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, 
which can lead to increased toxicity when used concurrently. 
Probenecid, weak organic acids, pyrazoles and non-steroidal anti-inflammatory agents 
Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the 
elimination of methotrexate and higher serum concentrations may be assumed inducing higher 
haematological toxicity. There is also a possibility of increased toxicity when low dose methotrexate 
and nonsteroidal anti-inflammatory medicinal products or salicylates are combined. 
Medicinal products with adverse reactions on the bone marrow 
In the case of medication with medicinal products which may have adverse reactions on the bone 
marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); 
attention should be paid to the possibility of pronounced impairment of blood formation. 
Medicinal products which cause folate deficiency 
The concomitant administration of products which cause folate deficiency (e.g. sulphonamides, 
trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is 
therefore advisable in the presence of existing folic acid deficiency. 
Products containing folic acid or folinic acid 
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may 
decrease the effectiveness of methotrexate. 
Other antirheumatic medicinal products 


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An increase in the toxic effects of methotrexate is, in general, not to be expected when Metoject is 
administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds, 
penicillamine, hydroxychloroquine, sulfasalazine, azathioprin, cyclosporin). 
Sulfasalazine 
Although the combination of methotrexate and sulfasalazine can cause an increase in efficacy of 
methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis 
through sulfasalazine, such undesirable effects have only been observed in rare individual cases in the 
course of several studies. 
Mercaptopurine 
Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and 
mercaptopurine may therefore require dose adjustment. 
Proton-pump inhibitors 
A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to 
interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal 
elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the 
metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case. 
Theophylline 
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored 
when used concurrently with methotrexate. 
Caffeine- or theophylline-containing beverages 
An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-
containing soft drinks, black tea) should be avoided during methotrexate therapy. 
4.6 Fertility, pregnancy and lactation 
Women of childbearing potential/Contraception in females 
Women must not get pregnant during methotrexate therapy, and effective contraception must be used 
during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating 
therapy, women of childbearing potential must be informed of the risk of malformations associated 
with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate 
measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically 
required (e.g. after any gap of contraception). Female patients of reproductive potential must be 
counselled regarding pregnancy prevention and planning. 
Contraception in males 
It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in 
animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. 
Limited clinical evidence does not indicate an increased risk of malformations or miscarriage 
following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there 
is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure. 
As precautionary measures, sexually active male patients or their female partners are recommended to 
use reliable contraception during treatment of the male patient and for at least 6 months after cessation 
of methotrexate. Men should not donate semen during therapy or for 6 months following 
discontinuation of methotrexate. 
 
Pregnancy 
Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3). If 
pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice 
should be given regarding the risk of harmful effects on the child associated with treatment and 
ultrasonography examinations should be performed to confirm normal foetal development. 
In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester 
(see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to 


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cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, 
central nervous system and extremity-related). 
Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, 
intrauterine growth restriction and congenital malformations in case of exposure during pregnancy. 
• Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose 
methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-
matched patients treated with drugs other than methotrexate. 
• Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate 
treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in 
disease-matched patients treated with drugs other than methotrexate. 
Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but 
higher rates of spontaneous abortions and congenital malformations are expected. 
When methotrexate was discontinued prior to conception, normal pregnancies have been reported. 
Breast-feeding 
Methotrexate is excreted in human milk. Because of the potential for serious adverse reactions in 
breastfed infants, Metoject is contraindicated during breast-feeding (see section 4.3). Therefore breast-
feeding must be discontinued prior to and throughout administration. 
Fertility 
Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, 
methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These 
effects appear to be reversible after discontinuation of therapy in most cases. 
4.7 Effects on ability to drive and use machines 
Central nervous symptoms such as tiredness and dizziness can occur during treatment, Metoject has 
minor or moderate influence on the ability to drive and use machines. 
4.8 Undesirable effects 
Summary of the safety profile 
Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, 
hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens- 
Johnson syndrome. 
Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal 
disorders e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite and abnormal liver 
function tests e.g. increased ALAT, ASAT, bilirubin, alkaline phosphatase. Other frequently 
(common) occurring adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, 
drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral 
ulcers, diarrhoea, exanthema, erythema and pruritus. 
Tabulated list of adverse reactions 
The most relevant undesirable effects are suppression of the haematopoietic system and 
gastrointestinal disorders. 
The following headings are used to organise the undesirable effects in order of frequency: 
Very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare 
( 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available 
data) 
Infections and infestations 
Uncommon: Pharyngitis. 
Rare: Infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis. 
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
Very rare: Lymphoma (see “description” below). 


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Blood and lymphatic system disorders 
Common: Leukopenia, anaemia, thrombopenia. 
Uncommon: Pancytopenia. 
Very rare: Agranulocytosis, severe courses of bone marrow depression, lymphoproliferative disorders 
(see “description” below). 
Not known: Eosinophilia. 
Immune system disorders 
Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia. 
Metabolism and nutrition disorders 
Uncommon: Precipitation of diabetes mellitus. 
Psychiatric disorders 
Uncommon: Depression, confusion. 
Rare: Mood alterations. 
Nervous system disorders 
Common: Headache, tiredness, drowsiness. 
Uncommon: Dizziness. 
Very rare: Pain, muscular asthenia or paraesthesia in the extremities, changes in sense of taste 
(metallic taste), convulsions, meningism, acute aseptic meningitis, paralysis. 
Not known: Encephalopathy/leukoencephalopathy. 
Eye disorders 
Rare: Visual disturbances. 
Very rare: Impaired vision, retinopathy. 
Cardiac disorders 
Rare: Pericarditis, pericardial effusion, pericardial tamponade. 
Vascular disorders 
Rare: Hypotension, thromboembolic events. 
Respiratory, thoracic and mediastinal disorders 
Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms 
indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, short 
of breath and fever. 
Rare: Pulmonary fibrosis, Pneumocystis carinii pneumonia, shortness of breath and bronchial asthma, 
pleural effusion. 
Not known: Epistaxis, pulmonary alveolar haemorrhage. 
Gastrointestinal disorders 
Very common: Stomatitis, dyspepsia, nausea, loss of appetite, abdominal pain. 
Common: Oral ulcers, diarrhoea. 
Uncommon: Gastrointestinal ulcers and bleeding, enteritis, vomiting, pancreatitis. 
Rare: Gingivitis. 
Very rare: Haematemesis, haematorrhea, toxic megacolon. 
Hepatobiliary disorders (see section 4.4) 
Very common: Abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and 
bilirubin). 
Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin. 
Rare: Acute hepatitis. 
Very rare: Hepatic failure. 
Skin and subcutaneous tissue disorders 
Common: Exanthema, erythema, pruritus. 
Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, skin ulcer, herpes zoster, 
vasculitis, herpetiform eruptions of the skin, urticaria. 


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Rare: Increased pigmentation, acne, petechiae, ecchymosis, allergic vasculitis. 
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), increased 
pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia. 
Musculoskeletal and connective tissue disorders 
Uncommon: Arthralgia, myalgia, osteoporosis. 
Rare: Stress fracture. 
Not known: Osteonecrosis of jaw (secondary to lymphoproliferative disorders). 
Renal and urinary disorders 
Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed 
micturition. 
Rare: Renal failure, oliguria, anuria, electrolyte disturbances. 
Not known: Proteinuria. 
Reproductive system and breast disorders 
Uncommon: Inflammation and ulceration of the vagina. 
Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal 
discharge. 
General disorders and administration site conditions 
Rare: Fever, wound-healing impairment. 
Very rare: Local damage (formation of sterile abscess, lipodystrophy) of injection site following 
intramuscular or subcutaneous administration. 
Not known: Asthenia. 
Description of selected adverse reactions 
The appearance and degree of severity of undesirable effects depends on the dose level and the 
frequency of administration. However, as severe undesirable effects can occur even at lower doses, it 
is indispensable that patients are monitored regularly by the doctor at short intervals. 
Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma 
and other lymphoproliferative disorders which subsided in a number of cases once treatment with 
methotrexate had been discontinued. 
When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) 
or damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur 
commonly. Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin 
reactions (such as burning sensations, erythema, swelling, discolouration, pruritus, severe itching, 
pain) were observed, decreasing during therapy. 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via (see details below). 
[To be completed nationally] 
4.9 Overdose 
a) Symptoms of overdose 
Toxicity of methotrexate mainly affects the haematopoietic system. 
b) Treatment measures in the case of overdose 
Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate. 
In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose 
of methotrexate should be administered intravenously or intramuscularly within one hour and dosing 
continued until the serum levels of methotrexate are below 10-7 mol/l. 


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In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent 
precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor 
peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of 
methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser. 
 
5. PHARMACOLOGICAL PROPERTIES 
5.1 Pharmacodynamic properties 
Pharmacotherapeutic group: Folic acid analogues, ATC code: L01BA01 
Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and 
polyarthritic forms of juvenile idiopathic arthritis. Immunomodulating and anti-inflammatory agent for 
the treatment of Crohn’s disease. 
Mechanism of action 
Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as 
antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus 
inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the 
management of psoriasis, psoriasis arthritis, chronic polyarthritis and Crohn’s disease, is due to an 
anti-inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase 
in extracellular adenosine concentration at inflamed sites contributes to these effects. 
International clinical guidelines reflect the use of methotrexate as a second choice for Crohn’s disease 
patients that are intolerant or have failed to respond to first-line immunomodulating agents as 
azathioprine (AZA) or 6-mercaptopurine (6-MP). 
The adverse events observed in the studies performed with methotrexate for Crohn’s disease at 
cumulative doses have not shown a different safety profile of methotrexate than the profile it is already 
known. Therefore, similar cautions must be taken with the use of methotrexate for the treatment of 
Crohn’s disease as in other rheumatic and non-rheumatic indications of methotrexate (see sections 4.4 
and 4.6). 
5.2 Pharmacokinetic properties 
Absorption 
Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of low-
dosed administration (dosages between 7.5 mg/m² and 80 mg/m² body surface area), the mean 
bioavailability is approx. 70 %, but considerable interindividual and intraindividual deviations are 
possible (25 – 100 %). Maximum serum concentrations are achieved after 1 – 2 hours. 
Bioavailability of subcutaneous, intravenous and intramuscular injection is comparable and nearly 
100%. 
Distribution 
Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body 
tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in 
particular, which can be retained for weeks or months. When administered in small doses, 
methotrexate passes into the cerebrospinal fluid in minimal amounts. The terminal half-life is on 
average 6 – 7 hours and demonstrates considerable variation (3 – 17 hours). The half-life can be 
prolonged to 4 times the normal length in patients who possess a third distribution space (pleural 
effusion, ascites). 
Biotransformation 
Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle 
metabolite is 7-hydroxymethotrexate. 
Elimination 


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Excretion takes places, mainly in unchanged form, primarily renal via glomerular filtration and active 
secretion in the proximal tubulus. 
Approx. 5 – 20 % methotrexate and 1 – 5 % 7-hydroxymethotrexate are eliminated biliary. There is 
pronounced enterohepatic circulation. 
In the case of renal impairment, elimination is delayed significantly. Impaired elimination with regard 
to hepatic impairment is not known. 
5.3 Preclinical safety data 
Animal studies show that methotrexate impairs fertility, is embryo- and foetotoxic and teratogenic. 
Methotrexate is mutagenic in vivo and in vitro. As conventional carcinogenicity studies have not been 
performed and data from chronic toxicity studies in rodents are inconsistent, methotrexate is 
considered not classifiable as to its carcinogenicity to humans. 
6. PHARMACEUTICAL PARTICULARS 
6.1 List of excipients 
Sodium chloride 
Sodium hydroxide for pH adjustment 
Water for injections 
6.2 Incompatibilities 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
6.3 Shelf-life 
2 years. 
6.4 Special precautions for storage 
Store below 25 °C. Keep the pre-filled syringes in the outer carton in order to protect from light. 
6.5 Nature and contents of container 
Nature of container 
Pre-filled syringes of colourless glass (type I) of 1 ml capacity with embedded injection needle. 
Plunger stoppers of chlorobutyl rubber (type I) and polystyrene rods inserted on the stopper to form 
the syringe plunger 
or 
Pre-filled syringes of colourless glass (type I) of 1 ml capacity with embedded injection needle. 
Plunger stoppers of chlorobutyl rubber (type I), polystyrene rods inserted on the stopper to form the 
syringe plunger and a safety system to prevent needle stick injury and reuse of the needle. 
or 
Pre-filled syringes of colourless glass (type I) of 1 ml capacity with enclosed injection needle. Plunger 
stoppers of chlorobutyl rubber (type I) and polystyrene rods inserted on the stopper to form the syringe 
plunger. 
Pack sizes 
Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml, 
0.55 ml or 0.60 ml solution are available in packs of 1, 4, 5, 6, 10, 11, 12 and 24 syringes with 
embedded s.c. injection needle and alcohol pads. 
and 
Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml, 
0.55 ml or 0.60 ml solution are available in packs of 1, 4, 5, 6, 10, 11, 12 and 24 syringes with 
embedded s.c. injection needle with safety system and alcohol pads. 


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and 
Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml, 
0.55 ml or 0.60 ml solution are available in packs of 1, 4, 5, 6, 10, 11, 12 and 24 syringes with 
enclosed s.c. injection needle and alcohol pads. 
For i.m and i.v use, a needle suitable for these routes of administration must be used: The needle 
enclosed in the pack is suitable for s.c. use only. 
All pack sizes are available with graduation marks. 
Not all pack sizes may be marketed. 
6.6 Special precautions for disposal and other handling 
The manner of handling and disposal must be consistent with that of other cytotoxic preparations in 
accordance with local requirements. Pregnant healthcare personnel should not handle and/or 
administer Metoject. 
Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the 
affected area must be rinsed immediately with ample amount of water. 
For single use only. 
Any unused medicinal product or waste should be disposed of in accordance with local requirements. 
In some regions Metoject may be marketed with a safety system to prevent needle stick injury and 
reuse of the needle. 
Instructions for subcutaneous use of Metoject without safety system 
The best places for the injection are: 
- upper thighs, 
- abdomen except around the navel. 
1.  
Clean the area around the chosen injection site (e.g. by using the enclosed alcohol pad). 
2.  
Pull the protective plastic cap straight off. 
3. 
 Build a skin fold by gently squeezing the area at the injection site. 
4.  
The fold must be held pinched until the syringe is removed from the skin after the injection. 
5.  
Push the needle fully into the skin at a 90-degree angle. 
6.  
Push the plunger down slowly and inject the liquid underneath the skin. Remove the syringe 
from the skin at the same 90-degree angle. 
Instructions for subcutaneous use of Metoject with safety system 
The best places for the injection are: 
- upper thighs, 
- abdomen except around the navel. 
1.  
Clean the area around the chosen injection site (e.g. by using the enclosed alcohol pad). 
2.  
Pull the protective plastic cap straight off. 
3.  
Build a skin fold by gently squeezing the area at the injection site. 
4.  
The fold must be held pinched until the syringe is removed from the skin after the injection. 
5.  
Push the needle fully into the skin at a 90-degree angle. 
6.  
Push the plunger down slowly and inject the liquid underneath the skin. Remove the syringe 
from the skin at the same 90-degree angle. 
7.  
A protective cover will automatically enclose the needle. 
Note: The protection system that is triggered by the release of the protective cover can only be 
activated when the syringe has been emptied completely by pushing down the plunger as far as it goes. 
7. MARKETING AUTHORISATION HOLDER 
medac 
Gesellschaft für klinische Spezialpräparate mbH 


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Page 77 / 77 
Theaterstr. 6 
22880 Wedel 
Germany 
8. MARKETING AUTHORISATION NUMBER 
<[To be completed nationally]> 
9. DATE OF FIRST MARKETING AUTHORISATION/RENEWAL OF THE 
AUTHORISATION 
Date of first authorisation: 02 October 2008 
Date of latest renewal: 02 October 2013 
10. DATE OF REVISION OF THE TEXT 
2018-10-05 
 

SAP_001.pdf: 
ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 1 of 101 
 
 
 
 
 
Statistical Analysis Plan 
 
ABX464-301 
 
Phase IIa study of ABX464 in moderate to severe active Rheumatoid 
Arthritis patients 
 
Prepared for: 
ABIVAX 
5 rue de la Baume 
75008 Paris - France 
Tel: +33 (0) 1 53 83 08 41 
Fax: +33 (0) 1 53 83 07 48 
 
Prepared by: 
ORION Clinical 
7 Bath Road, Slough 
Berkshire SL1 3UE UK 
Tel:  +44 (0) 1753 578080 
Fax:  +44 (0) 1753 578081 
 
 
CONFIDENTIAL 
 
 
Version  
Author 
Final 1.0 
Lilla Hanák 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 2 of 101 
 
 
 
Statistical Analysis Plan 
 
ABX464-301 
 
Phase IIa study of ABX464 in moderate to severe active Rheumatoid 
Arthritis patients 
Author:  
Lilla Hanák 
Version:  
Final 1.0 
 
The undersigned have reviewed and revised this SAP and find it to be consistent with the study 
requirements: 
 
 
 
 
 
Paul Gineste, Vice President, Clinical Operations, Abivax 
 
 
 
 
 
 
Date 
Lilla Hanák, Statistician, Simbec-Orion Group Ltd 
 
 
 
 
 
 
Date 
Virginie Combe, Head of Statistics, Simbec-Orion Group Ltd 
 
Date 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION ............................................................................................................................8 
1.1 
General ....................................................................................................................................................8 
1.2 
Changes from Protocol ........................................................................................................................8 
1.3 
Changes from Previous Versions of the SAP..................................................................................8 
2 
STUDY OBJECTIVES........................................................................................................................8 
2.1 
Primary Objective .................................................................................................................................8 
2.2 
Secondary Objectives ...........................................................................................................................8 
3 
STUDY DESIGN ..............................................................................................................................9 
3.1 
Overview .................................................................................................................................................9 
3.2 
Inclusion and Exclusion Criteria ..................................................................................................... 10 
3.2.1 
Inclusion criteria................................................................................................................................. 10 
3.2.2 
Exclusion criteria ............................................................................................................................... 11 
3.3 
Study Treatment ................................................................................................................................. 13 
3.4 
Study Timepoints ................................................................................................................................ 13 
3.5 
Sample Size Considerations ............................................................................................................. 14 
3.6 
Randomisation ..................................................................................................................................... 15 
4 
STUDY VARIABLES AND COVARIATES........................................................................................... 15 
4.1 
Primary Variable ................................................................................................................................. 15 
4.2 
Secondary Efficacy Variables ............................................................................................................ 15 
4.2.1 
Main Secondary Efficacy Endpoint ................................................................................................. 15 
4.2.2 
Other secondary endpoints ............................................................................................................ 16 
4.3 
Pharmacokinetic Variables ............................................................................................................... 17 
4.4 
Pharmacodynamic Variables............................................................................................................. 17 
4.5 
Other Outcome Variables ............................................................................................................... 17 
4.6 
Safety Variables ................................................................................................................................... 17 
5 
DEFINITIONS AND DERIVED VARIABLES ....................................................................................... 17 
5.1 
Definitions ............................................................................................................................................ 17 
5.2 
Derived variables ................................................................................................................................ 18 
5.2.1 
Disease Activity Score (DAS) 28-CRP (DAS28-CRP) and DAS28-ESR ............................... 18 
5.2.2 
Simplified Disease Activity Index (SDAI) ..................................................................................... 18 


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5.2.3 
Clinical Disease Activity Index (CDAI) ........................................................................................ 18 
5.2.4 
Categorical DAS28-CRP response ................................................................................................ 19 
5.2.5 
DAS28-ESR remission ...................................................................................................................... 19 
5.2.6 
Low Disease Activity (LDA) ........................................................................................................... 19 
5.2.7 
SDAI remission................................................................................................................................... 19 
5.2.8 
CDAI remission ................................................................................................................................. 19 
5.2.9 
ACR/EULAR remission: ................................................................................................................... 19 
5.2.10 Categorical ACR20/50/70 response ............................................................................................. 19 
5.2.11 Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue: ................................... 21 
6 
ANALYSIS SETS ............................................................................................................................ 22 
6.1 
Full Analysis Set .................................................................................................................................. 22 
6.2 
Safety Set .............................................................................................................................................. 22 
6.3 
Efficacy Set ........................................................................................................................................... 22 
6.3.1 
“raw” Efficacy Set............................................................................................................................... 22 
6.3.2 
Efficacy Set with imputation ............................................................................................................ 22 
6.4 
Per Protocol Set ................................................................................................................................. 22 
7 
SAFETY MONITORING ................................................................................................................. 23 
8 
INTERIM ANALYSES ..................................................................................................................... 24 
9 
DATA .......................................................................................................................................... 24 
9.1 
eCRF Data ............................................................................................................................................ 24 
9.2 
External Data ....................................................................................................................................... 24 
9.2.1 
Laboratory Data ................................................................................................................................. 24 
9.2.2 
Other non-CRF data ......................................................................................................................... 25 
9.3 
Randomisation list .............................................................................................................................. 25 
9.4 
Programming and Data Review ....................................................................................................... 26 
10 STATISTICAL METHODS ............................................................................................................... 26 
10.1 
General Principles .............................................................................................................................. 26 
10.2 
Stratification and Covariate Adjustment ....................................................................................... 28 
10.3 
Interactions .......................................................................................................................................... 28 
10.4 
Missing Data ......................................................................................................................................... 28 
10.5 
Pooling of Sites .................................................................................................................................... 28 
10.6 
Multiple Comparisons ....................................................................................................................... 28 
10.7 
Subgroup Analyses ............................................................................................................................. 28 
10.8 
Statistical Issues................................................................................................................................... 28 
11 STATISTICAL OUTPUT .................................................................................................................. 29 


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11.1 
Patient Disposition ............................................................................................................................. 29 
11.2 
Patient Characteristics at Baseline ................................................................................................. 29 
11.2.1 Demographic and Baseline Characteristics ................................................................................. 29 
11.2.2 Medical History and Current Medical Conditions ..................................................................... 29 
11.3 
Efficacy Analyses ................................................................................................................................. 29 
11.3.1 Primary Variable ................................................................................................................................. 30 
11.3.2 Secondary Variables .......................................................................................................................... 30 
11.4 
PK Analyses ......................................................................................................................................... 31 
11.5 
PD analyses .......................................................................................................................................... 31 
11.6 
Safety Analyses .................................................................................................................................... 31 
11.6.1 Adverse Events ................................................................................................................................... 31 
11.6.2 Laboratory Data ................................................................................................................................. 33 
11.6.3 Vital Signs ............................................................................................................................................. 33 
11.6.4 Physical Examination ......................................................................................................................... 34 
11.6.5 Electrocardiogram ............................................................................................................................. 34 
11.7 
Study Drug Exposure and Compliance ......................................................................................... 34 
11.8 
Prior and Concomitant Medication ............................................................................................... 34 
12 VALIDATION ................................................................................................................................ 36 
13 LITERATURE CITATIONS/REFERENCES .......................................................................................... 36 
14 LIST OF TABLES, FIGURES AND LISTINGS ...................................................................................... 37 
14.1 
List of Tables ....................................................................................................................................... 37 
14.2 
List of Listings ...................................................................................................................................... 39 
15 SHELLS FOR TABLES, FIGURES AND LISTINGS ............................................................................... 40 
16 APPENDICES .............................................................................................................................. 101 
16.1 
Study flowchart ................................................................................................................................. 101 
 
 
 
 


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GLOSSARY OF ABBREVIATIONS 
 
%CV 
Coefficient of Variation 
AE 
Adverse Event 
ALT 
Alanine Transaminase (also SGPT) 
AM 
Arithmetic Mean 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AST 
Aspartate Transaminase (also SGOT) 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Clinical Research Organisation 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria Adverse Event 
CV 
Coefficient of Variation 
DMP 
Data Management Plan 
DOB 
Date of Birth 
DRM 
Data Review Meeting 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GM 
Geometric Mean 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IQR 
Interquartile Range 
ITT 
Intention-to-treat 


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IV 
Intravenous 
LambdaZ 
Terminal phase rate constant 
LOCF 
Last Observation Carried Forward 
LS Mean 
Least Squares Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
ml 
Millilitre 
N 
Number of Patients 
n 
Number of Events 
NCS 
Not clinically significant 
od 
Once daily 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Partial Response 
PT 
Preferred Term 
q12h 
Every 12 hours 
QC 
Quality Control 
QoL 
Quality of Life 
RA 
Accumulation ratio 
RBC 
Red Blood Cell  
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell  
μg 
Microgram 
TEAE 
Treatment Emergent Adverse Event 
VAS 
Visual Analogue Scale 


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1 INTRODUCTION 
1.1 
GENERAL  
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under ABIVAX Protocol ABX464-301 and should be read in conjunction with 
the study protocol and case report form (CRF).   
This version of the plan has been developed using the protocol Version 4.0 dated 24OCT2019 (and 
CRF/ Electronic Data Capture (EDC) specifications dated 06FEB2020. Any further changes to the 
protocol or CRF will be reviewed for potential impact on the SAP which will be amended if it is deemed 
necessary. 
At the time of writing this version of the SAP, recruitment is ongoing. 
Draft 1 was reviewed by the Orion project manager, medical writer and statistical reviewer. The analysis 
plan will be finalised and approved by the sponsor prior to unblinding of study treatment codes for the 
planned interim analysis and prior to database lock. 
1.2 
CHANGES FROM PROTOCOL 
It is stated in the protocol that “Analysis of efficacy data will be carried out in the Full Analysis Set in which 
subjects who prematurely terminate the study will be considered failures.” 
Sponsor requested by email having 2 efficacy set. 
1.3 
CHANGES FROM PREVIOUS VERSIONS OF THE SAP 
No previous versions of the SAP exist. 
2 STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate the safety of ABX464 given at two different doses 
(100mg and 50 mg) vs placebo in combination with MTX when administered once daily in patients with 
moderate to severe active Rheumatoid Arthritis. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives are the followings: 


ABIVAX ABX464-301 
 
 
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• 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 8 
and Week 12 on the American College of Rheumatology (ACR) 20/50/70 response and each of 
its components versus placebo; 
• 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 8 
and Week 12 on disease activity scores (DAS28 scores, simplified disease activity score [SDAI] 
and clinical disease activity score [CDAI]) versus placebo; 
• 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 8 
and Week 12 on clinical response (DAS28 EULAR good and moderate responses), Low Disease 
Activity (LDA) or remission (DAS28-ESR remission, ACR/EULAR remission, SDAI and CDAI 
remission) versus placebo; 
• 
To evaluate the effects of the different dose groups of ABX464 at Week 2, Week 4, Week 8 
and Week 12 on the Patient Reported Outcome (PRO), Healthy Assessment Questionnaire – 
Disability Index (HAQ-DI); 
• 
To evaluate the expression of miR-124 in total blood (determined by qPCR) at baseline and 
Week 8; 
• 
To evaluate the effects of different dose groups of ABX464 at Week 8 on miR-124 expression 
in total blood versus placebo; 
• 
To assess the pharmacokinetics of the ABX464 and its main active metabolite N-Glu-ABX464 
after oral administration of different daily doses of ABX464 in patients with Rheumatoid 
Arthritis. 
3 STUDY DESIGN 
3.1 
OVERVIEW 
This Phase IIa study is a randomized, double blind, placebo controlled, parallel group, multiple dose study 
on ABX464 in combination with methotrexate (MTX), in patients with moderate to severe active 
Rheumatoid Arthritis who have inadequate response to MTX or/and to an anti- tumor necrosis factor 
alpha (TNFα) therapy, or intolerance to anti-TNFα therapy. 
Several experimental and clinical endpoints will be assessed to obtain information on preliminary efficacy 
in patients with moderate to severe active Rheumatoid Arthritis. Although no formal hypothesis will be 
tested, these endpoints will enable a broader understanding of the mechanism of action and potential 
for clinical efficacy of ABX464 in Rheumatoid Arthritis. No interim analysis is planned. 
Up to 60 patients will be randomized in this study. These patients will be enrolled in approximately 20 
sites located in Europe. At the beginning, the first 6 patients will be randomized to receive either ABX464 
50mg (n=4) or its matching placebo (n=2). The Data Safety Monitoring Board (DSMB) will review the 
safety of these first 6 patients dosed for at least 2 weeks. Once the DSMB recommendation is granted, 
the next patients will be randomized to receive either ABX464 50mg, ABX464 100mg or placebo. Then, 
a second DSMB meeting will be held after the next 6 patients are randomized to check the tolerability 


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Version date: 10 December 2020 
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of the 100mg dose. Once the DSMB recommendation is granted, the next patients will be randomized 
to receive either ABX464 50mg, ABX464 100mg or placebo. The study randomization ratio is 1:1:1. 
The recruitment period is between Q2 2019 and Q3 2020, the overall study period is between Q2 2019 
and Q1 2021. 
Patients will be treated for 12 weeks, followed by a follow-up period (21 days). The total duration of 
participation in the study will be approximately 15 to 19 weeks from screening to the last study visit 
(screening and baseline could occur at the same visit). From Baseline / Day 0 onwards, randomized 
patients will be seen at the investigational site after 1 Week (Day 7), 2 weeks (Day 14), 4 weeks (Day 
28), 8 weeks (Day 56) and 12 weeks (Day 84). 
At Week 12 (Day 84 +/- 2 days), patients willing to carry on the study treatment will be able to take 
part in an open-label study (ABX464-302). In any other case, the subjects will exit the study (EOS) and 
will be treated according to the standard of care. The ABX464-302 follow-up study is a separate clinical 
study subject to health authorities and ethics committee approvals. 
Study scheme: 
 
3.2 
INCLUSION AND EXCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must fulfil all inclusion criteria and not violate 
any exclusion criteria (for the protocol under which they are entered) during screening prior to 
randomisation.  
3.2.1 Inclusion criteria 
A patient will be eligible for inclusion in this study only if ALL of the following criteria apply: 
• 
Men or women age 18 - 75 years; 
• 
Patient with a confirmed and documented diagnosis of adult-onset rheumatoid arthritis, for at 
least 12 weeks, according to the revised 2010 ACR-EULAR classification criteria, including at 
least one positive criteria among the following: Rheumatoid Factor (RF), Anti-Citrullinated 
Peptide Antibody (ACPA) or bone erosion; 
• 
Swollen joint count of ≥ 4 (28-joint count) and tender joint count ≥4 (28-joint count) at 
screening; 
• 
Patient with a moderate to severe disease activity score DAS28 CRP of ≥ 3.2 and CRP ≥ 5 mg/L 
(≥ 4.76 nmol)/L) at screening; 


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• 
Patient who had an inadequate response (IR), or failed either methotrexate (MTX) or/and anti-
TNFα therapy (both administered for at least 12 weeks before IR) or were intolerant to anti- 
TNFα therapy.  
In addition, MTX treatment should be given at a stable dose ≥ 10 mg/week (for at least 4 weeks 
prior to randomization). The maximal dose of methotrexate should not exceed a total of 20 
mg/week.  MTX treatment should be associated with folic acid at a dose ≥ 5 mg/week. 
For the anti-TNFα therapy, the following wash-out period will be required: 
o 30 days prior to randomization for adalimumab and etanercept 
o 2 months prior to randomization for infliximab, certolizumab pegol, golimumab 
• 
Patients with the following hematological and biochemical laboratory parameters obtained 
within 14 days prior to baseline: 
o Hemoglobin > 9.0 g dL-1; 
o Absolute neutrophil count ≥ 1000 mm-3; 
o Platelets ≥ 100,000 mm-3; 
o Total serum creatinine ≤ 1.3 x ULN (upper limit of normal); 
o Creatinine clearance > 50 mL min-1 by the Cockcroft-Gault equation within 60 days 
prior to baseline; 
o Total serum bilirubin < 1.5 x ULN; 
o Alkaline phosphatase, AST (SGOT) and ALT (SGPT) < 1.5 x ULN; 
o Negative screening for TB and HIV, HCV, HBV 
• 
Patients are able and willing to comply with study visits and procedures as per protocol; 
• 
Patients should understand, sign and date the written voluntary informed consent form at the 
screening visit prior to any protocol-specific procedures are performed; 
• 
Patients should be affiliated to a social security regimen (for French sites only); 
• 
Females and males receiving the study treatment and their partners must agree to use a highly 
effective contraceptive method during the study and for 6 months after end of study or early 
termination. Contraception should be in place at least 2 weeks prior to screening. Women must 
be surgically sterile or if of childbearing potential must use a highly effective contraceptive 
method. Women of childbearing potential (WOCBP) will enter the study after confirmed 
menstrual period and a negative pregnancy test. Highly effective methods of contraception 
include true abstinence, intrauterine device (IUD) or hormonal contraception aiming at 
inhibition of ovulation, intrauterine hormone releasing system, bilateral tubal ligation, 
vasectomized partner. True abstinence is defined when this is in line with the preferred and 
usual lifestyle of the patient. In each case of delayed menstrual period (over one month between 
menstruations) confirmation of absence of pregnancy is required. This recommendation also 
applies to WOCBP with infrequent or irregular menstrual cycle. Female and male patients must 
not be planning pregnancy and male patients should use condom and must not donate sperm 
during the trial and for 6 months post completion of their participation in the trial. 
3.2.2 Exclusion criteria 
The following criteria should be checked at the time of screening. If ANY exclusion criterion applies, the 
patient will not be included in the study: 


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• 
Patient with a known positive anti-double stranded deoxyribonucleic acid (DNA [anti-dsDNA]) 
and confirmed diagnosis of systemic lupus erythematosus (SLE); 
• 
Patients with active infection or the following history of infection(s) (the list is not exhaustive): 
o 
Active infection (except benign infections, according to investigator’s opinion) within 
14 days prior to inclusion. 
o 
Serious infection, defined as an infection requiring hospitalization or IV infusion of 
anti-infective agents in the 2 months prior to inclusion. 
o 
A history of opportunistic, recurrent or chronic infections that, in the investigator’s 
opinion, could render this study detrimental to the patient. 
• 
Patients who have received or are expected to receive a live (including attenuated) vaccine 
within 3 months prior to baseline; 
• 
Acute, chronic or history of clinically relevant (as per investigator’s judgement) pulmonary, 
cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy 
or unstable CNS pathology such as seizure disorder, angina or cardiac arrhythmias, active 
malignancy or any other clinically significant medical problems as determined by physical 
examination and/or laboratory screening tests and/or medical history; 
• 
Acute, chronic or history of immunodeficiency or other autoimmune disease; 
• 
Patient previously treated with any (approved or investigational) non-anti-TNF biological 
disease-modifying antirheumatic drugs (bDMARDs), and targeted DMARDs (tDMARDS) prior 
to baseline. These treatments include: IL-6 antagonists, Janus Kinase (JAK) inhibitors, cytotoxic 
T lymphocyte-associated molecule CTLA-4Fc Chimera, rituximab; 
• 
Patient treated with systemic corticosteroids >10 mg/day during the 2 weeks prior to and at 
randomization; IV or IM injections of glucocorticoids 4 weeks prior to randomization and IA 
glucocorticoids 2 weeks prior to randomization; 
• 
Patients treated with other immunosuppressive drugs; 
• 
History of malignancy (other than resected cutaneous basal cell or squamous cell carcinoma that 
has been treated with no evidence of recurrence) unless it has been treated and a cure is 
achieved for at least 5 years; 
• 
Serious illness requiring systemic treatment and/or hospitalization within 3 weeks prior to 
baseline; 
• 
Pregnant or breast-feeding woman; 
• 
Illicit drug or alcohol abuse or dependency; 
• 
Use of any investigational or non-registered product within 3 months or within 5 half-lives 
preceding baseline, whichever is longer; 
• 
Any condition, which in the opinion of the investigator, could compromise the patient's safety 
or adherence to the study protocol. 
 
 


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• 
 
3.3 
STUDY TREATMENT 
Medications: 
• 
ABX464 or its matching placebo administered once daily; 
• 
MTX ≥ 10 mg/week, at stable dose, throughout the study; the maximal dose of methotrexate 
should not exceed a total of 20 mg/week; 
• 
Folic acid ≥ 5 mg/week post MTX dose, to minimize MTX toxicity. 
A total of 60 patients will be recruited sequentially to receive the following doses: 
 
Intervention/treatment Active Arm 
Group #1 (n=20): 100mg qd 
2 capsules of 50mg ABX464 
Group #2 (n=20): 50mg qd 
1 capsule of 50mg ABX464 + 1 capsule of matching 
placebo 
Group #3 (n=20): Placebo 
2 capsules of matching Placebo 
 
3.4 
STUDY TIMEPOINTS 
Eligible patients will be enrolled in study at the screening visit within 30 days prior to the first dosing / 
randomization (screening and baseline could occur at the same visit, if all laboratory results are available). 
Patients will be treated for 12 weeks, followed by a follow-up period (21 days).  
From Baseline / Day 0 onwards, randomized patients will be seen at the investigational site after 1 Week 
(Day 7), 2 weeks (Day 14), 4 weeks (Day 28), 8 weeks (Day 56) and 12 weeks (Day 84). 
At Week 12 (Day 84 +/- 2 days), patients willing to carry on the study treatment will be able to take 
part in an open-label study (ABX464-302). In any other case, the subjects will exit the study (EOS) and 
will be treated according to the standard of care. The ABX464-302 follow-up study is a separate clinical 
study subject to health authorities and ethics committee approvals. 
The end of study (EOS) visit will be performed three weeks after the end of treatment period.  
The total duration of participation in the study will be approximately 15 to 19 weeks from screening to 
the last study visit (screening and baseline could occur at the same visit). 
If more than one visit occurs within a window, the nearest to the scheduled time will be presented 
within the summaries. 
See Section 16.1 for the Study Schedule.  
 
 


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Visits and visit windows will be as follows: 
Visit 
 
Day 
Window 
1 
Screening 
-30 to -1 
 
2 
Baseline 
0 
 
3 
Week 1 
7 
± 2 days 
4 
Week 2 
14 
± 2 days 
5 
Week 4 
28 
± 2 days 
6 
Week 8 
56 
± 2 days 
7 
Week 12 
84 
± 2 days 
8 
Week 15 
105 (Follow-up) 
± 2 days 
 
3.5 
SAMPLE SIZE CONSIDERATIONS 
The primary efficacy endpoint is the rate of subjects meeting the ACR20. This response rate will be 
compared in subjects who received a given dose of ABX464 or placebo by likelihood ratio chi-square 
test. The result of the test will be interpreted in a descriptive manner therefore no adjustment for 
multiple comparison is applied. 
For the sample size assessment, the following assumptions will be made: 
• 
Response rate (ABX464): 0.65 
• 
Response rate (placebo): 0.25 
According to literature the ACR20 response rate for ABX464 + MTX treated subjects is expected to 
be between 50% and 65% while that in the placebo + MTX group is assumed to be approximately 25 to 
30% (Xeljanz® Summary of Product Characteristics; ORAL Standard Investigators - N Engl J Med 2012; 
367:508-519 August 9, 2012).  
• 
Type 1 error: 10% two-sided 
• 
Group allocation rate (ABX464 / placebo): 1:1:1 
If the above assumptions and definitions hold true with a sample size of 60 subjects receiving two doses 
of ABX464 or placebo in a ratio of 1:1:1 the study has 84% power to show a difference in response rate 
between one active study group and placebo.  
Subjects who terminates the study prematurely will be considered failures therefore no adjustment for 
drop-outs is needed. 
Primary safety endpoint is the rate of all treatment emergent adverse experiences. The above sample 
size is sufficient to detect an increase in general treatment emergent adverse experience rate from 10% 
to 50% with 89% power by likelihood ratio chi-square test on a 10%, two-sided significance level. 


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If approximately 20 subjects receive ABX464 the study has 88% chance to detect at least 1 specific 
treatment emergent AE if the underlying rate of occurrence is 1:10. When the underlying rate of 
occurrence is around 1:20 the sample size of 40 subjects receiving active treatment is sufficient to 
observe at least 1 such an event with a probability of 87% in the active treatment group. 
3.6 
RANDOMISATION 
Eligible patients (i.e. those who fulfil all inclusion/exclusion criteria) will be randomized according to a 
1:1:1 ratio into ABX464 100mg, ABX464 50mg or placebo treatment arms.  
Up to 60 patients will be randomized in this study. At the beginning, the first 6 patients will be 
randomized to receive either ABX464 50mg (n=4) or its matching placebo (n=2). The Data Safety 
Monitoring Board (DSMB) will review the safety of these first 6 patients dosed for at least 2 weeks. 
Once the DSMB recommendation is granted, the next patients will be randomized to receive either 
ABX464 50mg, ABX464 100mg or placebo. Then, a second DSMB meeting will be held after the next 6 
patients are randomized to check the tolerability of the 100mg dose. Once the DSMB recommendation 
is granted, the next patients will be randomized to receive either ABX464 50mg, ABX464 100mg or 
placebo.  
Randomization will be performed via a centralized treatment allocation system that will be available 24 
hours-a-day, 7 days-a-week. Randomization will be stratified according to previous exposure to anti-
TNFα therapy. The bottle numbers to be used for a specific patient will be assigned according to a pre-
defined randomization list. 
4 STUDY VARIABLES AND COVARIATES 
4.1 
PRIMARY VARIABLE 
The primary variable for statistical comparison between treatment groups will be the incidence of 
treatment-emergent adverse events in the ABX464 treated Patients versus placebo, categorized by 
severity. 
4.2 
SECONDARY EFFICACY VARIABLES 
The following secondary efficacy variables will be analysed: 
4.2.1 Main Secondary Efficacy Endpoint 
Proportion of patients achieving a categorical ACR20 response at Week 12. 
The components of ACR20 assessment include:  
• 
C-Reactive Protein (CRP) (mg/L),  
• 
Tender/painful joint count (TJC) (28 joints),  
• 
Swollen joint count (SJC) (28 joints),  
• 
Patient assessment of joint pain (Pain-VAS),  
• 
Patient global assessment of disease (PtGA),  


ABIVAX ABX464-301 
 
 
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• 
Physician's Global Assessment of Disease (PrGA),  
• 
HAQ-DI 
4.2.2 Other secondary endpoints 
• 
Change from Baseline in the following disease parameters at Week 2, Week 4, Week 8 and 
Week 12: 
o Individual components of the ACR20 response (CRP, TJC(28), SJC(28), Pain-VAS, PtGA, 
PrGA, HAQ-DI)  
o Erythrocyte Sedimentation Rate (ESR); 
o DAS28-CRP and DAS28-ESR. The components of DAS28 assessment include TJC(28), 
SJC(28), CRP/ESR, and PtGA; 
o SDAI score which includes TJC(28), SJC(28), CRP, PtGA, and PrGA; 
o CDAI score which includes TJC(28), SJC(28), PtGA, and PrGA; 
o Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score 
▪ 
Proportion of patients achieving at Week 2, Week 4, Week 8 and Week 12: 
o ACR20/50/70 response  
o Categorical DAS28-CRP response. Proportion of patients achieving categorical DAS28-
CRP response will be measured as moderate/good European League Against 
Rheumatism (EULAR) response at each assessment time point;  
o Low Disease Activity (LDA) (DAS28 ≤ 3.2) 
o DAS28-ESR remission (DAS28 < 2.6) 
o ACR/EULAR remission (TJC(28), SJC(28), CRP, and PtGA: all≤1); 
o SDAI remission (SDAI ≤ 3.3); 
o CDAI remission (CDAI ≤ 2.8). 
• 
Concentration of miR-124 expression in total blood (determined by qPCR) at baseline and week 
8 
• 
Change from Baseline in miR-124 expression in total blood at Week 8 
• 
PK parameters: 
o Pre-dose plasma concentration of ABX464/N-Glu at Week 2 and Week 8; 
o Post-dose plasma concentration of ABX464/N-Glu at 1-, 2- and 3-hours post-dose at 
Baseline, Week 2 and Week 8; 
o Trough plasma concentration of ABX464/N-Glu at End of Study Visit 
• 
The number of incidences of treatment-emergent serious adverse events; 
• 
The number of incidences of treatment-emergent adverse events of special interest; 
• 
The number of incidences of adverse events leading to investigational product discontinuation; 
• 
The number of incidences of clinically significant laboratory abnormalities; 
• 
The number of incidences of all AE (causally related and non-related) and SAE, further 
categorized by severity.  


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4.3 
PHARMACOKINETIC VARIABLES 
Pharmacokinetics will be measured via serum levels of plasma. 
4.4 
PHARMACODYNAMIC VARIABLES 
No pharmacodynamic variables will be measured. 
4.5 
OTHER OUTCOME VARIABLES 
Not applicable. 
4.6 
SAFETY VARIABLES 
Safety will be evaluated by the following: 
• 
Adverse events 
• 
Laboratory parameters 
• 
Vital signs (body temperature, weight, systolic and diastolic blood pressure, heart rate and 
respiratory rate) 
• 
Physical examination 
• 
ECG (PR, QRS, QT and QTc and Result: Normal, Abnormal NCS or Abnormal CS) 
5 DEFINITIONS AND DERIVED VARIABLES 
5.1 
DEFINITIONS 
Study Drug: Study drug is taken to mean either ABX464 or placebo. 
Baseline: Baseline is defined by patient and by variable as the last non-missing value before the first dose 
of study drug 
Study Day: Study day is the number of days since start of treatment where the date of first dose is 
counted as Day 0. 
Treatment Exposure: Treatment exposure is the number of days during the treatment period that the 
patient was exposed to the study treatment and is calculated as: 
(Date_of_last_dose) – (Date_of_first_dose) + 1 
Compliance: Compliance is the number of doses actually taken divided by the scheduled number of 
doses expressed as a percentage. 
Non-compliance: Non-compliance is defined as taking less than 80% or more than 120% of study 
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Protocol Deviation: a deviation related to study inclusion or exclusion criteria, conduct of the trial, 
patient management or patient assessment. This refers to any change, divergence, or departure from 
the study design or procedures defined in the protocol. Deviations recorded by the Project Manager or 
CRA, or detected by Data Management or by Statistical programming checks as described in Section 6.3 
will be identified and discussed at the Data Review Meeting before database lock to agree which should 
be included in Listing 16.2.2.  
Screening and enrollment: Screening is the process of active evaluation of potential participants for 
enrollment in a trial. After a patient is recruited, screening occurs during the enrollment period to see 
if they meet the inclusion and exclusion criteria. If they meet the criteria, the subject is eligible to enroll 
in the trial. 
Baseline and Screening failure: A patient is considered to be a baseline failure if the patient signs the 
informed consent but withdraws before the screening visit. A patient who does not fulfil the 
randomization criteria will be considered as a screening failure.  
5.2 
DERIVED VARIABLES 
5.2.1 Disease Activity Score (DAS) 28-CRP (DAS28-CRP) and DAS28-ESR 
The components of the DAS28 include: 
• 
tender/painful joint count (TJC) (28),  
• 
swollen joint count (SJC) (28),  
• 
CRP (in mg/L) or ESR (in mm/h), and  
• 
patient global assessment of disease (PtGA), expressed as a Visual Analog Scale (VAS) from 0 to 
100 mm 
They are calculated with the following formula: 
DAS28-CRP = 0.56 √ (TJC28) + 0.28 √ (SJC28) + 0.36 Ln [CRP(mg/L) + 1] + 0.014 PtGA(VAS100mm) 
+ 0.96 
DAS28-ESR = 0.56 √ (TJC28) + 0.28 √ (SJC28) + 0.70 Ln [ESR(mm/h)] + 0.014 PtGA(VAS100mm) 
5.2.2 Simplified Disease Activity Index (SDAI) 
This composite index is defined by this equation: 
SDAI = TJC28 + SJC28 + PtGA + PrGA + CRP 
• 
PtGA is expressed as a VAS from 0 to 10 cm,  
• 
Investigator global assessment of disease (PrGA) is expressed as a VAS from 0 to 10 cm, and 
• 
CRP (mg/L). 
5.2.3 Clinical Disease Activity Index (CDAI) 
This composite index is defined by this equation (no acute phase reactant): 
CDAI = TJC28 + SJC28 + PtGA + PrGA  
• 
PtGA is expressed as a VAS from 0 to 10 cm, 
• 
PrGA is expressed as a VAS from 0 to 10 cm. 


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5.2.4 Categorical DAS28-CRP response 
Proportion of patients achieving categorical DAS28-CRP response will be measured as moderate/good 
European League Against Rheumatism (EULAR) response. 
The EULAR response criteria are defined as follows: 
DAS28 improvement → 
> 1.2 
> 0.6 and ≤ 1.2 
≤ 0.6 
Present DAS28↓ 
≤ 3.2 
good response 
moderate response 
no response 
> 3.2 and ≤ 5.1 
moderate response 
moderate response 
no response 
> 5.1 
moderate response 
no response 
no response 
 
5.2.5 DAS28-ESR remission 
A remission is considered when DAS28-ESR <2.6. 
5.2.6 Low Disease Activity (LDA)  
The limit to consider a Low Disease Activity (LDA) is: DAS28-ESR ≤ 3.2. 
5.2.7 SDAI remission 
The SDAI remission is considered achieved if the SDAI score ≤ 3.3. 
5.2.8 CDAI remission 
The CDAI remission is considered achieved if the CDAI score ≤ 2.8. 
5.2.9 ACR/EULAR remission: 
In 2011, the American College of Rheumatology (ACR) and EULAR decided to set new criteria to define 
RA remission. 
Boolean-based criteria to be used for clinical trials are:  
• 
Tender/painful Joint Count (28) 
• 
Swollen Joint Count (28) 
• 
CRP 
• 
Patient Global assessment of disease (PtGA) [VAS scale 0 – 10cm] 
All ≤ 1. 
5.2.10 Categorical ACR20/50/70 response 
The component of ACR assessment include: 
• 
tender/painful joint count (28),  
• 
swollen joint count (28),  
• 
patient assessment of joint pain,  
• 
Patient Global Assessment of Disease (PtGA) 
• 
Physician's Global Assessment of Disease (PrGA),  


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• 
CRP and  
• 
Disability index of the healthy assessment questionnaire (HAQ-DI).  
 
Patient assessment of joint pain: VAS scale 0-10 cm. 
 
PtGA: Patient Global Assessment of disease activity (VAS scale 0 – 10cm). 
 
PrGA: Physician Global Assessment of disease activity (VAS scale 0 – 10cm). 
 
HAQ-DI: This patient reported outcome questionnaire is usually self-administered by the patient. 
The following 8 categories are assessed by the HAQ-DI:  
1. 
Dressing and grooming 
2. 
Arising 
3. 
Eating 
4. 
Walking 
5. 
Hygiene 
6. 
Reach 
7. 
Grip 
8. 
Common daily activities 
The patients report the amount of difficulty they have in performing some of these activities. Each 
question asks on a scale ranging from 0 to 3 if the categories can be performed without any difficulty 
(scale 0) up to cannot be done at all (scale 3).  
The highest score reported by the patient for any component question of the eight categories 
determines the score for that category. The sum of the computed categories scores is calculated and 
divided by the number of categories answered. This gives a total score in the 0 to 3 range. 
 
Definition of the ACR20% response:  
• 
≥ 20% improvement in tender join counts 
• 
≥ 20% improvement swollen join counts  
• 
≥ 20% improvement in 3 of the 5 remaining ACR core set measures:  
o PtGA,  
o PrGA,  
o patient assessment of joint pain,  
o HAQ-DI,  


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o CRP. 
For ACR50% and ACR70%, an improvement of respectively 50 and 70% of the same parameters has to 
be observed. 
5.2.11 Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue: 
This questionnaire is a measure to assess the patient fatigue in chronic diseases, and is validated in RA. 
It includes 13 items. 
The FACIT score calculation process is defined as follows: 
 
The FACIT scoring guide identifies those items that must be reversed before being added to obtain 
subscale totals.  Negatively stated items are reversed by subtracting the response from “4”.  After 
reversing proper items, all subscale items are summed to a total, which is the subscale score.  For all 
FACIT scales and symptom indices, the higher the score the better the QOL. 
Handling missing items:  If there are missing items, subscale scores can be prorated.  This is done by 
multiplying the sum of the subscale by the number of items in the subscale, then dividing by the number 
of items actually answered.  This can be done on the scoring guide or by using the formula below: 
Prorated subscale score = Sum of item scores x N of items in subscale ÷ N of items answered     
When there are missing data, prorating by subscale in this way is acceptable as long as more than 50% 
of the items were answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc).  The total score is then 


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calculated as the sum of the un-weighted subscale scores. In addition, a total score should only be 
calculated if ALL of the component subscales have valid scores.   
 
6 ANALYSIS SETS  
Membership of the analysis sets will be reviewed and agreed at a Data Review Meeting (DRM) before 
database lock. 
6.1 
FULL ANALYSIS SET  
The Full Analysis Set (FAS population) is defined as all patients included in the study, who have received 
at least one dose of the study treatment, and who have at least one baseline data. 
The FAS will be used for examining demographics and other baseline characteristics. Number of doses 
will be presented on the FAS population. 
6.2 
SAFETY SET 
The Safety dataset (SAF population) is defined as those patients included in the study, who have received 
at least one dose of the study treatment. 
The Safety Set will be used for all safety analyses. 
6.3 
EFFICACY SET  
6.3.1 “raw” Efficacy Set (Efficacy Set 1) 
A ”raw” efficacy set will take into consideration only patients at time point (N = nb of patients for whom 
efficacy variables are available at W12). 
6.3.2 Efficacy Set with imputation (Efficacy Set 2) 
Another efficacy set will use data imputation (LOCF) from Week 4.  
If there are no efficacy data available, then the dropout would be considered as treatment failure. 
6.4 
PER PROTOCOL SET 
The Per Protocol dataset (PP population) is defined as those patients of the FAS population without any 
major protocol deviation. 
Major protocol deviations are defined as deviations liable to bias the evaluation of the main efficacy 
endpoint. The following deviations will be considered as major (non-exhaustive list):  
• 
Noncompliance with the inclusion or exclusion criteria; 
• 
Noncompliance with the study treatment; 


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Intake of prohibited medication; 
• 
Noncompliance with time window. 
Limited programming checks e.g. prohibited medication (based on agreed codes), lab results, may be 
requested and reviewed on an ongoing basis. Other potential exclusions e.g. incorrect dosing of study 
medication may be discussed at the DRM. The final decision on inclusion in the PP Set will be agreed 
and documented before database lock. 
7 SAFETY MONITORING 
An independent Data Safety Monitoring Board (DSMB), with expertise and experience in the pathology, 
and without direct involvement in the conduct of the trial, will be set up specifically to guarantee effective 
protection of patients, ensure the ethical conduct of the trial, benefit/risk ratio of the trial, and to ensure 
the independent review of the scientific results during the trial and at the end of the trial. Besides, the 
DSMB may recommend the early termination of the trial at any time if an unacceptable toxicity occurs.  
The DSMB will meet after the first 6 patients are dosed (50mg or matching placebo) for at least 2 weeks 
to check the 50mg dose tolerability. Once the DSMB recommendation is granted, the next 6 patients 
will be randomized to receive either ABX464 50mg, ABX464 100mg or placebo.  A second DSMB 
meeting will then be held when these 6 next patients are treated for at least 2 weeks, to check the 
100mg dose tolerability and grant the recommendation to resume patient’s randomization. 
In addition, from the first DSMB onwards, meetings will be held every month during the study period. 
The DSMB will also review all potential causally-related Serious Adverse Events within 7 days of the 
initial report. 
A dose limiting toxicity (DLT) is defined as a grade 3 or higher adverse event as defined by the Common 
Terminology Criteria for Adverse Events (CTC-AE V5.0) considered by a safety review board as 
probably or definitely related to study treatment. If more than 2 DLTs occur in the first 12 treated 
patients for at least 14 days, then the enrolment of additional patients in the treatment group will be 
stopped, otherwise the enrolment of planned patients will be confirmed. In addition, in case of a life 
threatening (grade 4) adverse reaction enrolment in the treatment group, all treatment of ongoing 
patients will be immediately discontinued. In both cases, enrolment will only be resumed upon the 
decision of the sponsor if the Data Safety Monitoring Board can conclude that the causality of the event 
was unrelated or unlikely related to study treatment. 
The DSMB has only a consultative role. It will inform the Sponsor who will decide whether the DSMB 
recommendation will be followed. A DSMB charter must be available upon submission of the trial (initial 
protocol) to the respective competent authorities. 
The sponsor will prepare the Data Safety Monitoring Board Charter which will define the primary 
responsibilities of the DSMB, its relationship with other study components, its members, and the purpose 
and timing of its meetings. The Charter will describe the process for the evaluation of dose limiting 
toxicities and provide the decision criteria for study continuation. 


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Leading up to the meeting, the data will be extracted from the EDC Database by the Database 
Programmer and provided to Abivax. 
8 INTERIM ANALYSES 
No interim analysis is planned. 
The study analysis will be performed following database lock upon the completion of the last patient or 
upon its early discontinuation whichever occurs first. 
9 DATA 
9.1 
ECRF DATA 
CRF data will be provided by Orion data management to the statistics department as SAS data sets in 
Orion standard format which will be used for programming the outputs to be included in the CSR. 
Populated data sets will be available when programming starts. These may contain dummy data if real 
data is not yet available.  
9.2 
EXTERNAL DATA 
9.2.1 Laboratory Data 
Results from Local lab will be entered in CRF for Haematology, Chemistry, Pregnancy (Serum/ urine), 
Thyroid (for applicable sites only) and ESR (additionally for fibrinogen, troponin I & T,  prothrombin time 
and/or INR, depending upon CSP version they get consented to). 
The following table displays the clinical laboratory parameters: 


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HEMATOLOGY 
BIOCHEMISTRY 
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
WBC 
Chloride 
Neutrophils 
Calcium 
Lymphocytes 
Phosphate 
Monocytes 
Glucose  
Eosinophils 
BUN or urea  
Basophils 
Creatinine  
Platelet count 
AST / SGOT 
ESR 
ALT / SGPT 
Prothrombin time and/or INR* 
Alkaline phosphatase 
Fibrinogen* 
GLDH 
 
LDH 
 
Lipase 
 
Total cholesterol  
 
HDL cholesterol 
 
LDL cholesterol 
 
gGT 
 
Total bilirubin  
 
Total protein  
 
Albumin  
 
CRP 
 
T3, T4, TSH ( for French sites only) 
 
Troponin I & T* 
Tests of TB (Quantiferon TB Gold Plus), HIV (anti-HIV Ab), HCV (anti-HCV Ab), HBV (HBsAg, anti-HBs Ab), anti-
HCV Ab, will be performed only at screening. * Except at Week 1 & 2 
Reference ranges will be provided by the labs before site initiation and the required parameters will be 
transcribed onto the Data Management Laboratory Reference Range Form by the CRA. The CRA will 
provide reference ranges to the DM, who will use them to verify data on CRF. Further information or 
language translations will be provided by the responsible CRA if required. 
A negative or positive result will be counted in the tables under number of positive or number of negative 
values. For a parameter with only a result in the comment stated that it is inferior to a certain value  
(< X), all data will be flagged where there is a sign “<” to count how many data are inferior to the 
detection limit. 
No external data transfers are scheduled for this study. 
9.2.2 Other non-CRF data 
There will be no other non-CRF data. 
9.3 
RANDOMISATION LIST 
The randomisation list will be uploaded to a SAS dataset following database lock. 


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9.4 
PROGRAMMING AND DATA REVIEW 
Programming of analysis datasets, tables, figures and listings will be ongoing during the data management 
of the study. Outputs for the DSMB will be reviewed, but not fully QCd. Blind outputs may be reviewed 
by ABIVAX before DBL. 
When the final data is considered clean, key listings (to be agreed) will be run and distributed to the 
study team for review. A blind data review meeting will be held to discuss the outcome of this review, 
the imputations for the primary endpoint and the protocol deviations.  Once all data issues have been 
resolved and the analysis populations approved, the database will be locked.  The final run of outputs 
and quality control (QC) will then take place. 
A Data Review Meeting (DRM) may be held at the discretion of the Client. During this meeting, data 
listings (agreed in advance and provided by Simbec-Orion a few days before the meeting) will be used 
to review any outstanding problematic cases where evaluability of the data is unclear. The populations 
of patients for the statistical analysis and reporting of the study will be agreed and recorded by the study 
Statistician. 
The study Data Manager, Statistician or Statistical Programmer, Project Manager and a Medic of Simbec-
Orion will attend the DRM with representatives of Abivax. 
10 STATISTICAL METHODS 
10.1 GENERAL PRINCIPLES 
All statistical methods will be based on the International Conference on Harmonisation (ICH) E9 
document “Statistical Principles for Clinical Trials”. 
Data will be summarised by treatment group.  A total column showing all patients will be included for 
baseline and safety summaries.  Where appropriate, data will also be summarised by visit with summaries 
for each visit attended as scheduled and an additional summary for final (last scheduled visit or early 
withdrawal). The format of the summaries is defined in the shells at the end of this document. 
In summary and analysis tables of continuous variables, standard descriptive statistics (N, mean, standard 
deviation [SD], median, minimum and maximum) will be presented.  Least squares mean (LS mean), 
standard error (SE) and 95% confidence interval (CI) will be presented in the statistical analysis outputs 
as appropriate. For PK summaries, arithmetic mean (AM), geometric mean (GM) and coefficient of 
variation (%CV) will be used to summarise the data.  The minimum and maximum statistics will be 
presented in summary tables to the same number of significant figures as the original data.  The mean/AM, 
median, LS mean, GM, CI, SD and SE will be presented to one more significant than the original data.   
For numeric data which includes non-numeric values (e.g. PK data reported as Below Limit of 
Qualification (BLQ) or lab results reported as < 10 or >100) the following principles will be applied 
when summarising the data: 


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• 
BLQ will be replaced with a value that is ½ of the lower limit of quantification (LLQ); 
• 
Results reported as < x will be treated in the same way as BLQ with LLQ=x; 
• 
Otherwise AM, GM, SD, CI and %CV will not be calculated; 
• 
Whenever meaningful, minimum, median and maximum will be presented based on the reported 
data (e.g. minimum = <10, median = 20, maximum = >100). 
In summary tables of categorical variables, the number of non-missing observations by category will be 
presented with percentages. The number of missing observations will also be presented when non-zero. 
Unless otherwise specified, the denominator for each percentage will be the number of non-missing 
observations within the column. All percentages will be presented to one decimal place. 
Patient line plots will use actual time on the time axis. Mean plots will use a linear time scale for the 
nominal times of the visits and will be labelled by visit. Results from an early withdrawal visit will be 
excluded. 
If changes in severity for the same TEAE have been reported separately but with the same AE number, 
they will be collapsed to a single AE with maximum severity for the summary tables, but listed as 
reported. 
Classifications of medical history, concomitant medication and adverse events will be sorted 
alphabetically within the summary tables. 
If any laboratory assessments are repeated at the same visit, the result from the repeat assessment will 
be used in summaries. Both values will be listed. 
CRF data collected/ Data collected on the eCRF will be presented within data listings.  The data listings 
will be sorted by treatment group, country, centre number, patient number and visit/week/day. 
Treatment group will be as allocated (randomised). If any patients receive the wrong treatment this will 
be flagged in all listings. Visits outside the visit windows will be identified within the listings. For patients 
who complete the study, the last visit will be described in the listings as ‘<Day X>’; for those who 
withdraw early it will be described as ‘End of Study’. 
The date format for all output presentations will be ‘ddMMMyyyy’. 
All statistical analysis will be performed using SAS 9.2 or higher. 
All hypothesis testing will be carried out at the 5% (2-sided) significance level unless stated otherwise.  
P-values will be rounded to four decimal places.  P-values less than 0.0001 will be reported as <0.0001 
in tables.   
If any of the assumptions underlying the formal statistical methods proposed are violated during the 
analysis of the final data, alternative statistical methods will be used and any changes documented in the 
statistical methods section of the clinical study report (CSR), including the rationale for use. 


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10.2 STRATIFICATION AND COVARIATE ADJUSTMENT 
Randomization will be stratified according to a single factor: patients without previous exposure to anti-
TNFα therapy versus patients with previous exposure to anti-TNFα.  
10.3 INTERACTIONS 
The interaction between treatment in two different doses and placebo will be investigated for the 
primary endpoint (incidence of treatment-emergent adverse events categorized by severity). 
10.4 MISSING DATA 
For total scores and subscales with missing items the following rule will be used: 
If < 50% of the scale items are missing, the total (or subscale total) will be calculated using the mean 
score of the non-missing items for that scale or subscale to impute a score for the missing items. In 
practice the score is derived using the formula: 
total of non-missing items x number of items in (sub)scale / number of non-missing items 
If > 50% of the items were missing, no scale or subscale score will be calculated; the score will be 
considered missing.  
There will be no other imputation of missing data in this study. 
10.5 POOLING OF SITES 
Sites will be pooled for all analyses. There will be no adjustment for centre effect or treatment by centre 
interaction. 
10.6 MULTIPLE COMPARISONS 
There will be no corrections to nominal p-values for multiple comparisons because the results of the 
tests will be interpreted in a descriptive manner. 
10.7 SUBGROUP ANALYSES 
Not applicable. 
10.8 STATISTICAL ISSUES 
Not applicable. 


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11 STATISTICAL OUTPUT 
General principles for layout of the statistical output are described in Section 10.1, including specification 
of the table columns, and these are illustrated for each unique table in the table shells in Section 15. For 
clarity and brevity in this document the phrase “by treatment group” is understood for all summaries 
and is not included within the text of this section. 
11.1 PATIENT DISPOSITION 
A summary of the number of screened patients, baseline failures, screening failures and reasons for 
screening failure will be produced for all enrolled patients (Table 14.1.1).The patient disposition table 
(Table 14.1.2) will summarise the following data for all randomised patients: 
• 
The number (%) of patients in the FAS, 
• 
The number (%) of patients in the Safety Set, 
• 
The number (%) of patients in the PP Set. 
The number (%) of patients who withdraw from the study and the main reason for withdrawal will be 
summarised. (Table 14.1.3) 
A listing of all patients with protocol deviations will be presented.  A data listing presenting the eligibility 
for the analysis sets for each patient will also be presented.  
11.2 PATIENT CHARACTERISTICS AT BASELINE 
11.2.1 Demographic and Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment arm (Table 14.1.4). 
This analysis will be conducted on the FAS population. 
Age will be calculated using Date of Birth (DOB) and Date of first treatment (Visit 1) and presented as 
age at last birthday as an integer. 
BMI is the patient’s body weight in kilograms divided by the square of the patient’s height in metres. 
11.2.2 Medical History and Current Medical Conditions 
All conditions will be coded using the version 23.0 of the Medical Dictionary for regulatory Activities 
(MedDRA) defined in the Data Management Plan. Past medical/surgical history and current medical 
conditions will be summarised by system organ class (SOC) and preferred term (PT). The number (%) 
of patients reporting each condition will be presented using the FAS (Table 14.1.5.1 and 14.1.5.2). 
11.3 EFFICACY ANALYSES 
Analysis of efficacy data will be carried out on Efficacy Set 1 and will be repeated for Efficacy Set 2. 
Treatment comparisons will be ABX464 in two different doses vs. placebo. 


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11.3.1 Primary Variable 
The primary efficacy endpoint of the study, the ACR20 response rate, will be compared in subjects who 
received a given dose of ABX464 or placebo by likelihood ratio chi-square test on a 10% two-sided level 
(Table 14.2.1.1 and Table 14.2.1.2). 
The result of the test will be interpreted in a descriptive manner therefore no adjustment for multiple 
comparison is applied. 
11.3.2 Secondary Variables 
Descriptive statistics will be presented by treatment arm for all secondary efficacy variables for each 
measurement timepoints separately for the study groups: 
• 
Proportion of patients achieving a categorical ACR20 response at Week 12 (Table 14.2.2.1 and 
Table 14.2.2.2). 
• 
Change from Baseline in the individual components of the ACR20 response at Week 2, Week 
4, Week 8 and Week 12 (Table 14.2.3.1 and Table 14.2.3.2): 
o C-Reactive Protein (CRP) (mg/L),  
o Tender/painful joint count (TJC) (28 joints),  
o Swollen joint count (SJC) (28 joints),  
o Patient assessment of joint pain (Pain-VAS),  
o Patient global assessment of disease (PtGA),  
o Physician's Global Assessment of Disease (PrGA),  
o HAQ-DI. 
• 
Change from Baseline in the following disease parameters at Week 2, Week 4, Week 8 and 
Week 12: 
o ESR (Table 14.2.4.1.1 and Table 14.2.4.1.2); 
o DAS28-CRP (Table 14.2.4.2.1 and Table 14.2.4.2.2) and DAS28-ESR (Table 14.2.4.3.1 and 
Table 14.2.4.3.2); 
o SDAI score (Table 14.2.4.4.1 and Table 14.2.4.4.2); 
o CDAI score (Table 14.2.4.5.1 and Table 14.2.4.5.2); 
o FACIT-Fatigue score (Table 14.2.4.6.1 and Table 14.2.4.6.2). 
▪ 
Proportion of patients achieving: 
o ACR20/50/70 response; 
o Categorical DAS28-CRP response; 
o LDA; 
o DAS28-ESR remission; 
o ACR/EULAR remission; 
o SDAI remission; 
o CDAI remission 
at Week 2, Week 4, Week 8 and Week 12 (Table 14.2.5.1 and Table 14.2.5.2). 
These statistics include: 


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• 
Continuous variables: mean, standard deviation, minimum and maximum, stratified 95% 
confidence intervals, median and quartiles will be presented. 
• 
Categorical variables: counts, rates and stratified 95% confidence intervals for the rates will be 
calculated. 
In addition to descriptive statistics, mixed model analysis of covariance will be conducted for the 
following measurements: 
• 
The change from baseline in DAS28-CRP and DAS28-ESR; 
• 
The change from baseline in the individual components of the ACR20 response (CRP, TJC(28), 
SJC(28), Pain-VAS, PtGA, PrGA, HAQ-DI) and in ESR; 
• 
The change from baseline in SDAI and CDAI scores. 
In this model, treatments and stratum will be fixed effects, subjects will be random effect, and baseline 
values of the respective measurements will be covariates. Other explanatory variables will also be 
allowed to be included in the model. In order to normalize eventual skewed distributions transformation 
of the data will also be considered. Study groups will be compared within this model framework. All  
p-values will be interpreted in a descriptive manner. 
All other analyses will be descriptive. 
 
11.4 PK ANALYSES 
PK analysis will not be conducted by Simbec-Orion. 
11.5 PD ANALYSES 
Not applicable. 
11.6 SAFETY ANALYSES 
11.6.1 Adverse Events 
An overall summary table will be presented (any adverse event, any treatment emergent adverse event 
(TEAE), any serious adverse event (SAE), death, any grade 3 or higher adverse events from baseline to 
the end of Study) (Table 14.3.1.1). This analysis will be conducted on SAF population. 
Primary safety endpoint, the rate of all treatment emergent adverse experiences, will be compared in 
subjects who received a given dose of ABX464 or placebo by likelihood ratio chi-square test on a 10% 
two-sided significance level (14.3.1.2.1). 
Two periods will be defined for TEAE: 
• 
Period 1: any adverse event which occurs or worsens from first dosing to Day 84; 
• 
Period II: any adverse event which occurs after Day 84. 


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Adverse events will be described by primary system organ class and preferred term according to the 
two periods. Numbers and percentage of patients, and number of occurrences of adverse event will be 
presented for: 
• 
TEAE (Table 14.3.1.2.2 and Table Table 14.3.1.2.3); 
• 
Serious TEAE (Table 14.3.1.3.1 and Table Table 14.3.1.3.2); 
• 
TEAE leading to drug discontinuation (Table 14.3.1.4.1 and Table Table 14.3.1.4.2); 
• 
TEAE of grade 3 or 4 (Table 14.3.1.5.1 and Table Table 14.3.1.5.2); 
Further assessment of safety will be based on the frequency of adverse events (with and without regard 
to causality) graded according to the CTC-AE Classification and also, the review of individual values for 
clinical laboratory data, vital signs and ECG focusing on the detection of abnormal values and PCSAs 
[potentially clinically significant abnormalities (PCSAs) determined upon investigator considerations]. 
Adverse events will be tabulated (counts and percentages) by group. All adverse events will be listed, 
and the data will be tabulated by body system/organ class. Adverse event tabulations will include all 
treatment emergent adverse events, which will be further classified by severity, and relationship to 
treatment and dose level. 
All adverse events (AE) will be classified using the version of the MedDRA coding dictionary specified in 
the DHM.  
Events will be classified as treatment-emergent if they started or increased in severity on or after the 
first date and time of medication dosing at Visit 1 and up to study closure or withdrawal date. If an event 
start date is partial, then the start day, month, year or stop date will be used to determine if the event 
is treatment-emergent.  If the classification of the AE cannot be determined from the data available, then 
the event will be considered treatment-emergent. 
Treatment-emergent adverse events (TEAEs) will be further classified as follows: 
Severe TEAEs: Severity classified as ‘severe’ (Common Toxicity Criteria [CTC] grade 3 or 4) or missing. 
Serious TEAEs: Serious classified as ‘yes’ or missing. 
Drug-related TEAEs: Relationship to study drug classified as ’related’ or missing. 
Serious drug-related TEAEs: Both serious and drug-related, as specified above. 
TEAEs leading to withdrawal from study: Action taken classified as ‘discontinued’. 
All AE summary tables will show the number (%) of patients having at least one event and the number 
of events in each treatment group and overall. Median duration of AEs (from baseline to occurrence) 
will be presented in the tables. Note: If a patient has multiple AEs with the same preferred term, these 
will be summarised once within the count for N (%) of patients, but each event will be counted within 
the number of reports n of each AE. Changes in severity of the same AE (if collected) will be counted 
only once within the number of reports n of each AE. 
The following will be presented in listing format within the data summaries: 
• 
Deaths (Table 14.3.2.1); 


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• 
Serious Adverse Events (Table 14.3.2.2); 
• 
Adverse Events which Led to Withdrawal (Table 14.3.2.3). 
All adverse events (including non-treatment-emergent events) recorded on the CRF will be listed within 
the data listings.  
11.6.2 Laboratory Data 
For hematology and biochemistry panels, local laboratory will be used.  
Descriptive statistics (n, mean, SD, SEM, median, minimum and maximum) for laboratory parameters 
will be computed at each scheduled assessment (Table 14.3.3.1 and Table 14.3.3.2). If relevant for some 
parameter, change from baseline will also be tabulated. 
Each laboratory value that is outside of the institution’s normal range will be identified. The Investigator 
will be responsible for assessing the clinical significance of laboratory abnormalities. If the Investigator is 
uncertain about the clinical significance of a laboratory abnormality, he/she will consult with the Sponsor 
medical monitor. 
Laboratory data listings will be presented in two ways: 
• 
Abnormal values (presented within the data summaries) (Table 14.3.3.3) 
• 
All laboratory data (presented within the data listings)  
The absolute values of each parameter will be summarised at each visit. 
In addition, shift tables from baseline will be presented. 
If lab results are repeated at the same visit, the repeated result will be used in summaries (instead of the 
original one) provided the sample was taken within the visit window, otherwise the original result will 
be used. All results will be listed.  
Lab results at unscheduled visits will be included in the listings but will not be summarised. 
Serum pregnancy data will be listed only. 
11.6.3 Vital Signs 
Vital signs will be summarized by using descriptive statistics (n, mean, SD, SEM, median, minimum and 
maximum) (Table 14.3.4). Number of patients with at least one abnormal value will be tabulated (counts 
and percentages) for each parameter in summary shift tables, by group and dose. 
Measurements of vital signs will be done at each visit (Blood pressure, Heart Rate, Body temperature). 
The investigator should ensure that each parameter outside the normal range is assessed for clinical 
significance. For any deviation assessed clinically significant, the investigator has to document the change 
as an AE in the CRF.  
In addition, it is at the discretion of the investigator to document any change or trend over time in vital 
signs as an AE if he considers the change to be clinically significant, even if the absolute value is within 
the alert limit or reference range. 


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11.6.4 Physical Examination 
A routine physical examination (including body weight) will be done at each study visit. Physical 
examinations will cover eyes, ears, nose, throat, lungs/thorax, heart/cardiovascular system, abdomen, 
skin and mucosae, nervous system, lymph nodes, musculo-skeletal system, and, if applicable, others. Any 
new clinically relevant finding compared to baseline must be documented as adverse event. 
Shift tables will be presented showing changes from baseline to each visit for normal / abnormal physical 
examination results (Table 14.3.5). 
11.6.5 Electrocardiogram 
Electrocardiograms will be performed at Screening, Baseline / Day 0, Week 8 / Day 56 and at the EOS 
visit (in case of premature discontinuation only). At least a 12-lead ECG with recordings of at least 6 
action potentials in lead II (paper speed 25mm/s, amplitude 10mm/mV) will be measured at a resting 
position. Resting ECG should be performed before any examinations. 
All abnormal findings must be documented in the CRF. Any clinically relevant findings compared to ECG 
done at Day 0 / Baseline must be documented as adverse events. 
The absolute values of PR, QRS, QT and QTc will be summarised at each visit done (screening, baseline, 
week 8 and EOS) (Table 14.3.6). 
The number and percentage of the patients with Normal / Abnormal NCS / Abnormal CS ECG results 
will be summarised. 
11.7 STUDY DRUG EXPOSURE AND COMPLIANCE 
Treatment exposure (ABX464 50mg, 100mg or placebo) and compliance (yes/no) will be summarised 
for the FAS (Table 14.3.7). 
11.8 PRIOR AND CONCOMITANT MEDICATION 
All medications taken by patients on entry to the study or during the study will be recorded in the CRF. 
Medications will be classified using the version of the World Health Organisation Drug Dictionary 
(WHODD) coding dictionary defined in the Data Management Plan. The Anatomical Therapeutic 
Chemical (ATC) Classification and WHO-DRUG PT will be used to list and summarise the data.    
If required by client, conmeds can be summarised at 3 levels: ATC levels 1 and 2 and preferred term. 
Prior medications are defined as medication that started and stopped before Day 1. Only medications 
where the stop date is prior to Day 1 will be considered prior. If the stop date is unknown or incomplete 
and the medications cannot definitely be considered as stopped prior to Day 1 then the medications will 
be considered as concomitant medications at randomisation or change in concomitant medication, 
depending on the start date.  
Concomitant medications at randomisation are defined as medications that started before Day 1 
and either stopped on Day 1 or continued into the study. Partial start dates where the medication cannot 


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definitely be considered as starting prior to Day 1 will lead to a categorisation of the medications as 
having started on or after dosing. 
Change in concomitant medication is defined as medication that started on or after Day 1. If the 
medication start or stop dates are partial then the rules for prior and concomitant medication, detailed 
above will be observed prior to assigning a category. 
The number (%) of patients reporting the use of any prior medications and the number (%) of patients 
taking each drug by ATC classification and PT will be summarised using the FAS (Table 14.3.8). This table 
will be repeated for concomitant medications at randomisation (Table 14.3.9.1) and for change in 
concomitant medication (Table 14.3.9.2) 
Mandatory concomitant treatments are the followings: 
• 
MTX ≥ 10 mg/week, at stable dose, throughout the study; 
• 
Folic acid ≥ 10 mg/week post MTX dose, to minimize MTX toxicity. 
Allowed Concomitant Medications are the followings: 
• 
Corticosteroids at stable dose of prednisone and prednisone equivalent ≤10 mg/day during the 
study; 
• 
Non-steroidal anti-inflammatory drugs (NSAIDs) at stable dose during the study; 
• 
Antalgics including class III at stable dose during the study; 
• 
Other non-rheumatologic medications. 
Potential other concomitant medications (not indicated for rheumatoid arthritis) should be kept at 
constant dose during the course of the study and properly reported in the medical file of the patient and 
the eCRF. 
Prohibited concurrent medications are the followings: 
• 
Any non-anti-TNFα biological or targeted DMARDs: IL-6 antagonists, JAK inhibitors, CTLA-4Fc 
Chimera, rituximab; 
• 
Any immunosuppressive drugs; 
• 
Vaccination with live components during the study and up to 8 Weeks after the last dosing;  
• 
Drugs that could interact with ABX464 should be avoided especially the CYP1A2 substrates. 
The following CYP1A2 substrates with a narrow therapeutic margin are prohibited during the 
whole course of the study (rifampicin, clozapine, theophylline, ropinirole, warfarin and 
methadone). In case of concomitant treatment with ondansetron, the maximal daily dose must 
be limited to 8 mg; 
• 
Use of any investigational or non-registered product within 3 months preceding baseline. 


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12 VALIDATION 
All tables, figures and listings will be subject to independent quality control and visual review. Unique 
tables will be independently programmed. Findings will be documented in a quality control form and 
actions taken will also be documented.  
The completed form will be reviewed and signed by both programmers and by the head of biostatistics. 
13 LITERATURE CITATIONS/REFERENCES 
Not applicable 
  
 
 


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14 LIST OF TABLES, FIGURES AND LISTINGS 
14.1 LIST OF TABLES 
Demographic Data 
 
 
Table 14.1.1 
Screening Failures   
All 
Enrolled 
Patients 
Table 14.1.2 
Patient Disposition  
All Randomised 
Patients 
Table 14.1.3  
Study Termination and Primary Reason for Withdrawal  
All Randomised 
Patients 
Table 14.1.4  
Demographic and Baseline Characteristics  
Full Analysis Set 
Table 14.1.5.1  
Medical History  
Full Analysis Set 
Table 14.1.5.2  
Current Medical Conditions  
Full Analysis Set 
 
Efficacy Data 
 
 
Table 14.2.1.1  
Analysis of ACR20 Response Rate 
Efficacy Set 1 
Table 14.2.1.2 
Analysis of ACR20 Response Rate  
Efficacy Set 2 
Table 14.2.1.3 
Analysis of ACR20 Response Rate  
PP Set 
Table 14.2.2.1 
Summary of Categorical ACR20 Response at Week 12 
Efficacy Set 1 
Table 14.2.2.2 
Summary of Categorical ACR20 Response at Week 12 
Efficacy Set 2 
Table 14.2.3.1 
Analysis of the individual components of the ACR20 
response  
Efficacy Set 1 
Table 14.2.3.2 
Analysis of the individual components of the ACR20 
response  
Efficacy Set 2 
Table 14.2.4.1.1 
Analysis of ESR 
Efficacy Set 1 
Table 14.2.4.1.2 
Analysis of ESR 
Efficacy Set 2 
Table 14.2.4.2.1 
Analysis of DAS28-CRP 
Efficacy Set 1 
Table 14.2.4.2.2 
Analysis of DAS28-CRP 
Efficacy Set 2 
Table 14.2.4.3.1 
Analysis of DAS28-ESR 
Efficacy Set 1 
Table 14.2.4.3.2 
Analysis of DAS28-ESR 
Efficacy Set 2 
Table 14.2.4.4.1 
Analysis of SDAI Score 
Efficacy Set 1 
Table 14.2.4.4.2 
Analysis of SDAI Score 
Efficacy Set 2 
Table 14.2.4.5.1 
Analysis of CDAI Score 
Efficacy Set 1 


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Table 14.2.4.5.2 
Analysis of CDAI Score 
Efficacy Set 2 
Table 14.2.4.6.1 
Summary of FACIT-Fatigue Score 
Efficacy Set 1 
Table 14.2.4.6.2 
Summary of FACIT-Fatigue Score 
Efficacy Set 2 
Table 14.2.5.1 
Summary of Patients Different Responses and Remissions 
Efficacy Set 1 
Table 14.2.5.2 
Summary of Patients Different Responses and Remissions 
Efficacy Set 2 
 
Safety Data 
 
 
Table 14.3.1.1 
Summary of Adverse Events 
Safety Set 
Table 14.3.1.2.1 
Analysis of all Treatment-Emergent Adverse Events 
Safety Set 
Table 14.3.1.2.2 
Treatment-Emergent Adverse Events, by SOC and PT: 
Period 1 
Safety Set 
Table 14.3.1.2.3 
Treatment-Emergent Adverse Events, by SOC and PT: 
Period 2 
Safety Set 
Table 14.3.1.3.1 
Serious Treatment-Emergent Adverse Events, by SOC and 
PT: Period 1  
Safety Set 
Table 14.3.1.3.2 
Serious Treatment-Emergent Adverse Events, by SOC and 
PT: Period 2 
Safety Set 
Table 14.3.1.4.1 
Treatment-Emergent Adverse Events Leading to Study 
Drug Discontinuation, by SOC and PT: Period 1  
Safety Set 
Table 14.3.1.4.2 
Treatment-Emergent Adverse Events Leading to Study 
Drug Discontinuation, by SOC and PT: Period 2 
Safety Set 
Table 14.3.1.5.1 
Treatment-Emergent Adverse Events of Grade 3 or 4 by 
SOC and PT: Period 1 
Safety Set 
Table 14.3.1.5.2 
Treatment-Emergent Adverse Events of Grade 3 or 4 by 
SOC and PT: Period 2 
Safety Set 
Table 14.3.2.1 
Listing of Deaths 
Safety Set 
Table 14.3.2.2 
Listing of Serious Adverse Events 
Safety Set 
Table 14.3.2.3 
Listing of Withdrawals Due to Adverse Events 
Safety Set 
Table 14.3.3.1 
Summary of Laboratory Parameters: Haematology  
Safety Set 
Table 14.3.3.2 
Summary of Laboratory Parameters: Biochemistry 
Safety Set 
Table 14.3.3.3 
Listing of Abnormal Laboratory Values 
Safety Set 
Table 14.3.4 
Vital Signs 
Safety Set 
Table 14.3.5 
Shift Table of Physical Examination 
Safety Set 
Table 14.3.6 
Electrocardiogram 
Safety Set 
Table 14.3.7 
Study Drug Exposure and Compliance 
Full Analysis Set 


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Table 14.3.8 
Prior Medications  
Full Analysis Set 
Table 14.3.9.1 
Concomitant Medications  
Full Analysis Set 
Table 14.3.9.2 
Changes in Concomitant Medications  
Full Analysis Set 
 
14.2 LIST OF LISTINGS 
Patient Data Listings 
 
Listing 16.2.1.1 
Patient Disposition 
Listing 16.2.1.2 
Discontinued Patients  
Listing 16.2.2  
Protocol Deviations  
Listing 16.2.3  
Analysis Datasets 
Listing 16.2.4 
Demographic Data  
Listing 16.2.5  
Study Drug Exposure and Compliance  
Listing 16.2.6  
Efficacy Response Data: ACR20/50/70 Response 
Listing 16.2.7  
Adverse Event Listing 
Listing 16.2.8.1 
Laboratory Measurements: Haematology 
Listing 16.2.8.2 
Laboratory Measurements: Biochemistry 
 
Individual Patient Data Listings 
(Archive) 
 
Listing 16.4.1 
Final Status 
Listing 16.4.2  
Patient Visit Dates 
Listing 16.4.3.1  
Inclusion Criteria 
Listing 16.4.3.2 
Exclusion Criteria 
Listing 16.4.4 
Medical History   
Listing 16.4.5.1 
Raw Efficacy Data: Individual Components of the ACR20 
Response 
Listing 16.4.5.2 
Raw Efficacy Data: ESR, DAS28-CRP, DAS28-ESR, SDAI 
Score, CDAI Score and FACIT-Fatigue Score 
Listing 16.4.5.3 
Raw Efficacy Data: Different Responses and Remissions 
Listing 16.4.9 
Vital Signs  
Listing 16.4.10 
Physical Examination 
Listing 16.4.11 
12-Lead Electrocardiogram 
Listing 16.4.12.1  
Prior Medications  


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Listing 16.4.12.2  
Concomitant Medications 
Listing 16.4.12.3 
Changes to Medications 
Listing 16.4.13 
Pregnancy Test 
Listing 16.4.14 
Laboratory Samples Collection 
 
15 SHELLS FOR TABLES, FIGURES AND LISTINGS 
The intended layouts for tables, figures and listings are presented. However, it may be appropriate for 
the Orion programmer to change the layouts, upon review of the data available, for completeness and 
clarity.  
QCd output will be produced as Rich Text Format (.rtf) files for convenient inclusion in the CSR. 
Subject to this, the following will apply: 
• 
Layout will be landscape, fixed width, font size 8.  
• 
Each output will have the heading: 
ABX464-301 (left); date ddMMMyyyy (right) 
• 
Table headings will define the analysis set used for the summary/analysis. 
• 
All outputs will have a footer specifying the SAS program path and filename (left); page x/y (right) 
• 
Tables will have a footer specifying the source listing 
• 
Figures will have a footer specifying the source table or listing 
• 
Additional footnotes will be included where appropriate for clarification. 
• 
Treatment group and patient number and will be included in all listings. 
 


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ABX464-301 
ddMMMyyyy 
Table 14.1.1 Screening Failures (All Enrolled Patients) 
 
 
Total Enrolled 
(N=xx) 
 
 
Total number of enrolled patients 
xx  
  Screened 
xx (xx.x%) 
  Randomised 
xx (xx.x%) 
  Screening failure 
xx (xx.x%) 
  Baseline failure 
Xx (xx.x%) 
 
 
Primary Reason for screening failure 
 
  Inclusion criterion not met 
xx (xx.x%) 
  Exclusion criterion 
xx (xx.x%) 
  Withdrawal by patient 
xx (xx.x%) 
  Etc 
 
 
 
The denominator for each percentage is the number of enrolled patients. 
 
Source: Listing 16.2.1.1 and 16.2.1.2 
Path\Filename  
Page x/y 
 


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ABX464-301 
ddMMMyyyy 
 
Table 14.1.2 Patient Disposition (All Randomised Patients)  
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Full Analysis Set 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Safety Set 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Efficacy Set 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Efficacy Set 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Per Protocol Set 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
  
 
 
 
 
The denominator for each percentage is the number of randomized patients in the column. 
 
Source: Listing 16.2.1.1 and 16.2.1.2 
Path\Filename  
 
Page x/y 
 
 


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ABX464-301 
ddMMMyyyy 
 
Table 14.1.3 Study Termination and Primary Reason for Withdrawal (All Randomised Patients) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Randomised 
xx  
xx 
xx  
xx  
Completed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Early withdrawal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Main reason for early withdrawal 
 
 
 
 
  Investigator’s decision 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Adverse event  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Major protocol violation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Patient’s decision 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Withdrawal of consent  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Etc 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
The denominator for each percentage is the number of randomized patients in the column. Completed defined as performed follow-up visit. 
 
Source: Listing 16.2.1.1 and 16.2.1.2 
Path\Filename  
 
Page x/y 


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ABX464-301 
ddMMMyyyy 
 
Table 14.1.4 Demographic and Baseline Characteristics (Full Analysis Set) 
 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
Age (years) 
N 
xx 
xx 
xx 
xx 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Sex 
N 
xx 
xx 
xx 
xx 
 
Male 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Female 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Height (cm) 
N 
xx 
xx 
xx 
xx 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Weight (kg) 
N 
xx 
xx 
xx 
xx 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
BMI (kg/m2) 
N 
xx 
xx 
xx 
xx 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 


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ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
The denominator for each percentage is the number of non-missing observations within the column 
Age was calculated using DOB and date of first treatment (Visit 1) and presented as age at last birthday. 
BMI is the patient’s body weight in kilograms divided by the square of the patient’s height in metres. 
 
Source: Listing 16.2.4 
Path\Filename  
 
Page x/y 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 46 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
 
Table 14.1.5.1 Medical History (Full Analysis Set) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Any medical/surgical history 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
SOC 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  PT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Etc 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
SOC 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  PT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Etc 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
The denominator for each percentage is the number of patients within the column. 
Medical history refers to conditions which stopped prior to or at the screening visit. 
 
Source: Listing 16.4.4 
Path\Filename  
 
 
Page x/y 
 
This layout also applies to: 
Table 14.1.5.2 Current Medical Conditions (Full Analysis Set) [Programmer’s Note: Update footnote to medical conditions definition.] 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
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ABX464-301 
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Table 14.2.1.1 Analysis of ACR20 Response Rate (Efficacy Set 1) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
p-value 
 
 
 
 
 
 
ACR20 Response 
N 
xx 
xx 
xx 
 
 
Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Chi-squared test 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
Response rate between treatments is compared using likelihood ratio chi-square test at a two-sided 10% significance level. 
 
Source: Listing 16.2.6 
Path\Filename 
  
Page x/y 
 
 
This layout also applies to: 
Table 14.2.1.2 Analysis of ACR20 Response Rate (Efficacy Set 2) 
Table 14.2.1.3 Analysis of ACR20 Response Rate (PP Set) 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
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ABX464-301 
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Table 14.2.2.1 Summary of Categorical ACR20 Response at Week 12 (Efficacy Set 1) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
Week 12 
N 
xx  
xx  
xx  
 
Rate 
xx.x % 
xx.x % 
xx.x % 
 
Stratified 95% CI 
xx.x % - xx.x % 
xx.x % - xx.x % 
xx.x % - xx.x % 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.6 
Path\Filename  
 
Page x/y 
 
This layout also applies to: 
Table 14.2.2.2 Summary of Categorical ACR20 Response at Week 12 (Efficacy Set 2) 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 49 of 101 
 
 
 
ABX464-301 
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Table 14.2.3.1 Analysis of the individual components of the ACR20 response (Efficacy Set 1) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
p-value 
CRP 
 
 
 
 
 
  Baseline 
N 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Mean 
Stratified 95% CI 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.xx – xx.xx 
 
 
SD 
Minimum 
Maximum 
Median 
Quartiles 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx – xx.xx 
 
 
 
 
 
 
 
  Week 2 
N 
Mean 
Etc 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
 
 
 
 
 
 
 
  Change from baseline to Week 2 
N 
Mean 
Etc 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
 
 
 
 
 
 
 
  Analysis of Covariance (change 
  from baseline to Week 2) 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
  Week 4 
N 
Mean 
Etc 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
 
 
 
 
 
 
 
  Etc 
 
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
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Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mixed model analysis of covariance is conducted for the changes of baseline for each parameter. 
 
Source: Listing 16.4.5.1 
Path\Filename  
 
Page x/y 
 
 
 
Programmer’s Note: list of variables consists of CRP, TJC, SJC, Pain-VAS, PtGA, PrGA, HAQ-DI. 
 
 
This layout also applies to: 
Table 14.2.3.2 Analysis of the individual components of the ACR20 response (Efficacy Set 2) 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 51 of 101 
 
 
 
ABX464-301 
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Table 14.2.4.1.1 Analysis of ESR (Efficacy Set 1) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
p-value 
Baseline 
N 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Mean 
Stratified 95% CI 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.xx – xx.xx 
 
 
SD 
Minimum 
Maximum 
Median 
Quartiles 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx – xx.xx 
 
 
 
 
 
 
 
Week 2 
N 
Mean 
Etc 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
 
 
 
 
 
 
 
Change from baseline to Week 2 
N 
Mean 
Etc 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
 
 
 
 
 
 
 
Analysis of Covariance (change 
from baseline to Week 2) 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
Week 4 
N 
Mean 
Etc 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
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Mixed model analysis of covariance is conducted for the changes of baseline for each parameter. 
 
Source: Listing 16.4.5.2 
Path\Filename  
 
Page x/y 
 
This layout also applies to: 
Table 14.2.4.1.2 Analysis of ESR (Efficacy Set 2) 
Table 14.2.4.2.1 Analysis of DAS28-CRP (Efficacy Set 1) 
Table 14.2.4.2.2 Analysis of DAS28-CRP (Efficacy Set 2) 
Table 14.2.4.3.1 Analysis of DAS28-ESR (Efficacy Set 1) 
Table 14.2.4.3.2 Analysis of DAS28-ESR (Efficacy Set 2) 
Table 14.2.4.4.1 Analysis of SDAI Score (Efficacy Set 1) 
Table 14.2.4.4.2 Analysis of SDAI Score (Efficacy Set 2) 
Table 14.2.4.5.1 Analysis of CDAI Score (Efficacy Set 1) 
Table 14.2.4.5.2 Analysis of CDAI Score (Efficacy Set 2) 
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
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ABX464-301 
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Table 14.2.4.6.1 Summary of FACIT-Fatigue Score (Efficacy Set 1) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Baseline 
N 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Mean 
Stratified 95% CI 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.xx – xx.xx 
 
SD 
Minimum 
Maximum 
Median 
Quartiles 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx – xx.xx 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx – xx.xx 
 
 
 
 
 
Week 2 
N 
Mean 
Etc 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
 
 
 
 
 
Change from baseline to Week 2 
N 
Mean 
Etc 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
 
 
 
 
 
Week 4 
N 
Mean 
Etc 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
xx (xx.x %) 
xx.xx 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
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Source: Listing 16.4.5.2 
Path\Filename 
  
Page x/y 
 
This layout also applies to: 
Table 14.2.4.6.2 Summary of FACIT-Fatigue Score (Efficacy Set 2) 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 55 of 101 
 
 
 
 
ABX464-301 
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Table 14.2.5.1 Summary of Patients Achieving Different Responses and Remissions (Efficacy Set 1) 
 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
ARC20 Response 
 
 
 
 
  Week 2 
N 
xx  
xx  
xx  
 
Rate 
xx.x % 
xx.x % 
xx.x % 
 
Stratified 95% CI 
xx.x % - xx.x % 
xx.x % - xx.x % 
xx.x % - xx.x % 
 
 
 
 
 
  Week 4 
N 
xx  
xx  
xx  
 
Rate 
xx.x % 
xx.x % 
xx.x % 
 
Stratified 95% CI 
xx.x % - xx.x % 
xx.x % - xx.x % 
xx.x % - xx.x % 
 
 
 
 
 
  Etc 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.4.5.3 
Path\Filename  
 
Page x/y 
 
Programmer’s Note: list of variables consists of ACR20/50/70 response, Categorical DAS28-CRP response, LDA, DAS28-ESR remission, 
ACR/EULAR remission, SDAI remission, CDAI remission. 
 
This layout also applies to: 
Table 14.2.5.2 Summary of Patients Achieving Different Responses and Remissions (Efficacy Set 2) 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 56 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
 
Table 14.3.1.1 Summary of Adverse Events (Safety Set) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total (N=xx) 
 
n      N (%) 
n      N (%) 
n      N (%) 
n      N (%) 
 
 
 
 
 
Any Adverse Event 
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
Any Treatment-Emergent Adverse Event 
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
Any Serious Adverse Event 
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
Adverse Event leading to death 
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
Any grade 3 or higher Adverse Event 
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
 
 
 
 
 
The table presents number of events (n) and number and percentage of patients (N(%)). 
The denominator for each percentage is the number of patients within the column. 
 
 
Source: Listing 16.2.7  
Path\Filename  
 
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 57 of 101 
 
 
 
 
ABX464-301 
ddMMMyyyy 
Table 14.3.1.2.1 Analysis of Treatment-Emergent Adverse Events (Safety Set) 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
p-value 
 
 
 
 
 
 
Any Treatment-Emergent Adverse Event 
N 
xx 
xx 
xx 
 
 
Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Chi-squared test 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
The denominator for each percentage is the number of patients within the column 
TEAE rate between treatments is compared using likelihood ratio chi-square test at a two-sided 10% significance level. 
 
Source: Listing 16.2.7  
Path\Filename  
 
Page x/y 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 58 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
 
Table 14.3.1.2.2 Treatment-Emergent Adverse Events, by SOC and PT: Period 1 (Safety Set) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
100mg 
(N=xx) 
Placebo 
(N=xx) 
Total (N=xx) 
 
n      N (%)    duration 
                (days) 
n      N (%)    duration 
                (days) 
n      N (%)    duration 
                (days) 
n      N (%)    duration 
                (days) 
 
 
 
 
 
Any Treatment-Emergent 
Adverse Event 
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
xx   xx (xx.x%)  
 
 
 
 
 
SOC 
xx   xx (xx.x%)  xx.xx  
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
 PT 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
 PT 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
SOC 
 Etc 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
xx   xx (xx.x%)  xx.xx 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
The table presents number of events (n) and number and percentage of patients (N(%)). 
The denominator for each percentage is the number of patients within the column. 
Duration (days) represents median duration of AEs (from baseline to occurrence). 
 
Source: Listing 16.2.7  
Path\Filename 
  
Page x/y 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 59 of 101 
 
 
 
 
This layout also applies to: 
Table 14.3.1.2.3 Treatment-Emergent Adverse Events, by SOC and PT: Period 2 (Safety Set) 
Table 14.3.1.3.1 Serious Treatment-Emergent Adverse Events, by SOC and PT: Period 1 (Safety Set) 
Table 14.3.1.3.2 Serious Treatment-Emergent Adverse Events, by SOC and PT: Period 2 (Safety Set) 
Table 14.3.1.4.1 Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation, by SOC and PT: Period 1 (Safety Set) 
Table 14.3.1.4.2 Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation, by SOC and PT: Period 2 (Safety Set) 
Table 14.3.1.5.1 Treatment-Emergent Adverse Events of Grade 3 or 4 by SOC and PT: Period 1 (Safety Set) 
Table 14.3.1.5.2 Treatment-Emergent Adverse Events of Grade 3 or 4 by SOC and PT: Period 2 (Safety Set) 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
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ABX464-301 
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Table 14.3.2.1 Listing of Deaths (Safety Set) 
 
 
Treatment 
Patient number 
Date of death 
Cause of death 
 
 
 
 
xxxxxx 
xxx-xxxx 
ddMMMyyyy 
xxxxxxxxxxxxxxxxxxx 
 
 
 
 
xxxxxx 
xxx-xxxx 
ddMMMyyyy 
xxxxxxxxxxxxxxxxxxx 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
Path\Filename  
 
Page x/y 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 61 of 101 
 
 
 
ABX464-301 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 14.3.2.2 Listing of Serious Adverse Events 
 
 
Path\Filename  
 
Page x/y 
 
Treatment 
Centre/ 
Patient 
number 
Adverse 
Event 
  PT 
    SOC 
Onset date  
Resolution 
date / 
ongoing 
Outcome 
Relationship 
to study 
drug 
Action taken 
with study drug 
Other action 
taken 
 
xxxxx 
 
xxx-xxxx 
 
xxxxxxxxxx 
  xxxxxxxx 
    xxxx 
 
ddMMMyyyy 
 
ddMMMyyyy / 
ongoing 
 
Resolved/ 
Resolved 
without 
sequelae/ 
Etc 
 
Yes/No 
 
None/ Temporary 
discontinuation/ 
Etc 
 
Concomitant 
medication 
(CM no.)/ 
Procedure 
(PR no.) 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxxxx 
  xxxxxxxx 
    xxxx 
ddMMMyyyy 
ddMMMyyyy / 
ongoing 
Resolved/ 
Resolved 
without 
sequelae/ 
Etc 
Yes/No 
None/ Temporary 
discontinuation/ 
Etc 
Concomitant 
medication 
(CM no.)/ 
Procedure 
(PR no.) 
 
 
Etc 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 62 of 101 
 
 
 
This layout also applies to: 
Table 14.3.2.3 Listing of Withdrawals Due to Adverse Events (Safety Set) 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 63 of 101 
 
 
 
 
ABX464-301 
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Table 14.3.3.1 Summary of Laboratory Parameters: Haematology (Safety Set) 
 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
Haematocrit  
 
 
 
 
 
  Baseline  
N 
xx 
xx 
xx 
xx 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SEM 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
  Week 1  
N 
Mean 
Etc 
xx 
xx.xx 
Xx 
xx.xx 
Xx 
xx.xx 
Xx 
xx.xx 
 
 
 
 
 
 
  Change from baseline to Week 1 
N 
Mean 
Etc 
xx 
xx.xx 
Xx 
xx.xx 
Xx 
xx.xx 
Xx 
xx.xx 
 
 
 
 
 
 
  Etc 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.8.1 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
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Path\Filename 
  
Page x/y 
 
Programming note: start each parameter on a new page 
 
This layout also applies to: 
Table 14.3.3.2 Summary of Laboratory Parameters: Biochemistry (Safety Set) 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 65 of 101 
 
 
 
ABX464-301 
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Table 14.3.3.3 Listing of Abnormal Laboratory Values (Safety Set)  
 
Treatment 
Patient number 
Visit 
Laboratory Parameter 
Value 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
Week x 
xxxxxxxxxxxxxxxxxxx 
xx.xx 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxxxxx 
xx.xx 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
Path\Filename  
 
Page x/y 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 66 of 101 
 
 
 
ABX464-301 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ddMMMyyyy 
 
Table 14.3.4 Vital Signs (Safety Set) 
 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
Systolic BP (mmHg)  
 
 
 
 
 
  Baseline  
N 
 
Normal 
Abnormal NCS 
Abnormal CS 
 
xx 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SD 
SEM 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
  Week 1 
N 
Normal 
Etc 
xx 
xx (xx.x %) 
 
xx 
xx (xx.x %) 
 
xx 
xx (xx.x %) 
 
xx 
xx (xx.x %) 
 
 
 
 
 
 
 
  Etc 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
The denominator for each percentage is the number of non-missing observations within the column. 
NCS = Not Clinically Significant; CS = Clinically Significant 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
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Source: Listing 16.4.9 
Path\Filename  
 
Page x/y 
 
Programmer’s Note: list of variables consists of body temperature, weight, systolic and diastolic blood pressure, heart rate and 
respiratory rate. 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 68 of 101 
 
 
 
ABX464-301 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ddMMMyyyy 
 
Table 14.3.5 Shift Table of Physical Examination (Safety Set) 
 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
normal 
abnormal 
normal 
abnormal 
normal 
abnormal 
normal 
abnormal 
 
 
 
 
 
 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
  Baseline  
N 
xx (xx.x %) 
xx (xx.x %) 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
  Week 1  
N 
xx (xx.x %) 
xx (xx.x %) 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   
 
 
 
 
 
  Etc 
 
 
 
 
 
 
 
 
 
 
 
Ears 
 
 
 
 
 
 
 
 
 
 
 
  Baseline  
N 
xx (xx.x %) 
xx (xx.x %) 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
  Week 1  
N 
xx (xx.x %) 
xx (xx.x %) 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   
 
 
 
 
 
  Etc 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
The denominator for each percentage is the number of non-missing observations within the column. 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 69 of 101 
 
 
 
Source: Listing 16.4.10 
Path\Filename  
 
Page x/y 
 
Programmer’s Note: list of variables consists of eyes, ears, nose, throat, lungs/thorax, heart/cardiovascular system, abdomen, skin and 
mucosae, nervous system, lymph nodes, musculo-skeletal system, and, if applicable, others. 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 70 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
 
Table 14.3.6 Electrocardiogram (Safety Set)  
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
PR interval 
 
 
 
 
 
  Baseline 
N 
 
Normal 
Abnormal NCS 
Abnormal CS 
 
xx 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum  
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
  Week 1 
N 
xx 
xx 
xx 
xx 
 
Normal 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Etc 
 
 
 
 
 
 
 
 
 
 
  Etc 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
The denominator for each percentage is the number of non-missing observations within the column. 
NCS = Not Clinically Significant; CS = Clinically Significant 
 
Source: Listing 16.4.11  
Path\Filename  
 
Page x/y 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 71 of 101 
 
 
 
Programmer’s Note: The absolute values of PR, QRS, QT and QTc will be summarised at each visit. 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 72 of 101 
 
 
 
 
ABX464-301 
ddMMMyyyy 
 
Table 14.3.7 Study Drug Exposure and Compliance (Full Analysis Set) 
 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
Number of dose intakes 
N 
xx 
xx 
xx 
xx 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Study drug exposure (days) 
N 
xx 
xx 
xx 
xx 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Etc 
 
 
 
 
 
 
 
 
 
 
Compliance 
N 
Yes 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug exposure (days) is calculated as (date of last dose) - (date of first dose) + 1. 
 
Source: Listing 16.2.5  
Path\Filename  
Page x/y 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 73 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
 
Table 14.3.8 Prior Medications (Full Analysis Set)  
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Any prior medication1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
X, xxxxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 X0N, xxxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  X0NXX, xxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   xxxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Etc 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
  X0NXX, xxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   xxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Etc 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
X0N, xxxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  X0NXX, xxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   xxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Etc 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 Etc 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
1 Medication that stopped prior to date of first dose. 
WHO-DDE version <XX.X> 
The denominator for each percentage is the number of patients in the full analysis set within the column. 
 
Source: Listing 16.4.12.1  


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 74 of 101 
 
 
 
Path\Filename  
 
Page x/y 
 
This layout also applies to: 
Table 14.3.9.1 Concomitant Medications (Full Analysis Set) 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 75 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
 
Table 14.3.9.2 Change in Concomitant Medications (Full Analysis Set) 
 
 
 
ABX-464 
100mg 
(N=xx) 
ABX-464 
50mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Any concomitant medication 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
X, xxxxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 X0N, xxxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  X0NXX, xxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   xxxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Etc 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
  X0NXX, xxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   xxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Etc 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
X0N, xxxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  X0NXX, xxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   xxxxxxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Etc 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 Etc 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
WHO-DDE version <XX.X> 
The denominator for each percentage is the number of patients in the full analysis set within the column. 
 
Source: Listing 16.4.12.3 
Path\Filename  


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 76 of 101 
 
 
 
 
Page x/y 
 
 
 
 
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 77 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.2.1.1 Patient Disposition 
 
Treatment Centre/ 
Patient 
number 
First 
dose date 
Last dose 
date 
Completed 
study 
Date of 
completion/ 
withdrawal 
If not completed 
specify 
Did subject complete 
the follow-up visit? 
Death Date 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-
xxxx 
ddMMMyyyy 
ddMMMyyyy 
Yes/No 
ddMMMyyyy 
specify 
Yes/No (specify 
reason) 
ddMMMyyyy 
 
xxx-
xxxx 
ddMMMyyyy 
ddMMMyyyy 
Yes/No 
ddMMMyyyy 
specify 
Yes/No (specify 
reason) 
ddMMMyyyy 
 
xxx-
xxxx 
ddMMMyyyy 
ddMMMyyyy 
Yes/No 
ddMMMyyyy 
specify 
Yes/No (specify 
reason) 
 
 
xxx-
xxxx 
ddMMMyyyy 
ddMMMyyyy 
Yes/No 
ddMMMyyyy 
specify 
Yes/No (specify 
reason) 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename 
 
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 78 of 101 
 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.2.1.2 Discontinued Patients 
 
Treatment 
Centre/  
Patient number 
First dose date 
Last dose date 
Date of withdrawal 
Main reason for withdrawal 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename 
 
Page x/y 
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 79 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.2.2 Protocol Deviations 
 
Treatment 
Centre/ 
Patient 
number 
Major 
deviation 
Protocol deviation 
 
 
 
 
xxxxxx 
xxx-xxxx 
Yes/No 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
xxx-xxxx 
Yes/No 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
xxx-xxxx 
Yes/No 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
xxx-xxxx 
Yes/No 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
Path\Filename  
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 80 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.2.3 Analysis Datasets 
 
Treatment Centre/ Patient number 
Full Analysis Set 
Per Protocol Set 
Safety Set 
Efficacy Set 1 
Efficacy Set 2 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
xxx-xxxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
xxx-xxxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
xxx-xxxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename 
Page x/y 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 81 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.2.4 Demographic Data  
 
Treatment 
Centre/ 
Patient 
number 
Date of 
screening 
Date of 
birth 
Age 
(years) 
Gender 
Race 
Weight 
(kg) 
Height 
(cm) 
BMI (kg/m2) 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
xx 
xxxx 
xxxx 
xx.x 
xxx.x 
xx.x 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
xx 
xxxx 
xxxx 
xx.x 
xxx.x 
xx.x 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
xx 
xxxx 
xxxx 
xx.x 
xxx.x 
xx.x 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
xx 
xxxx 
xxxx 
xx.x 
xxx.x 
xx.x 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
xx 
xxxx 
xxxx 
xx.x 
xxx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename 
 
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 82 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.2.5 Study Drug Exposure and Compliance 
 
Treatment 
Centre/ 
Patient 
number 
Date of 
compliance 
check 
Date of 
first dose 
Date of 
last dose 
Duration of 
exposure 
(days) 
Capsules 
used 
Capsules 
expected to be 
used 
Capsules 
returned 
Capsules lost 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xx 
xx 
xx 
xx 
xx 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xx 
xx 
xx 
xx 
xx 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xx 
xx 
xx 
xx 
xx 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xx 
xx 
xx 
xx 
xx 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xx 
xx 
xx 
xx 
xx 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xx 
xx 
xx 
xx 
xx 
 
xxx-xxxx 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
xx 
xx 
xx 
xx 
xx 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Outside the visit window 
 
Path\Filename 
 
Page x/y 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 83 of 101 
 
 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.2.6 Efficacy Response Data: ACR20/50/70 Response 
 
Treatment 
Centre/ Patient number 
ACR20 Response  
ACR50 Response 
ACR70 Response 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
Yes/No  
Yes/No  
Yes/No  
 
xxx-xxxx 
Yes/No  
Yes/No  
Yes/No  
 
xxx-xxxx 
Yes/No  
Yes/No  
Yes/No  
 
xxx-xxxx 
Yes/No  
Yes/No  
Yes/No  
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
Path\Filename   
 
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 84 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.2.7 Adverse Event Listing 
 
Treatment 
Centre/ 
Patient 
number 
Baseline 
date 
Adverse 
Event 
 SOC 
  PT 
Onset 
date 
Resolution 
date 
/ongoing 
Outcome 
Serious 
Severity Relationship 
to study 
drug 
Action taken 
with study drug 
Other 
action 
taken 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxx 
xxx- 
xxxx 
ddMMMyyyy 
xxxxxxxxx 
 xxxxxxxx 
  xxxxxxx 
ddMMMyyyy 
ddMMMyyyy/ 
Ongoing 
Resolved/resolved 
without sequelae 
/Etc 
Yes /No 
Grade 1/ 
Grade 2/ 
etc 
Yes/No  
None /Temporary 
discontinuation 
/Etc 
Concomitant 
medication 
(CM no.)/ 
Procedure 
(PR No.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ddMMMyyyy 
xxxxxxxxx 
 xxxxxxxx 
  xxxxxxx 
ddMMMyyyy 
ddMMMyyyy/ 
Ongoing 
Resolved/resolved 
without sequelae 
/Etc 
Yes /No 
Grade 1/ 
Grade 2/ 
etc 
Yes/No 
None /Temporary 
discontinuation 
/Etc 
Concomitant 
medication 
(CM no.)/ 
Procedure 
(PR No.) 
 
 
 
Etc 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename 
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 85 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.2.8.1 Laboratory Measurements: Haematology 
 
Parameter 
Treatment 
Centre/ 
Patient 
number 
Visit 
Was sample taken? 
Result 
Unit 
Investigator’s interpretation 
 
 
 
 
 
 
 
 
Haemoglobin 
xxxxxxx 
xxx-xxxx 
Screening 
Yes/ No (reason) 
xxx.xx 
xxxx 
Normal/ Abnormal CS/ Abnormal NCS 
 
 
 
Baseline 
Yes/ No (reason) 
xxx.xx 
xxxx 
Normal/ Abnormal CS/ Abnormal NCS 
 
 
 
Week 1* 
Yes/ No (reason) 
xxx.xx 
xxxx 
Normal/ Abnormal CS/ Abnormal NCS 
 
 
 
Etc 
 
xxx.xx 
xxxx 
Normal/ Abnormal CS/ Abnormal NCS 
 
 
 
 
 
 
 
 
 
 
xxx-xxxx 
Screening 
 
xxx.xx 
xxxx 
Normal/ Abnormal CS/ Abnormal NCS 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Outside the visit window 
CS=Clinically Significant; NCS=Non Clinically Significant 
 
Path\Filename  
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 86 of 101 
 
 
 
This layout also applies to: 
Listing 16.2.8.2 Laboratory Measurements: Biochemistry 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 87 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.1 Final Status 
 
Treatment 
Centre/ 
Patient 
number 
First 
dose date 
Last dose 
date 
Completed 
treatment 
Primary reason for 
discontinuation 
(specify) 
Was the randomisation code 
broken? (date and reason) 
Will subject enter follow-
up? 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx ddMMMyyyy 
ddMMMyyyy 
Yes/No 
xxxxxxxxxx 
(specify) 
Yes (ddMMMyyy; xxxxxx)/ No 
Yes/No 
 
xxx-xxxx ddMMMyyyy 
ddMMMyyyy 
Yes/No 
xxxxxxxxxx 
(specify) 
Yes (ddMMMyyy; xxxxxx)/ No 
Yes/No 
 
xxx-xxxx ddMMMyyyy 
ddMMMyyyy 
Yes/No 
xxxxxxxxxx 
(specify) 
Yes (ddMMMyyy; xxxxxx)/ No 
Yes/No 
 
xxx-xxxx ddMMMyyyy 
ddMMMyyyy 
Yes/No 
xxxxxxxxxx 
(specify) 
Yes (ddMMMyyy; xxxxxx)/ No 
Yes/No 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename  
Page x/y 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 88 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.2 Patient Visit Dates 
 
Treatment 
Centre/ Patient number 
Visit 
Date 
 
 
 
 
xxxxxx 
xxx-xxxx 
xx 
ddMMMyyyy 
 
 
xx 
ddMMMyyyy 
 
 
xx* 
ddMMMyyyy 
 
 
xx 
ddMMMyyyy 
 
 
 
 
Etc 
 
 
 
 
 
 
 
*Outside the visit window 
 
Path\Filename 
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 89 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.3.1 Inclusion Criteria 
Protocol version: XXXX 
Definition of criterion 
 
1 
xxxxxxxxxxxxxxxxx 
2 
xxxxxxxxxxxxxxxxx 
3 
Etc 
4 
 
5 
 
6 
 
7 
 
8 
 
Etc 
 
 
 
 
Path\Filename  
Page x/y 
 
 
 
Programmer’s Note: The list of criteria will be presented on the first page of the listing. Patient data will start on page 2. Repeat for 
each protocol amendment if the criteria change. 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 90 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.3.1 Inclusion Criteria 
 
Treatment Centre/ 
Protocol 
version 
Criteria 
 
Patient 
number 
1 
2 
3 
4 
5 
6 
7 
8 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-
xxxx 
x.xx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
xxx-
xxxx 
x.xx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
xxx-
xxxx 
x.xx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
xxx-
xxxx 
x.xx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename  
Page x/y 
 
 
 
This layout also applies to: 
Listing 16.4.3.2 Exclusion Criteria 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 91 of 101 
 
 
 
ABX464-301 
  
 
 
ddMMMyyyy 
Listing 16.4.4 Medical History 
 
Treatment 
Centre/  
Patient number 
Date of UC 
Diagnosis 
Any other 
conditions? 
Condition 
  SOC 
    PT 
Date of diagnosis Ongoing/ End date 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
ddMMMyyyy 
Yes/No 
xxxxxxxxxxxxxx 
  xxxxxxxxxxxx 
    xxxxxxxxxx 
ddMMMyyyy 
Yes/ No 
(ddMMMyyyy) 
 
 
ddMMMyyyy 
Yes/No 
xxxxxxxxxxxxxx 
  xxxxxxxxxxxx 
    xxxxxxxxxx 
ddMMMyyyy 
Yes/ No 
(ddMMMyyyy) 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename 
Page x/y 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 92 of 101 
 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.5.1 Raw Efficacy Data: Individual Components of the ACR20 Response 
 
Treatment Centre/ 
Patient 
number 
Visit  
C-Reactive 
Protein 
(CRP) (mg/L) 
Tender/ 
painful 
joint count 
(TJC) (28 
joints) 
Swollen 
joint count 
(SJC) (28 
joints) 
Patient 
assessment 
of joint 
pain (Pain-
VAS) 
Patient 
global 
assessment 
of disease 
(PtGA) 
Physician's 
Global 
Assessment 
of Disease 
(PrGA) 
HAQ-DI 
 
 
 
 
 
 
 
 
  
 
 
 
xxxxxx 
xxx-xxxx 
Baseline xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Etc* 
 
 
 
 
 
  
 
 
 
Etc 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
*Outside the visit window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename 
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 93 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.5.2 Raw Efficacy Data: ESR, DAS28-CRP, DAS28-ESR, SDAI Score, CDAI Score and FACIT-Fatigue Score 
 
*Outside the visit window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename 
Page x/y 
 
 
 
Treatment 
Centre/ 
Patient 
number 
Visit  
ESR 
DAS28-CRP 
DAS28-ESR 
SDAI Score 
CDAI Score 
FACIT-Fatigue Score 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
Baseline xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Etc* 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 94 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.5.3 Raw Efficacy Data: Different Responses and Remissions 
 
*Outside the visit window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename 
Page x/y 
 
 
Treatment 
Centre/ 
Patient 
number 
Visit  
Categorical 
DAS28-CRP 
response 
LDA 
DAS28-ESR 
remission 
ACR/EULAR 
remission 
SDAI remission 
CDAI remission 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
Baseline Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
Etc* 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 95 of 101 
 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.9 Vital Signs 
 
Treatment 
Centre/ 
Patient 
number 
Visit 
Date of 
visit 
Body 
temperature 
(°C) 
Weight  
(kg) 
Systolic BP 
(mmHg) 
Diastolic BP 
(mmHg)  
Heart rate 
(beats/min) 
Respiratory 
rate (/min) 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
xx 
ddMMMyyyy 
xx.x 
xx.x 
xxx 
xxx 
xxx 
xx.x 
 
 
xx 
ddMMMyyyy 
xx.x 
xx.x 
xxx 
xxx 
xxx 
xx.x 
 
 
xx* 
ddMMMyyyy 
xx.x 
xx.x 
xxx 
xxx 
xxx 
xx.x 
 
 
xx 
ddMMMyyyy 
xx.x 
xx.x 
xxx 
xxx 
xxx 
xx.x 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Outside the visit window 
 
Path\Filename 
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 96 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.10 Physical Examination 
 
Treatment Centre/ 
Patient 
number 
Visit 
Date of 
Visit 
Body system 
Status 
Abnormality 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
Screening 
ddMMMyyyy 
Eyes 
Normal/ Abnormal NCS/ 
Abnormal CS/ Not done 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Ear/Nose/Throat 
Normal/ Abnormal NCS/ 
Abnormal CS/ Not done 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Lungs/Thorax 
Normal/ Abnormal NCS/ 
Abnormal CS/ Not done 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
xx* 
ddMMMyyyy 
Eyes 
Normal/ Abnormal NCS/ 
Abnormal CS/ Not done 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Outside the visit window 
CS=Clinically Significant; NCS=Non Clinically Significant 
 
Path\Filename  
Page x/y 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 97 of 101 
 
 
 
 
ABX464-301 
 
 
 
 
 
 
ddMMMyyyy 
Listing 16.4.11 12-Lead Electrocardiogram 
 
Treatment Centre/ 
Patient 
number 
Visit 
Date of 
visit 
Time 
PR interval 
(msec) 
QRS width 
(msec) 
QT interval 
(msec) 
QTc interval 
(msec) 
Investigator’s 
interpretation 
Abnormality 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-
xxxx 
Baseline ddMMMyyyy hh:mm xx 
xx 
xx 
xx 
Normal/ 
Abnormal NCS/ 
Abnormal CS 
xxxxxxxxxxx 
 
 
Week 8 
ddMMMyyyy hh:mm xx 
xx 
xx 
xx 
Normal/ 
Abnormal NCS/ 
Abnormal CS 
xxxxxxxxxxx 
 
 
Etc* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Outside the visit window 
CS=Clinically Significant; NCS=Non Clinically Significant 
 
Path\Filename 
Page x/y 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 98 of 101 
 
 
 
ABX464-301 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ddMMMyyyy 
Listing 16.4.12.1 Prior Medications 
 
Treatment Centre/ 
Patient 
number 
Therapy 
  ATC Code 
    PT 
Indication Dose Unit Frequency Route Start date 
(Stop date / 
Ongoing) 
Given for pre-
existing 
condition 
(Related medical 
history number) 
Given for 
adverse event?  
(Related adverse 
event number) 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
xxxxxxxxxxxxxxx 
  xxxxxxxxxxxxx 
    xxxxxxxxxxx 
xxxxxxx 
xx.x xxx 
xxx 
xxx 
ddMMMyyyy 
(ddMMMyyyy) 
Yes (xxx) / No 
Yes (xxx) / No 
 
 
xxxxxxxxxxxxxxx 
  xxxxxxxxxxxxx 
    xxxxxxxxxxx 
xxxxxxx 
xx.x xxx 
xxx 
xxx 
ddMMMyyyy 
(ddMMMyyyy) 
Yes (xxx) / No 
Yes (xxx) / No 
 
 
xxxxxxxxxxxxxxx 
  xxxxxxxxxxxxx 
    xxxxxxxxxxx 
xxxxxxx 
xx.x xxx 
xxx 
xxx 
ddMMMyyyy 
(ddMMMyyyy) 
Yes (xxx) / No 
Yes (xxx) / No 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path\Filename  
 
 
Page x/y 
 
This layout also applies to: 
Listing 16.4.12.2 Concomitant Medications (Programming note: can have stop date as ‘ongoing’) 
Listing 16.4.12.3 Changes to Medications  
 
 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 99 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.13 Pregnancy Test 
 
Treatment 
Centre/ 
Patient number 
Visit 
Test done 
Reason not done 
Date of test 
Result 
 
 
 
 
 
 
 
xxxxxx 
xxx-xxxx 
Screening 
Yes/No/Not 
applicable 
xxxxxxxxxxxxx 
ddMMMyyyy 
Positive/Negative 
 
 
xx 
Yes/No/Not 
applicable 
xxxxxxxxxxxxx 
ddMMMyyyy 
Positive/Negative 
 
 
xx* 
Yes/No/Not 
applicable 
xxxxxxxxxxxxx 
ddMMMyyyy 
Positive/Negative 
 
 
xx 
Yes/No/Not 
applicable 
xxxxxxxxxxxxx 
ddMMMyyyy 
Positive/Negative 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Outside the visit window 
 
Path\Filename  
Page x/y 
 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 100 of 101 
 
 
 
ABX464-301 
ddMMMyyyy 
Listing 16.4.14 Laboratory Samples Collection 
 
Parameter 
Treatment 
Centre/ 
Patient 
number 
Visit 
Sample 
taken 
Reason not 
done 
Date of 
test 
Result 
Interpretation 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxx 
xxx-xxxx 
Screening 
Yes/No 
xxxxxxxxxxxxx 
ddMMMyyyy 
xx 
Normal/ Abnormal CS/ Abnormal NCS 
 
 
 
xx 
Yes/No 
xxxxxxxxxxxxx 
ddMMMyyyy 
xx 
Normal/ Abnormal CS/ Abnormal NCS 
 
 
 
xx* 
Yes/No 
xxxxxxxxxxxxx 
ddMMMyyyy 
xx 
Normal/ Abnormal CS/ Abnormal NCS 
 
 
 
xx 
Yes/No 
xxxxxxxxxxxxx 
ddMMMyyyy 
xx 
Normal/ Abnormal CS/ Abnormal NCS 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Outside the visit window 
CS=Clinically Significant; NCS=Non Clinically Significant 
Path\Filename  
Page x/y 
 


ABIVAX ABX464-301 
 
 
   Statistical Analysis Plan 
 
 
 
 
Version date: 10 December 2020 
Page 101 of 101 
 
 
 
16 APPENDICES 
16.1 STUDY FLOWCHART  
 
Screening 
Period 
 
Study Treatment Period 
Follow-
up 
Period 
 
D-30 to D-1 
D0 
D7 
D14 
D28 
D56 
D84 
D105 
 
 
W0 
W1 
W2 
W4 
W8 
W12 
W15 
Time 
Window 
(time 
between 
two 
visits≤30 days)  
 
 
± 2 days 
± 2 
days 
± 2 days ± 2 days ± 2 days 
± 2 days 
 
Screening Baseline 
V1  
V2 
V3 
V4 
V5 
EOS 
Obtained Inform Consent 
X 
 
 
 
 
 
 
 
Check of IN/EX Criteria 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Height Measurement (cm) 
X 
 
 
 
 
 
 
 
Body Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12 lead) 
X 
X 
 
 
 
 
X 
X* 
Blood Pregnancy test (WOCBP) 
X 
 
 
 
X 
X 
X 
X 
Urine Pregnancy test (WOCBP) 
 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
ABX464/placebo treatment dispensation 
 
X 
 
 
X 
X 
 
 
Hematology + Biochemistry# 
X# 
X 
X 
X 
X 
X 
X 
X 
Blood samples drug PK (pre-dose) 
 
 
 
X 
 
X 
 
X** 
Blood samples drug PK  
(1- , 2- & 3- hours post-dose) 
 
X 
 
X 
 
X 
 
 
Blood samples for Cytokines (gel tube) 
 
X 
X 
X 
X 
X 
X 
 
Blood samples for Cytokines (Truculture®
tube)  
 
X 
 
 
 
X 
 
 
Blood samples for flow cytometry cells 
count*** 
 
X 
 
 
 
X 
 
 
Blood samples for CRP, ESR 
X 
X 
X 
X 
X 
X 
X 
 
Blood samples for miR-124 (Paxgene® 
tube) 
 
X 
 
 
 
X 
 
 
Tender Joint Count (28) 
X 
X 
 
X 
X 
X 
X 
 
Swollen Joint Count (28) 
X 
X 
 
X 
X 
X 
X 
 
Patient Global Assessment of Disease 
(PtGA-VAS) 
X 
X 
 
X 
X 
X 
X 
 
Patient assessment of Joint Pain (Pain-
VAS) 
 
X 
 
X 
X 
X 
X 
 
Investigator 
Global 
Assessment 
of 
Disease (PrGA-VAS) 
 
X 
 
X 
X 
X 
X 
 
Health 
Assessment 
Questionnaire 
– 
Disease Index (HAQ-DI) 
 
X 
 
X 
X 
X 
X 
 
Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue 
 
X 
 
X 
X 
X 
X 
 
Patient diary (dispensation/check) 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events recording 
X 
X 
X 
X 
X 
X 
X 
X 
Follow_up Headache Questionnaire in 
case of persistent headache (see section 
5.3.2) 
 
X (throughout the study, if needed) 
Dermatologist consultation in case of skin 
effect (see section 5.3.2) 
 
X (throughout the study, if needed) 
#Tests of TB, HIV, HCV, HBV only at screening; *ECG at EOS visit in case of early termination only; **trough levels PK samples; 
***Only in French Coordinating Investigator’s Site; Two visits should not be conducted more than 30 days apart