A Phase 2/3, Randomized, Double Blind, Placebo-controlled Study to Evaluate the Efficacy and the Safety of ABX464 in Treating Inflammation and Preventing COVID-19 Associated Acute Respiratory Failure in Patients Aged ≥ 65 and Patients Aged ≥18 With at Least One Additional Risk Factor Who Are Infected With SARS-CoV-2.
Phase: PHASE2
Conditions: COVID-19
Sponsor: Abivax S.A.

PRO0027 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
ABX464-401 (MiR-AGE Study) 
 
Sponsor: 
ABIVAX 
 
5, rue de la Baume 
 
75008 Paris 
 
FRANCE 
 
Investigational product: 
 
ABX464  
Product code: 
 
ABX464 
Therapeutic indication: 
 
Adult patients infected by SARS-CoV-2 with high-risk of COVID-19 associated 
respiratory failure 
Study code: 
 
 
ABX464-401 
EudraCT number: 
 
2020-001673-75 
Phase 
 
 2/3 
Protocol title:  
 
A phase 2/3, randomized, double blind, placebo-controlled study to evaluate the 
efficacy and the safety of ABX464 in treating inflammation and preventing COVID-19 
associated acute respiratory failure in patients aged ≥ 65 and patients aged ≥18 with 
at least one additional risk factor who are infected with SARS-CoV-2. (the MiR-AGE 
study). 
Document version number: 
4.0  
Release date: 
 
 
26-Jan.-2021 
 
 
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 
 

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Study code: ABX464-401 
 
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CLINICAL STUDY PROTOCOL VALIDATION PAGE 
Study code 
ABX464-401 
EudraCT number 
2020-001673-75 
Detailed Title 
A phase 2/3, randomized, double blind, placebo-controlled study to evaluate the efficacy 
and the safety of ABX464 in treating inflammation and preventing COVID-19 associated 
acute respiratory failure in patients aged ≥ 65 and patients aged ≥18 with at least one 
additional risk factor who are infected with SARS-CoV-2. (the MiR-AGE study). 
Document date & version 
26-Jan.-2021 – Version 4.0  
Validation 
Prof. Hartmut J. Ehrlich, M.D. (CEO, CMO):  
 
 
Date: 
Paul GINESTE (VP, Clin Ops): 
 
 
Date:  
Alexandra Pearce (VP, Regulatory Affairs): 
 
 
Date:  
 

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Study code: ABX464-401 
 
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CONTACTS 
Sponsor 
ABIVAX 
5 rue de la Baume 
75008 PARIS - France 
Prof. Hartmut J. Ehrlich, M.D.  
CEO, Chief Medical Officer 
Cell: +33 (0)6 15 16 20 19 
Dr Paul GINESTE 
VP, Clinical Operations 
Cell: + 33 (0)6 25 83 07 83 
 
Coordinating investigator (EU) 
Dr. Eric CUA 
CHU de Nice - Hôpital Archet 1 
CS 23079 
151 route de St Antoine de Ginestière 
06202 NICE cedex 3 
FRANCE 
Tel. : +33 (0)4 92 03 54 67 
Central Laboratory 
Hematology Department 
Inserm UMR-S 1140 (Team 1) and Director of Biosurgical Research 
Lab (Carpentier Foundation) 
Paris Descartes University and European Georges Pompidou 
Hospital, Paris, France 
miRNA-124 determination  
Acobiom 
Cap Delta,  
1682 Rue de la Valsière,  
34790 Grabels – France  
Quantitative analysis of SARS-CoV-2 
Hematology Department 
Inserm UMR-S 1140 (Team 1) and Director of Biosurgical Research 
Lab (Carpentier Foundation) 
Paris Descartes University and European Georges Pompidou 
Hospital, Paris, France  
Pharmacovigilance 
IntuVigilance Limited 
Scotsbridge House, Scots Hill 
Rickmansworth WD3 3BB 
Hertfordshire – UK 
 
 
 

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INVESTIGATOR AGREEMENT PAGE 
 
EudraCT number 
 
2020-001673-75 
Detailed Title:  
A phase 2/3, randomized, double blind, placebo-controlled study to evaluate the 
efficacy and the safety of ABX464 in treating inflammation and preventing 
COVID-19 associated acute respiratory failure in patients aged ≥ 65 and patients 
aged ≥18 with at least one additional risk factor who are infected with SARS-CoV-
2. (the MiR-AGE study). 
 
 
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 ICH GCP (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, EudraLex GMP guidelines Annex 13, 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:   
 
 
 
________________________________________ 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL VALIDATION PAGE 
2 
CONTACTS 
3 
INVESTIGATOR AGREEMENT PAGE 
4 
TABLE OF CONTENTS 
5 
ABBREVIATIONS 
7 
SYNOPSIS 
8 
1. 
INTRODUCTION AND STUDY RATIONALE 
16 
1.1. 
SARS-COV-2 INFECTION 
16 
1.2. 
MANAGEMENT OF PATIENTS 
16 
1.3. 
STUDY RATIONALE 
16 
1.4. 
INVESTIGATIONAL TREATMENT DESCRIPTION 
17 
1.4.1. 
INVESTIGATIONAL PRODUCT DESCRIPTION 
18 
1.4.2. 
INVESTIGATIONAL PRODUCT MODE OF ACTION 
18 
1.6. 
PREVIOUS CLINICAL EXPERIENCE WITH ABX464 
22 
1.7. 
DOSE JUSTIFICATION 
22 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
23 
2.1. 
PRIMARY OBJECTIVE AND ENDPOINT 
23 
2.2. 
SECONDARY OBJECTIVES AND ENDPOINTS 
23 
3. 
INVESTIGATIONAL PLAN 
25 
3.1. STUDY DESIGN AND METHODOLOGY 
25 
3.2. DOSE LIMITING TOXICITY (DLT) 
26 
3.3. DATA AND SAFETY MONITORING BOARD 
26 
3.4. STEERING COMMITTEE 
26 
3.5. 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 
30 
5.2.1. 
VISIT 1 – DAY 0 (D0 / BASELINE) 
30 
5.2.2. 
FOLLOW-UP OF OUT-PATIENTS BETWEEN D0 AND D14 
31 
5.2.3. 
VISIT 2 – DAY 7 (+/- 2 DAYS) 
31 
5.2.4. 
VISIT 3 & 4 – DAY 14 & 21 (+/- 2 DAYS) 
32 
5.2.5. 
VISIT 5 / END OF TREATMENT VISIT (EOT) – DAY 28 (+/- 2 DAYS) 
32 
5.2.6. 
VISIT 6 / END OF STUDY VISIT (EOS) – DAY 48 (+/- 2 DAYS) 
33 
5.2.7. 
VISIT 7 – 3-MONTHS FOLLOW-UP VISIT (+/- 7 DAYS) 
33 
5.2.8. 
UNSCHEDULED VISIT 
33 
5.3. 
DETAIL OF THE STUDY ASSESSMENTS 
34 
5.3.1. 
PHYSICAL EXAMINATION AND VITAL SIGNS 
34 
5.3.2. 
ADVERSE EVENTS OF INTEREST 
34 
5.3.3. 
PREGNANCY 
34 
5.3.4. 
ECG 
35 
5.3.5. 
CHEST CT-SCANS 
35 
5.3.6. 
RESPIRATORY FUNCTION EXPLORATION 
35 
5.3.6.1. 
MEDICAL RESEARCH COUNCIL (MRC) DYSPNEA SCALE 
35 
5.3.6.2. 
PFT AND CMDC ASSESSMENT (OPTIONAL PROCEDURES) 
35 
5.3.7. 
LABORATORY PARAMETERS 
36 
5.3.7.1. 
MIRNA-124 MODULATION 
36 
5.3.7.2. 
VIRAL LOAD ASSESSMENT 
36 
5.3.7.3. 
LYMPHOCYTE PHENOTYPING, CYTOKINE SERUM CONCENTRATIONS 
36 
5.3.8. 
VOLUME OF BLOOD SAMPLING. 
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 
39 
6.6. 
PACKAGING 
40 
6.7. 
STORAGE 
40 
6.8. 
PRODUCT ACCOUNTABILITY 
40 
6.9. 
PRIOR AND CONCOMITANT MEDICATION 
40 
6.9.1. 
ALLOWED CONCOMITANT TREATMENT 
40 

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6.9.2. 
PROHIBITED CONCURRENT MEDICATIONS 
40 
7. 
STUDY COMPLETION 
41 
7.1. 
PATIENT COMPLETION 
41 
7.2. 
PATIENT PREMATURE TRIAL DISCONTINUATION 
41 
7.3. 
BASELINE FAILURES 
41 
7.4. 
STUDY DISCONTINUATION 
42 
7.5. 
END OF TRIAL 
42 
8. 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) 
43 
8.1. 
DEFINITIONS 
43 
8.1.1. 
DEFINITION OF AN ADVERSE EVENT (AE) 
43 
8.1.2. 
DEFINITION OF AN ADVERSE DRUG REACTIONS (ADR) 
43 
8.1.3. 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) OR SERIOUS ADVERSE DRUG REACTION (SADR) 
43 
8.1.4. 
DEFINITION OF A SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) 
44 
8.2. 
EVENTS AND/OR OUTCOMES NOT QUALIFYING AS SAES 
44 
8.3. 
EVENTS OR OUTCOMES QUALIFYING AS AES OR SAES 
44 
8.3.1. 
COVID-19 RELATED AE/SAES 
44 
8.3.2. 
CLINICAL LABORATORY PARAMETERS 
44 
8.3.3. 
PREGNANCY REPORT 
44 
8.4. 
ADVERSE EVENTS FROM PREVIOUS CLINICAL TRIALS 
45 
8.5. 
TIME PERIOD, AND FREQUENCY OF DETECTING AES AND SAES 
45 
8.6. 
RECORDING AES AND SAES 
45 
8.7. 
REPORTING OF SAES TO ABIVAX OR ITS DESIGNEE 
46 
8.8. 
REPORTING OF SAES TO REGULATORY AUTHORITIES 
46 
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. 
SAFETY ANALYSES 
48 
9.3. 
EFFICACY ANALYSIS 
49 
9.3.1. 
GENERALITIES 
49 
9.3.2. 
ANALYSIS OF PRIMARY EFFICACY ENDPOINT 
49 
9.3.3. 
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS 
50 
9.4. 
CLINICAL LABORATORY EVALUATION 
51 
9.5. 
DETERMINATION OF SAMPLE SIZE 
51 
9.6. 
MULTIPLICITY ADJUSTMENT: 
51 
9.7. 
INTERIM ANALYSIS AND OVERALL CONTROL OF TYPE I ERROR RATE AND SAMPLE SIZE REASSESSMENT: 
51 
10. 
STUDY CONDUCT CONSIDERATION 
53 
10.1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
53 
10.1.1. 
GENERAL REQUIREMENTS 
53 
10.1.2. 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
53 
10.1.3. 
PATIENT INFORMED CONSENT 
53 
10.1.4. 
COMPENSATION TO PATIENTS 
54 
11. 
STUDY MANAGEMENT 
55 
11.1. 
REMOTE DATA ENTRY 
55 
11.2. 
DATA MANAGEMENT 
55 
11.3. 
DATA CODING 
55 
11.4. 
RANDOMIZATION 
55 
11.5. 
STUDY MONITORING 
55 
11.6. 
RECORDS RETENTION 
56 
11.7. 
QUALITY ASSURANCE AND INSPECTION BY AUTHORITIES 
56 
11.8. 
STUDY AND SITE CLOSURE 
57 
11.9. 
STUDY REPORT AND PUBLICATION 
57 
11.10. 
OWNERSHIP AND CONFIDENTIALITY 
57 
12. 
REFERENCES 
58 
13. 
APPENDICES 
59 
13.1. APPENDIX 1: CYPIA2 SUBSTRATES 
59 
13.2. APPENDIX 2: IMMUNOSUPPRESSORS AND/OR IMMUNOMODULATORS 
59 
 
 

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ABBREVIATIONS 
Abbreviation or Term 
Definition 
ABX 
Abivax 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvate transaminase 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
BMI 
Body Mass Index  
CBC 
Cap Binding Complex 
CI 
Confidence Interval 
Cmax 
peak plasma concentration 
CMDC 
Carbon Monoxide Diffusing Capacity 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
COVID-19 
Corona Virus Disease provoked by SARS-CoV-2 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CTC-AE 
Common Terminology Criteria for Adverse Events, version 5.0 
CTFG 
Clinical Trial Facilitation Group 
CYP 
Cytochrome 
DBP 
Diastolic Blood Pressure  
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
FEV 
Forced Expiratory Volume 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
GHAS 
Global Histological Assessment Score 
GLDH 
Glutamate Dehydrogenase 
GM 
Geometric Mean 
H 
Hours 
HIV 
Human Immunodeficiency Virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
IBD 
Inflammatory Bowel Disease 
ICF 
informed consent form  
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL-X 
Interleukine X 
IMP 
Investigational Medicinal Product 
IMV 
Invasive Mechanical Ventilation 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
Min 
Minimum 
miR 
micro-RNA 
mL 
Milliliter 
mmHg 
millimeters of mercury 
NIV 
Non-Invasive mechanical Ventilation 
NOAEL 
No Observed Adverse Effect Level 
o.d. 
Once Daily 
PCSA 
potentially clinically significant abnormalities 
PD 
Pharmacodynamics 
PFT 
Pulmonary Function Test 
PK 
Pharmacokinetics 
PT 
Preferred Term 
QoL 
Quality of Life 
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 
R 
Accumulation ratio 
RNA 
Ribonucleic Acid 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
system organ class 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
t1/2 
terminal half-life 
TB 
Tuberculosis 
TEAE 
treatment emergent adverse event 
tmax 
time to peak plasma concentration 
TMS 
Total Mayo Score 
TNF 
Tumor Necrosis Factor 
UC 
Ulcerative Colitis 
ULN 
Upper Limit Normal 
VC 
Vital Capacity 
Vd/F 
volume of distribution 
vs. 
Versus 
W 
Week 
 
 

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SYNOPSIS 
Study n° 
ABX464-401 
Clinical Phase 
2/3 
 
 
Type of Study 
Efficacy, Safety Study 
Study title 
A phase 2/3, randomized, double blind, placebo-controlled study to evaluate the efficacy and the safety 
of ABX464 in treating inflammation and preventing COVID-19 associated acute respiratory failure in 
patients aged ≥ 65 and patients aged ≥18 with at least one additional risk factor who are infected with 
SARS-CoV-2. (the MiR-AGE study). 
Short title 
Phase 2/3 study of ABX464, once daily oral capsule, in high risk patients infected by SARS-CoV-2 prior 
to COVID-19 associated respiratory distress. 
Investigators 
and study 
centers 
Approximately 75 sites (either hospital, or nursing home linked to hospital) located in Europe and Latin 
America will participate in the study. 
 
Study Duration 
Recruitment period: 
Jul. 2020 – Apr. 2021 (10 months) 
Overall Study period: 
Jul. 2020 – Jul. 2021 (13 months) 
Investigational 
product 
Clinically, SARS-CoV-2 or COVID-19 infection can lead to a cytokine storm syndrome, acute respiratory 
distress syndrome (ARDS) and multiple organ failure. The hyperinflammatory syndrome associated with 
COVID-19 disease severity includes increased MCP1, IL-1b, TNFa, IL-17, G-CSF and IL-6 levels. 
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 fueling 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, a well-known physiological inhibitor of systemic and pulmonary 
inflammation (potent reduction of MCP1, IL-1b, TNFa, IL-17, G-CSF and IL-6). 
ABX464 has anti-inflammatory properties in Dextran Sulfate Sodium (DSS) induced colitis and collagen 
induced rheumatoid arthritis models, with good systemic and tissue bioavailability in blood, lung, kidney 
and brain. Administration of ABX464 has demonstrated clinical efficacy in patients with moderate to 
severe Ulcerative Colitis (UC).  
In addition, ABX464 has recently been tested in primary pulmonary cells infected by with SARS-CoV-2 
(MucilAir cells). At 48h post infection, the viral load measured in the supernatant by qPCR was reduced 
by 1 log with ABX464 and even 2 logs with its active metabolite: ABX464-N-glucuronide. 
ABX464 was safe and well tolerated in more than 300 volunteers and patients in phase 1 and 2 clinical 
trials some of whom have been treated for over two years. 
Study 
Design 
and 
Methodology 
 
This phase 2/3 study will evaluate the efficacy and safety of ABX464 50mg QD (oral capsule), on treating 
inflammation and preventing acute respiratory failure in patients infected with SARS-CoV-2. 
Eligible patients will be randomized according to a 2:1 ratio into 2 treatment cohorts as follows: 
- 
Standard of Care + Placebo cohort: 267 patients 
- 
Standard of Care + ABX464 50mg QD: 533 patients 
Upon randomization, patients will be stratified according to:  
- 
Age ≥ 65 years or < 65 years (with at least one risk factor) 
- 
Inpatient or outpatient, at the time of enrolment 
Study design: 
The study will consist of 2 periods: 
- 
Treatment phase: randomized patients will be treated for 28 days  
- 
Safety follow-up phase of 21 days  
- 
Exploratory follow-up of the pulmonary function 3 months after the last study drug intake.  

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Study n° 
ABX464-401 
Clinical Phase 
2/3 
 
 
Type of Study 
Efficacy, Safety Study 
 
From Day 0 onwards, randomized patients will be followed by the investigational site at 7 days (D7 +/- 2 
days), 14 days (D14 +/- 2 days), 21 days (D21+/- 2 days) and finally 28 days (D28 +/- 2 days) after 
randomization.  
Should a patient be hospitalized at D0, Day 7 visit will be an on-site visit. 
Should a patient not be hospitalized, considering a quarantine period might be applied for infected 
patients, a remote medical monitoring will be performed by the investigator or his designee every 2 
days from D0 and until D14. Every attempt to perform the Day 7 on-site visit should be made anyway. 
For outpatients, an oximeter will be provided at Day 0. During the remote medical monitoring, the 
patient will be asked to self-measure every day the oxygen saturation, body temperature and will be 
asked for any potential signs of COVID-19 infection worsening. Subsequent, D14, D21 and D28 will 
be on-site visits. 
If no quarantine period is applied or if patient migration to the study site is acceptable as per local 
regulation, outpatients will perform a D7 visit on-site, and the same examinations as hospitalized 
patients will be done. 
At randomization visit, all patients must have been diagnosed for SARS-CoV-2 infection by PCR or Rapid 
Antigen tests either performed on site or in a private laboratory prior to the visit. The time between PCR 
or Rapid Antigen tests diagnosis and first study drug intake should not exceed 48 hours. 
A long-term follow-up is scheduled as an onsite visit for patients having been hospitalized during the 
course of the study. This follow-up will be performed 3 months after the last study drug intake and will 
consist of a respiratory function exploration. In addition, investigators will report the disease severity rating 
using a 7-point ordinal scale. 
For patients with no hospitalization during the course of the study, a remote follow-up will be performed 
by phone and will take place 3 months after the last study drug intake. During this contact, the site will 
collect patients’ survival status. 
Approximately 800 patients will participate in this study. However, following the interim analysis the 
sample size may be extended to 1034 patients maximum. 
Study 
Objectives and 
endpoints 
Primary Objective and endpoint: 
 
The primary objective of the study is to determine the efficacy of ABX464 50mg to prevent respiratory 
failure or death in study patients. 
− 
Rate of patients who do not require use of high-flow oxygen (use of high-flow oxygen being 
defined as settings of 3 L/min or greater AND with at least one SpO2 measurement < 92%, with 

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Study n° 
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Clinical Phase 
2/3 
 
 
Type of Study 
Efficacy, Safety Study 
or without O2 supplementation) or, invasive or non-invasive mechanical ventilation (IMV and 
NIV, respectively) within 28 days and who are alive at the end of the 28 days period. 
Secondary Objectives and endpoints: 
 
The secondary objectives are: 
To evaluate the proportion of patients requiring hospitalization during the study compared to the 
{Standard of care + placebo} group 
− 
Rate of patients hospitalized 
To assess the proportion of patients reporting each severity rating on a 7-point ordinal scale 
during the course of the study compared to the {Standard of care + placebo} group 
− 
Percentage of patients reporting each severity rating on a 7-point ordinal scale at each study 
visit (i.e. Not hospitalized, no limitations on activities; Not hospitalized, limitation on activities; 
Hospitalized, not requiring supplemental oxygen; Hospitalized, requiring supplemental oxygen; 
Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, on invasive 
mechanical ventilation or ECMO; Death);  
To assess the time to an improvement of one category of the 7-point on an ordinal scale from baseline, 
compared to the {Standard of care + placebo} groups 
− 
Change in the ranking on an ordinal scale from baseline to days 7, 14, 21, 28, 48 and at 4 months 
To evaluate and compare the effect of ABX464 on oxygen saturation before hospitalization 
− 
% change and AUC over time of oxygen saturation measured by daily pulse oximetry before 
hospitalization 
To evaluate and compare the effect of ABX464 on oxygen saturation level at the end of the study 
treatment 
− 
Rate of patients with SpO2 ≤94% and rate of patients with SpO2 ≤92% at Day 28 
To evaluate and compare the effect of ABX464 on immunophenotyping (in selected sites only) and 
cytokines levels during the study in patients enrolled in both treatment groups. 
− 
Change from enrolment in inflammatory markers in plasma (i.e. MCP-1, MIP-1 α, G-CSF, IL-1b, 
IL-2, IL-6, IL-7, IL-10, IL-17, INFg and TNFa) and in immune phenotype and assessment of cell-
activation markers in PBMCs at D14, D28. 
To evaluate the proportion of patient requiring oxygen supplementation (>3L/min) during the study 
compared to the {Standard of care + placebo} group. 
− 
Rate of patients requiring oxygen supplementation 
To assess the time to hospitalization (all causes and Covid-19 related hospitalization) during the study 
compared to {Standard of care + placebo} treated group. 
− 
Time to hospitalization from baseline. 
To evaluate the time to application of invasive and non-invasive mechanical ventilation (IMV and NIV, 
respectively) or high flow oxygen therapy excluding simple oxygen supplementation) and oxygen 
supplementation during the study compared to {Standard of care + placebo} treated group. 
− 
Time to assisted ventilation and oxygen supplementation (log rank) from baseline. 
To assess the IMV and/or NIV duration compared to {Standard of care + placebo} treated group. 
− 
Number of days of assisted ventilation. 
To assess the oxygen supplementation (>3L/min) duration compared to {Standard of care + placebo} 
treated group. 
− 
Number of days of oxygen supplementation. 

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Study n° 
ABX464-401 
Clinical Phase 
2/3 
 
 
Type of Study 
Efficacy, Safety Study 
To assess the hospital stay duration in both treatment groups for patients hospitalized because of Covid-
19 infection consequences compared to {Standard of care + placebo} treated group. 
− 
Number of days at the hospital from admission to discharge. 
To evaluate the effect of ABX464 on miR-124 expression in whole blood (PAXgene®) vs placebo (in 
selected sites and in hospitalized patients). 
− 
Change from baseline in microRNA-124 levels in total blood (PAXgene®) at D0, D7 and D28. 
To assess the change over time in CRP, Troponin I & T and D-dimer levels compared to {Standard of 
care + placebo} group. 
− 
AUC and % of change from enrolment in CRP, Troponin I & T and D-dimer levels. 
To evaluate the prevention of Covid-19 related deaths compared to {Standard of care + placebo} group  
− 
Time to death and mortality rate (all causes, and Covid-19 related). 
To evaluate the improvement in the 7-point ordinal scale during the course of the study compared to 
{Standard of care + placebo} group. 
− 
Time to improvement of one level in è-point ordinal scale. 
To evaluate SARS-CoV-2 infection in subjects during the course of the study compared to {Standard of 
care + placebo} group. 
− 
SARS-CoV-2 virus in nasopharyngeal sample and/or in blood at Day 0, 7 (hospitalized patients), 
14, 21, and 28. 
To evaluate outpatients SpO2 evolution from D0 to D14  
− 
Change in SpO2 values from D0 to D14 in the outpatient’s population. 
To evaluate the long-term effect of ABX464 on all cause mortality from first study drug intake to 3-months 
follow-up visit  
− 
Rate of participants deceased during the course of the study and follow-up, and time to event 
(in weeks).  
To evaluate the safety of ABX464 in study patients (from D0 to D48) 
− 
Number and rates of participants with Treatment Emergent Adverse Event 
− 
Cumulative incidence of serious adverse events (SAEs) including serious adverse drug 
reactions (SARs) and suspected unexpected serious adverse reactions (SUSARs)  
− 
Cumulative incidence of Grade 3 and 4 adverse events (AEs) 
− 
Number of participants with a discontinuation or temporary suspension of study drugs (for any 
reason) 
 
Exploratory criteria: 
To assess the radiological findings for patients hospitalized because of Covid-19 infection consequences. 
− 
Central blinded review of the hospitalization discharge CT-Scans for descriptive analysis with 
regards to the disease severity and outcomes. 
To assess the long-term effect (4 months) of ABX464 on the respiratory function recuperation in patients 
having been hospitalized at least once throughout the study 
− 
Change from last dosing day in the Medical Research Council (MRC) dyspnea scale in the 
hospitalized patient’s population according to treatment group. 
− 
Optional: Change from last dosing day in Pulmonary Function Tests (PFT) (Forced Expiratory 
Volume (FEV) and slow and forced Vital Capacity (VC)) and Carbon Monoxide Diffusing 
Capacity (CMDC) tests in the hospitalized patients population according to treatment group. 
Main Selection 
criteria 
Inclusion criteria: 
A patient will be eligible to participate in this study if ALL the following criteria are met: 

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1. Adult (≥ 18 years old) men or women, hospitalized or not hospitalized, diagnosed for SARS-
CoV-2 infection by PCR or Rapid Antigen tests (approximately 48 hours prior to randomization), 
with at least one associated risk factor. Considered risk factors are: 
 
Age ≥ 65 years 
 
Obesity defined as BMI ≥ 30 
 
Recent history of uncontrolled High Blood Pressure  
 
Treated diabetes (type I or II) 
 
History of ischemic cardiovascular disease  
2. Symptomatic patients must present at least 1 of the following symptoms at enrollment: fever or 
perceived fever (for more than 24 hours, headache, sore throat, dry cough, fatigue, chest pain 
or choking sensation (with no associated respiratory distress), myalgia, anosmia, ageusia or 
gastro-intestinal symptoms. 
3. Patients with pulse oximetry arterial saturation (SpO2) ≥ 92 % on room air at enrolment. 
4. Patients with the following hematological and biochemical laboratory parameters obtained within 
7 days prior to D0: 
 
Hemoglobin > 9.0 g dL-1 
 
Absolute Neutrophil Count ≥ 1000 mm-3; 
 
Platelets ≥ 100,000 mm-3; 
 
Creatinine clearance ≥ 50 mL min-1 by the Cockcroft-Gault formula  
 
Total serum bilirubin < 2 x ULN 
 
Alkaline phosphatase < 2 x ULN, AST (SGOT) and ALT (SGPT) < 3 x ULN; 
5. Women of childbearing potential and men receiving the study treatment and their partners must 
agree to use a highly effective contraceptive method during the study and for 6 months (180 
days) after end of study or early termination. Contraception should be in place at least 2 weeks 
prior to enrolment. 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 during the trial and for 6 months post completion of their participation 
in the trial. In addition, male patients should use condom during the trial and for 6 months (180 
days) post completion of their participation in the study. Male patients must not donate sperm as 
long as contraception is required. For the purpose of this protocol, a woman is considered of 
childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Finally a man 
is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
6. Patients must understand, sign and date the written voluntary informed consent form at the visit 
prior to any protocol-specific procedures. 
7. Patients able and willing to comply with study visits and procedures as per protocol. 
8. Patients should be affiliated to a social security regimen (for French sites only). 
Exclusion Criteria: 
Patients who meet any of the following exclusion criteria will be excluded from the study: 

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1. Patients with moderate or severe acute respiratory failure or requiring non-invasive ventilation 
or oxygen or with SpO2 < 92% or tachypnea (respiratory rate ≥ 30 breaths/min). 
2. Patients treated with immunosuppressors and/or immunomodulators (cf. Appendix #2). 
3. Engrafted patients (organ and/or hematopoietic stem cells). 
4. Patients with uncontrolled auto-immune disease. 
5. Patients with known or suspected active (i.e. not controlled) bacterial, viral (excluding COVID-
19) or fungal infections. 
6. Patients with preexisting, severe and not controlled organ failure. 
7. History or active malignancy requiring chemotherapy or radiation therapy (excluding 2 years 
disease free survivor patients). 
8. Pregnant or breast-feeding women. 
9. Illicit drug or alcohol abuse or dependence that may compromise the patient's safety or 
adherence to the study protocol. 
10. Use of any investigational or non-registered product within 3 months or within 5 half-lives 
preceding baseline, whichever is longer. 
11. Hypersensitivity to ABX464 and/or its excipients. 
12. 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 with food. 
Allowed Concomitant medications 
The standard of care in non-hospitalized patients, according the WHO recommendations, consists 
mainly of symptomatic treatments and antibiotic therapies as appropriate at the physician’s discretion. 
The use of concomitant medications will be recorded in the eCRF. 
The standard of care in hospitalized patients may vary between sites and depends upon patient status 
and will remain at the physician’s discretion. 
Concomitant treatment with either corticosteroids (e.g. dexamethasone) or remdesivir is allowed 
providing they are part of a Standard of Care duly authorized in the respective countries where the 
study is conducted. 
Prohibited Concomitant Medications: 
 
Immunosuppressors and/or immunomodulators (cf. Appendix #2). 
 
Drugs that could interact with ABX464 should be avoided especially the CYP1A2 substrates (cf. 
Appendix #1). The following CYP1A2 substrates with a narrow therapeutic margin are prohibited 
during the whole course of the study (clozapine, theophylline, ropinirol, warfarin and methadone). In 
case of concomitant treatment with ondansetron the maximal daily dose must be limited to 8 mg. 
 
Inhibitors or inducers of the CYP1A2 (cf. Appendix #1). 
 
Use of any investigational or non-registered product within 3 months or within 5 half-lives before 
baseline, whichever is longer. 
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. Specifically, 
an elevation ≥ 3.0 x ULN in liver transaminases (AST/SGOT and/or ALT/SGPT), or Alkaline 
phosphatase or in total bilirubin compared to baseline requires close observation with repeating liver 
enzymes and serum bilirubin tests every 2 days. Discontinuation of the study treatment should occur 
if: 
• 
ALT or AST > 8xULN 
• 
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%). 

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• 
Alkaline phosphatase ≥ 2.0 x ULN 
 
Serious adverse event with suspected causal relationship to the IMP 
 
Any relevant toxicity or negative change in the risk/benefit assessment leading to an unacceptable 
risk for the patient (i.e. occurrence of adverse events which character, severity or frequency is new 
in comparison to the existing risk profile), or any data deriving from other clinical trials or toxicological 
studies which negatively influence the risk/benefit assessment.  
 
Major protocol violation. 
 
Withdrawal of consent. 
 
Administrative reasons from Sponsor. 
Patient Follow-
up  
After the End of Treatment visit (D28), patients will enter a phase of safety follow-up of 21 days (D48). 
Then a long-term follow-up 3 months after the last study drug intake will be done. During this period, 
should patients still need a treatment, the sites standard of care will be applied.  
After the visit or phone contact at 4 months, patients will exit the study and will be treated/follow-up 
according to the site standard of care. 
Sample Size 
calculation 
The primary efficacy endpoint is the rate of patients who do not require oxygen supplementation 
(>3L/min) or non-invasive mechanical ventilation (IMV and NIV, respectively) and who are alive at the 
end of the 28 days period.  
The primary endpoint will be compared between patients who received {Standard of care + ABX464} and 
{Standard of care + placebo}. 
For the sample size calculation, the following assumptions will be made: 
• 
Response rate (ABX464): 84 % 
• 
Response rate (placebo): 75 %  
• 
Type 1 error probability: 2.5% one-sided 
• 
2:1 (ABX464 50mg: placebo) study treatment allocation ratio.  
• 
One futility interim analysis after approximately 300 patients complete Day 28 assessment or 
reach end of study: non-binding futility criterion is a conditional power (calculated under observed 
effect) ≤ 10%.  
If the above assumptions hold true, then an initial total sample size of 800 patients will lead to a power of 
78%. At the interim analysis, a sample size re-assessment is planned, and the total sample size may be 
increased to 1034 patients 
Statistical 
Methods 
 
Interim analysis: 
One interim analysis is planned after approximately 300 patients complete the day 28 assessment or 
reach end of study.  
Safety monitoring will be performed in this study based on the DSMB and/or study steering committee 
recommendations at regular intervals of time.  
Efficacy:  
The primary efficacy endpoint will be analyzed by Mantel–Haenszel test (MH) stratified for factors used 
in the randomization. 
Descriptive statistics will be presented by treatment arm for all secondary efficacy variables for each 
measurement timepoint. Continuous variables: mean, standard deviation, minimum and maximum, 95% 
confidence intervals, median and quartiles will be presented when considered relevant. Categorical 
variables: Counts, rates and 95% CIs will be calculated. Time-to-event variables will be analyzed by 
Kaplan-Meier plots. In addition, an attempt will be made to compare the study groups in respect of 
changes from baseline in different measurements by mixed model analysis of covariance. 
Safety: 
Analysis of safety will be performed on the safety data set consisting in all patients who received at least 
one dose of ABX464 in the study. The 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 

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Study n° 
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Type of Study 
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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. 
Clinical laboratory parameters, vital signs, ECG will be summarized by using descriptive statistics (n, 
mean, SD, SEM, median, minimum and maximum). The number of patients with at least one abnormal 
value will be tabulated (counts and percentages) for each parameter in summary shift tables by group. 
End 
of 
trial 
definition 
The study will end once all the recruited patients have performed their safety follow-up and the long-term 
follow-up and all the data have been analyzed and computed in the clinical study report (CSR). As per 
the current study schedule, the CSR should be issued in Q2 2021. 

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1. INTRODUCTION AND STUDY RATIONALE 
1.1. SARS-CoV-2 infection 
Coronaviruses are a large family of viruses that are known to cause illness ranging from the common cold to more 
severe diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome 
(SARS). 
A novel coronavirus SARS-CoV-2 (previously known as 2019-nCoV) was identified in 2019 in Wuhan, China. This is 
a new coronavirus that has not been previously identified in humans. The precise etiology is unknown and therefore 
medical therapy to cure the disease is not yet available. 
The coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by this novel coronavirus, that 
shows sustained human-to-human transmission, and has been exported around the globe to reach pandemic 
proportion (1). The World Health Organization (WHO) officially declared the COVID-19 pandemic as a public health 
emergency of international concern. The novel coronavirus uses the same cell surface receptor, angiotensin-
converting enzyme 2 (ACE2) as SARS-CoV, for entry, and infects preferentially the respiratory tract where this receptor 
is expressed (2). The elderly and people with underlying diseases are most prone to serious outcomes, which appear 
to be associated with acute respiratory distress syndrome (ARDS) and cytokine storm syndrome (1). 
1.2. Management of patients 
Two therapeutic strategies are currently being explored: 
• 
To limit the spread of the COVID-19 infection by blocking the replication of the virus. This may be achieved 
through inhibition of the viral RNA dependent polymerase (RdRp) or by preventing the entry of the virus into 
pulmonary target cells or by serotherapy using immunized patient’s plasma, 
• 
To dampen the body’s inflammatory response in the pulmonary tract. 
Antiviral drugs for managing infection with human coronaviruses are not yet approved, posing a serious challenge to 
current global efforts aimed at containing the outbreak of COVID-19. Companies, including Gilead and AbbVie, are 
testing antiviral combination therapy, especially nucleoside analogues to block RdRp, and protease inhibitors in clinical 
trials, in order to block the entry of the virus into cells. Chloroquine is being evaluated based on its ability to block viral 
processes and maturation. 
Several companies, including Sanofi, Abbvie, Roche/Genetech, are testing monoclonal antibody therapy to block the 
inflammatory response by inhibiting individual inflammatory receptor pathways.  
Additional therapies focused on thromboembolic complications and standard intensive care treatments are also being 
studied. 
The response to each of these therapies is highly uncertain and, given the scope of this pandemic, other treatment 
options that more broadly target the immune “Cytokine Storm” syndrome must urgently be explored in well-designed 
clinical trials. 
1.3. Study rationale 
Developed initially as an inhibitor of HIV replication (3-5) and HIV reservoir reduction (6), ABX464 binds to the Cap 
Binding Complex (CBC) that regulates splicing and export of mRNA from the nucleus (3). ABX464-CBC interactions 
were shown to strengthen the RNA quality control of HIV-RNA biogenesis preventing the production of unspliced HIV 
RNA (3), thereby reducing the viral reservoirs of HIV infected patients (6). 
While capable of directly altering the splicing of ~0.1% of transcripts in cells, the examination of the effects of ABX464 
on the microRNA population using the Affymetrix Genechip microRNA array 2.0, and a TaqMan® Array Human 
microRNA for confirmation, showed that the selective expression of a single microRNA was significantly increased by 
ABX464: miR-124 (7). 
MicroRNAs are small noncoding RNAs that regulate gene expression by binding to the 3′ UTR of their target mRNAs 
to induce translational repression and mRNA deadenylation and decapping (8). As a result, microRNAs reduce 
expression of target genes by increasing degradation of the respective RNA and/or inhibiting their translation into 
proteins. Often, microRNAs regulate sets of genes belonging to the same pathway. 
miR-124 is transcribed from 3 genomic loci, locus 1 (exonic), locus 2 (monocistronic) and locus 3 (monocistronic). 
Studies have demonstrated that ABX464 induces miR-124 expression from locus 1 only. Locus 1 contains the long 

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non-coding RNA, lncRNA00599-205 from which miR-124 is derived by splicing. Mutation of the splice sites of 
lncRNA00599-205 prevented the overexpression of miR-124 with ABX464 treatment (7). 
The RNA targets of miR-124 have been shown to be related to the cytokine and pro-inflammatory response of innate 
immune cells, especially tissue-resident macrophages. The JAK-STAT pathway that is downstream of cytokine 
signaling is affected by miR-124, especially STAT3 (9), as is NFkB, the master transcription factor of pro-inflammatory 
responses (10). In addition, miR-124 has been shown to have a direct effect on the translational downregulation of 
MCP-1, monocyte chemoattractant protein (11), as well as the IL-6 receptor (10). In conjunction with these effects, the 
increase of miR-124 has been associated with the maintenance of the M2 differentiation of the tissue-resident 
macrophage. Indeed, M2 macrophages control tissue inflammation by producing type 2 cytokines such as IL-4 and 
IL-10, two mediators of tissue homeostasis (12). In summary, miR-124 is anti-inflammatory by reducing protein levels 
of these pro-inflammatory pathways, and also anti-proliferative by affecting some of the important cell cycle transcripts 
(10). 
In the mouse model of Dextran Sodium Sulphate (DSS) exposure in which colonic inflammation is triggered, ABX464 
demonstrated a marked decrease in the inflammatory colitis (13, 14). This effect was associated with prevention of 
proliferation of Th17 cells in both peripheral blood and mesenteric lymph nodes. Th17 cells, the CD4+ T-cell subset 
that produces interleukin-17 (IL-17) and are pro-inflammatory and are dependent on STAT3 for proliferation (15, 16). 
IL-17 is a highly inflammatory cytokine with robust effects on stromal cells in many tissues. ABX464 showed also 
efficacy in animal models related to rheumatoid arthritis (CIA mice model) as well as a good bioavailability in lung 
tissues. 
In addition, a reduction of SARS-CoV-2 replication in an in-vitro reconstituted human airway epithelial model showed 
comparable efficacy between remdesivir (5µM) and ABX464 (0.1, 1 and 5µM). 
 
Based on Day 1 human PK plasma data (Cmax) for ABX464, the concentration range used in this assay is achievable 
in human using the 50mg QD dose. The mean Cmax of ABX464 is approximatively 0.2µM. Furthermore, from the 
radiolabelled rat study (cf current version of IB), ABX464 is known to distribute in the whole body leading to a favourable 
exposure in lung tissue as presented in the table below. 
 
 
1 hour 
4 hours 
8 hours 
24 hours 
Plasma * 
0.461 
1.25 
1.18 
0.203 
Lung 
1.19 
1.89 
1.45 
0.457 
Numbers are in µg equivalents/g for all measurements. Concentrations of radioactivity in tissues of male albino rats after a single oral administration 
of [14C]-ABX464 at a nominal dose level of 20mg/kg body weight 
 
1.4. Investigational treatment description 
ABX464 is a novel, oral, safe and potent anti-inflammatory drug candidate, with impressive Phase 2a clinical results 
in ulcerative colitis. As described above, the drug candidate is in a Phase 2b clinical trial in Europe, Canada and in the 
US (IND 141396). 
More than 300 patients have been treated with ABX464 with a good safety profile; some patients have received 
ABX464 for over 2 years. 

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ABX464 selectively up-regulates a microRNA, mir-124, a physiological negative regulator of inflammation, that acts 
on several key pathways of inflammatory cytokines signaling, especially STAT3 (Signal Transducers and Activators 
of Transcription). Indeed, many Covid-19 patients develop acute respiratory distress syndrome (ARDS), which leads 
to pulmonary edema and lung failure (20). Elevated pro- inflammatory cytokines involved in Th17 responses in COVID-
19 infected patients may be the cause of vascular permeability and leakage (21). Attenuation of Th17 proliferation, in 
addition to its inhibition of inflammatory cytokines, by ABX464 could be a way to prevent the severe acute respiratory 
syndrome-related caused by Covid-19 infection. 
ABX464 has the potential to alter the clinical course of Covid-19 infection by limiting the body’s cytokine-mediated 
inflammatory response (cytokine storm). 
1.4.1. 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). 
1.4.2. Investigational product Mode of Action 
The mechanism of action of ABX464 in inflammatory conditions is mediated throughout the observed effect on miR-
124 observed in vitro and in patients. In addition, a reduction of SARS-CoV-2 replication in an in-vitro reconstituted 
human airway epithelial model showed comparable efficacy between remdesivir (5µM) and ABX464 (0.1, 1 and 5µM). 
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. In the presence of DSS, ABX464 compensated for most of the expression 
differences 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 anti-inflammatory cytokines: 
IL-6 (2x), TNF (7.5x) and MCP-1 (6x). 
In-Vitro assays 
 
Modulation of miR-124 by ABX464 
Study ABX464PHA011 performed in humans PBMCs ad monocyte-derived macrophages (huMDM)revealed that 
both ABX464 and its primary metabolite ABX464-N-Glu 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. 
 
Cytokines/chemokine modulation in huMDM 
ABX464 and ABX464-N-Glu treatment induced a significant decrease in pro­inflammatory proteins in HuMDM (IL-6, 
TNFa, IL-1b), but has no significant effect on the active form of IL-12 and IFNg. ABX464 and ABX464-N-Glu treatment 
resulted in a decrease of expression of adhesion and migration proteins (ICAM-1: responsible for tissue transmigration 
of leukocytes, MIF: responsible for inhibiting macrophage migration). More importantly, chemokines CXCLl (neutrophil 
chemoattractant activity) and the CCL2/MCP-1 (chemokine monocyte chemoattractant protein-1) are also significantly 
reduced. Down-regulation of CCL2 is associated with up-regulation of miR-124. ABX464 and ABX464-N-Glu up-
regulate miR-124 and thus may explain their anti-inflammatory effects. 
 
SARS-CoV-2 replication in reconstituted human airway epithelial (MucilAir®, Epithelix)   
ABX464 showed comparable efficacy on SARS-CoV-2 replication with remdesivir in reconstituted human airway 
epithelial. Three doses of ABX464 were tested 0,1µM – 1µM – 5µM with a positive control of remdesivir at 5µM. 
Results of viral replication performed on the supernatants are presented in the figure below. 

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In-Vivo assays 
 
DSS mice model 
ABX464 and its primary metabolite, ABX464-N-Glu were tested in a mouse model of colon inflammation. This study 
tested the protective properties of ABX464 in a DSS-induced experimental model of colitis. 
In this model inflammation is specifically induced in the colon via the administration of DSS in drinking water for 
approximately 5-8 days. ABX464 was administered for 8 days via gavage. These results showed that DSS-induced 
weight loss, an established symptom of intestinal injury, was significantly reduced in mice receiving ABX464 (Figure 
2). This induced intestinal inflammation is usually strongest 3 days after the termination of the DSS challenge. The 
weight of ABX464-treated mice had already returned to pre-treatment levels at that time point, and the mice displayed 
decreased disease parameters such as smaller and fewer colonic lesions as well as decreased shrinkage of colon 
length. Importantly, ABX464 did not affect the colons of mice not exposed to DSS. Noteworthy, the disease dampening 
influence of ABX464 in DSS-colitis was observed in experiments performed in different animal facilities, suggesting 
that this phenomenon is not dependent on a particular intestinal flora. 
 
Figure 2: ABX464 treatment suppresses disease severity in DSS-induced colitis. (A) C57BL/6 mice (n=12 each cohort) Subjected to the DSS 
colitis protocol shown received orally once a day ABX464 (50 mg/kg) in methylcellulose or methylcellulose only through gavage. (B) Weight 
development in ABX464 and methylcellulose (MC) only treated mice during DSS-induced colitis. Control cohorts included mice not exposed to DSS. 
(C, D, E) At the end of the protocol described in A mice (n=6 or n=11) were sacrificed and colons were analyzed by histology for colitis severity including 
number of lesion (C), lesion size (D) and colon size (E). (F) Representative images of hematoxylin and eosin staining of paraffin-embedded colon 
sections prepared as “Swiss rolls”. Single lesions are delimited by black lines. (G) Representative images of lesions with different pathological grade 
according to Hao et al. Grade 1: Immune cell infiltration in lamina propria (LP); intact epithelial barrier and GI structure. Grade 2: Immune cell infiltration 
in LP; crypt distorsion or loss; gobelet cell loss; intact, but abnormal epithelial barrier. Grade 3: Immune cell infiltration in LP and submucosa; epithelial 
barrier loss and ulceration/necrosis.  
Abivax tested whether the protective effect of ABX464 is maintained during prolonged DSS exposure (Figure 3A), 
which typically is lethal for mice. However, the daily application of ABX464 allowed the mice to be exposed to DSS for 
at least 63 days. Following a moderate initial body weight loss of approximately 5%, the mice recovered and 
maintained their initial body weight (Figure 3B). The mice that received ABX464 for only the first 20 days during the 
prolonged DSS exposure displayed similar body weight development and survival rates to those that received ABX464 
for the entire study. Nevertheless, the colons of these two mouse cohorts displayed significant differences when 
examined for histopathological parameters including lesion size (Figure 3 C D). This finding suggests that the 20-day 
administration of ABX464 provided a partially protective effect that was maintained for the duration of the 63-day DSS 
challenge. 

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Figure 3: The protective effect of ABX464 is maintained in mice during continuous DSS-treatment. (A) C57BL/6 mice (n=8 each cohort) were 
challenged with DSS for 63 days. Mice received orally once a day ABX464 in methylcellulose during the whole protocol (group 1) or only for the first 
20 days followed by methylcellulose only administration (group 2). Mice of group 3 received methylcellulose during DSS-treatment and had to be 
scarified at day 10. (B) Weight development in ABX464-treated mice during DSS-administration. (C, D) Colons were analyzed by histology for lesion 
size (C) and colitis severity (D) at the end of the protocol. Histological scoring was performed as stated above.  
In humans, ABX464 is rapidly metabolized into one main metabolite, ABX464-N-Glucuronide. (ABX464-N-Glu). Thus, 
ABIVAX studied in the same DSS-mice model the efficacy of the ABX464-N-Glucuronide. Like ABX464, in the same 
DSS-mice model, ABX464-NGlu (40 mg/kg) protects mice from DSS-induced weight loss (Figure 53). This finding has 
substantial implications in light of treating inflammatory ulcerative colitis (UC) disease since studies in healthy patients 
demonstrated that: 
 ABX464-NGlu Cmax was approximately 160-fold higher than those of ABX464 and had a much longer t1/2 (90 to 
110 hours) than the parent compound (2-3 hours), resulting in a > 1000-fold difference in AUC between the 2 
compounds.  
 The markedly higher plasma concentrations of ABX464-N-Glu, and its ability to protect mice from DSS-induced 
colitis, may allow the use of lower doses of the parent compound ABX464 for a longer period in UC patients. 
 
Figure 4: ABX464-N-Glu treatment suppresses disease severity in DSS-induced colitis. (A) C57BL/6 mice (n=10 for DSS and-n=9 for DSS + 
ABX464 and for DSS + ABX464 N-Glucuronide subjected to the DSS colitis protocol shown received orally once a day ABX464 40 mg/kg (DSS + 
ABX464, in green), or ABX464-N-Glucuronide 40 mg/kg (DSS + ABX464 N-Glucuronide, in orange ) in methylcellulose or methylcellulose only (DSS, 
in red) through gavage. (B) Weight development in ABX464, in ABX464-N-Glu and methylcellulose only treated mice during DSS-induced colitis 
Taken together, these in-vivo studies demonstrated the potency of the drug candidate ABX464 to dampen intestinal 
inflammation in DSS-treated mice (Figure 4). Through this anti-inflammatory effect, ABX464 might be able to modulate 
important disease parameters in both HIV and inflammatory ulcerative colitis (UC) disease because it demonstrates 
long-lasting control of the HIV-virus in humanized mice as well as the critical features of DSS-induced colitis. 
 
CIA mouse model  
In order to assess the activity of ABX464 on rheumatoid arthritis, DBA-1 mice were exposed to the CIA model. Bovine 
collagen II was injected in intradermic on the base of the tail at two different sites of injection (100µg in 100µl, dissolved 
in Acetic acid 0.05M and emulsified with Freund Complete adjuvant CFA 1:1) at day 0 (W0) and day 21 (W3).  The 4 
paws were measured using a caliper sagitally. A mean of the 4 paws is calculated. The development of arthritis is 

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considered if this mean paw thickness exceeded 2 mm on two consecutive measures. The measures are performed 
every 2 to 3 days from the 5th week following the 1st injection of CFA + bovine collagen II (W5).  
The incidence of arthritis was drastically reduced in the ABX464 groups, as assessed by arthritis-survival free curves. 
The average of joint thickness observed at week 12 following the 1st injection of bovine collagen and CFA (21 weeks 
of age) was reduced in ABX464 groups compared to MC or H20 groups (4 A and B, phase 1). The median [IQR] joint 
thickness was 0.19 cm [0.18-0.20] in ABX464 vs 0.21 [0.19-0.23] in MC (Mann-Whitney p=0.06) and for INF006002, 
median [IQR] joint thickness was 0.19 cm [0.18-0.20] in ABX464 vs 0.21 [0.19-0.22] in MC 0.20 [0.19-0.22] in H20 
groups (Kruskall-Wallis p=0.002). 
 
Figure 5. Study DBA1 Joint swelling development in mice. 
Mean thickness of joints (mean of 4 paws) measured at week 12 (21 weeks of age) in INF006001 (A) and INF006002 
(B). Mann-Whitney test performed in A and Kruskall-Wallis with post-hoc Dunn’s analysis in B. 
In this study, we have found a specific effect of ABX464 on Collagen Induced Arthritis (CIA). The daily contribution of 
40mg/kg of ABX464 in “per-os” allows to reduce significantly with two independent experiments the inflammation 
noticed by joint swelling in this model. 
1.5. Non-Clinical background information 
The toxicity of ABX464 and ABX464-N-Glu was studied in a range of rodent and nonrodent species (rats, rabbits, 
dogs, cynomolgus and marmoset monkeys, and mini-pigs) with treatment durations ranging from 2-weeks to 6/9 
months. These studies have demonstrated that ABX464 and ABX464-N-Glu are overall well tolerated. Vomiting and 
ptyalism were the major clinical signs, and the main target organs of ABX464 toxicity were the gastro-intestinal tract 
and the liver. The adverse effects noted on these organs were essentially mild/moderate but showed reversibility during 
the recovery phases. 
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. 
Reproductive toxicity was assessed from fertility to postnatal development, in five studies. In rabbits, the maternal 
NOAEL was considered to be 9mg/kg od. and the NOAEL for the embryo-fetal development less than 1mg/kg od. In 
rats, the maternal NOAEL and the NOAEL for pup development and survival is considered to be lower than 15 mg/kg 
od. The F1 generation NOAEL is considered to be 40mg/kg od. in absence of adverse effect at this dose-level. 
In minipigs the main adverse finding was centrilobular hepatocellular degeneration/necrosis associated with 
hemorrhage, fibrosis and /or extramedullary hematopoiesis observed at dose levels of 10mg/kg and above. The liver 
lesions observed in the single animal administered 5mg/kg od, were not considered adverse. Based on this 
observation, the NOAEL is 5mg/kg od. 
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. Nevertheless, 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’s Brochure. 
 

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1.6. Previous clinical experience with ABX464 
ABX464 has been tested in healthy volunteers, patients with HIV infection and in patients with ulcerative colitis. miR-
124 was shown to be up-regulated in all ABX464-treated subjects tested during the clinical program, and all patients 
came back to pre-dosing levels once the administration of ABX464 was stopped. To date, more than 300 subjects 
have received ABX464 in completed and ongoing clinical trials, and the results have shown a favorable safety profile 
and no serious adverse drug reactions. 
ABX464 has completed a Phase 2a induction study (Study ABX464-101) in patients with moderate to severe ulcerative 
colitis. The results showed a rapid onset of clinical improvements, including efficacy in patients resistant to prior 
treatment with biologics. The subsequent long-term open-label maintenance study showed impressive 12-month data 
which were presented during the United European Gastroenterology Conference (UEG), Barcelona on October 21st, 
2019 by Prof. Severine Vermeire, M.D., Ph.D., Head of the IBD Center at the University Hospitals Leuven, Belgium. 
19 of 22 patients completed one year of open-label maintenance. Patients showed continued improvement as 
demonstrated by a 78% reduction of Total Mayo Score, 89% reduction of endoscopic subscore and 97% reduction of 
fecal calprotectin biomarker (normalized). Endoscopy at Month 12 was performed in 16 / 19 patients, of whom 12 
(75%) achieved clinical remission. A continued good long-term safety profile was observed, with no reported serious 
adverse drug reactions as of the annual safety reporting cut off-date (31 October 2019). 
In summary, the impressive efficacy seen in the 8 weeks induction study was not only durable, but even substantially 
improved in this one-year maintenance study, with 75% of the patients with endoscopy having achieved a clinical 
remission. 
Furthermore, the following studies have been initiated: i) a phase 2b study has been initiated in 232 patients with 
moderate to severe ulcerative colitis, and ii) a phase 2a study in 60 patients with rheumatoid arthritis. A Phase 2b study 
in patients with Crohn’s Disease is planned. 
For further information, please refer to the current Investigator’s Brochure for Covid-19. 
1.7. Dose justification 
ABX464 administered at 50mg QD is safe and efficacious in patients suffering from moderate to severe Ulcerative 
Colitis. Over 300 patients have safely been exposed to ABX464, some of them for more than 2 years. Thus, 50mg 
QD may be the appropriate dose for use in inflammatory conditions including the Cytokine Storm which is observed in 
some COVID-19 patients. Indeed, this regimen has been shown to lead to statistically significant upregulation of the 
mir-124 which is the cornerstone of the mode of action of ABX464. 
In addition, ABX464 has recently been tested in primary pulmonary cells infected by with SARS-CoV-2 (MucilAir cells). 
At 48h post infection, the viral load measured in the supernatant by qPCR was reduced by 1 log with ABX464 and 
even 2 logs with its active metabolite: ABX464-N-glucuronide. 
Table 1. Percentage of inhibition induced by ABX464 or its main metabolite ABX464-N-Glu.  
 
% of viral inhibition (mean; n=2) 
ABX464 0.1 µM 
32,45 % 
ABX464 1 µM 
93,25 % 
ABX464 5 µM 
95,54 % 
ABX464-N-Glu 0.1 µM 
No inhibition 
ABX464-N-Glu 1 µM 
29,00 % 
ABX464-N-Glu 10 µM 
87,95 % 
 
Based on day 1 human pk plasmatic data (Cmax), the concentration range used in this assay is achievable in human 
using the 50mg qd dose (abx464: ≈0.2 µm and abx464-n-glu ≈5 µm). Thus, this 50 mg qd dose regimen is deemed 
sufficient to provide efficacy both from an antiviral and anti-inflammatory perspectives. 
 
 

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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Primary objective and endpoint 
The primary objective of the study is to determine the efficacy of ABX464 50mg to prevent respiratory failure or death 
in study patients. 
− 
Rate of patients who do not require use of high-flow oxygen (use of high-flow oxygen being defined as settings 
of 3 L/min or greater AND with at least one SpO2 measurement < 92%, with or without O2 supplementation) 
or, invasive or non-invasive mechanical ventilation (IMV and NIV, respectively) within 28 days and who are 
alive at the end of the 28 days period. 
2.2. Secondary objectives and endpoints 
The secondary objectives are: 
To evaluate the proportion of patients requiring hospitalization during the study compared to the {Standard of care + 
placebo} group 
− 
Rate of patients hospitalized 
To assess the proportion of patients reporting each severity rating on a 7-point ordinal scale during the 
course of the study compared to the {Standard of care + placebo} group 
− 
Percentage of patients reporting each severity rating on a 7-point ordinal scale at each study visit (i.e. Not 
hospitalized, no limitations on activities; Not hospitalized, limitation on activities; Hospitalized, not requiring 
supplemental oxygen; Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation 
or high flow oxygen devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death);  
To assess the time to an improvement of one category of the 7-point on an ordinal scale from baseline, compared to 
the {Standard of care + placebo} groups 
− 
Change in the ranking on an ordinal scale from baseline to days 7, 14, 21, 28, 48 and at 4 months 
To evaluate and compare the effect of ABX464 on oxygen saturation before hospitalization 
− 
% change and AUC over time of oxygen saturation measured by daily pulse oximetry before hospitalization 
To evaluate and compare the effect of ABX464 on oxygen saturation level at the end of the study treatment 
− 
Rate of patients with SpO2 ≤94% and rate of patients with SpO2 ≤92% at Day 28 
To evaluate and compare the effect of ABX464 on immunophenotyping (in selected sites only) and cytokines levels 
during the study in patients enrolled in both treatment groups. 
− 
Change from enrolment in inflammatory markers in plasma (i.e. MCP-1, MIP-1 α, G-CSF, IL-1b, IL-2, IL-6, IL-
7, IL-10, IL-17, INFg and TNFa) and in immune phenotype and assessment of cell-activation markers in 
PBMCs at D14, D28. 
To evaluate the proportion of patient requiring oxygen supplementation (>3L/min) during the study compared to the 
{Standard of care + placebo} group. 
− 
Rate of patients requiring oxygen supplementation 
To assess the time to hospitalization (all causes and Covid-19 related hospitalization) during the study compared to 
{Standard of care + placebo} treated group. 
− 
Time to hospitalization from baseline. 
To evaluate the time to application of invasive and non-invasive mechanical ventilation (IMV and NIV, respectively) or 
high flow oxygen therapy excluding simple oxygen supplementation) and oxygen supplementation during the study 
compared to {Standard of care + placebo} treated group. 
− 
Time to assisted ventilation and oxygen supplementation (log rank) from baseline. 
To assess the IMV and/or NIV duration compared to {Standard of care + placebo} treated group. 
− 
Number of days of assisted ventilation. 

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To assess the oxygen supplementation (>3L/min) duration compared to {Standard of care + placebo} treated group. 
− 
Number of days of oxygen supplementation. 
To assess the hospital stay duration in both treatment groups for patients hospitalized because of Covid-19 infection 
consequences compared to {Standard of care + placebo} treated group. 
− 
Number of days at the hospital from admission to discharge. 
To evaluate the effect of ABX464 on miR-124 expression in whole blood (PAXgene®) vs placebo (in selected sites 
and in hospitalized patients). 
− 
Change from baseline in microRNA-124 levels in total blood (PAXgene®) at D0, D7 and D28. 
To assess the change over time in CRP, Troponin I & T and D-dimer levels compared to {Standard of care + placebo} 
group. 
− 
AUC and % of change from enrolment in CRP, Troponin I & T and D-dimer levels. 
To evaluate the prevention of Covid-19 related deaths compared to {Standard of care + placebo} group  
− 
Time to death and mortality rate (all causes, and Covid-19 related). 
To evaluate the improvement in the 7-point ordinal scale during the course of the study compared to {Standard of care 
+ placebo} group. 
− 
Time to improvement of one level in è-point ordinal scale. 
To evaluate SARS-CoV-2 infection in subjects during the course of the study compared to {Standard of care + placebo} 
group. 
− 
SARS-CoV-2 virus in nasopharyngeal sample and/or in blood at Day 0, 7 (hospitalized patients), 14, 21, and 
28. 
To evaluate outpatients SpO2 evolution from D0 to D14  
− 
Change in SpO2 values from D0 to D14 in the outpatient’s population. 
To evaluate the long-term effect of ABX464 on all cause mortality from first study drug intake to 3-months follow-up 
visit  
− 
Rate of participants deceased during the course of the study and follow-up, and time to event (in weeks).  
To evaluate the safety of ABX464 in study patients (from D0 to D48) 
− 
Number and rates of participants with Treatment Emergent Adverse Event 
− 
Cumulative incidence of serious adverse events (SAEs) including serious adverse drug reactions (SARs) and 
suspected unexpected serious adverse reactions (SUSARs)  
− 
Cumulative incidence of Grade 3 and 4 adverse events (AEs) 
− 
Number of participants with a discontinuation or temporary suspension of study drugs (for any reason) 
 
 
Exploratory criteria: 
To assess the radiological findings for patients hospitalized because of Covid-19 infection consequences 
− 
Central blinded review of the hospitalization discharge CT-Scans for descriptive analysis with regards to the 
disease severity and outcomes. 
To assess the long-term effect (3 months) of ABX464 on the respiratory function recuperation in patients having been 
hospitalized at least once throughout the study 
− 
Change from last dosing day in the Medical Research Council (MRC) dyspnea scale in the hospitalized 
patient’s population according to treatment group. 
− 
Optional: Change from last dosing day in Pulmonary Function Tests (PFT) (Forced Expiratory Volume (FEV) 
and slow and forced Vital Capacity (VC)) and Carbon Monoxide Diffusing Capacity (CMDC) tests in the 
hospitalized patient’s population according to treatment group. 

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3. INVESTIGATIONAL PLAN 
3.1. Study design and methodology 
This phase 2/3 study will evaluate the efficacy and safety of ABX464 50mg QD (oral capsule), on treating 
inflammation and preventing acute respiratory failure in patients infected with SARS-CoV-2. 
Eligible patients will be randomized according to a 2:1 ratio into 2 treatment cohorts as follows: 
• 
Standard of Care + ABX464 50mg QD: 533 patients 
• 
Standard of Care + Placebo cohort: 267 patients 
Upon randomization, patients will be stratified according to:  
• 
Age ≥ 65 years or < 65 years (with at least one risk factor) 
• 
Inpatient or outpatient, at the time of enrolment 
Study design: 
The study will consist of 3 periods: 
• 
Treatment phase: randomized patients will be treated for 28 days  
• 
Safety follow-up phase of 21 days  
• 
Exploratory follow-up of the pulmonary function 3 months after the last study drug intake.  
 
From Day 0 onwards, randomized patients will be followed by the investigational site at 7 days (D7 +/- 2 days), 14 
days (D14 +/- 2 days), 21 days (D21+/- 2 days) and finally 28 days (D28 +/- 2 days) after randomization.  
Should a patient be hospitalized at D0, Day 7 visit will be an on-site visit. 
Should a patient not be hospitalized, considering a quarantine period might be applied for infected patients, a remote 
medical monitoring will be performed by the investigator or his designee every 2 days from D0 and until D14. Every 
attempt to perform the Day 7 on-site visit should be made anyway. For outpatients, an oximeter will be provided at 
Day 0. During the remote medical monitoring, the patient will be asked to self-measure every day the oxygen 
saturation, body temperature and will be asked for any potential signs of COVID-19 infection worsening. 
Subsequent, D14, D21 and D28 will be on-site visits. 
If no quarantine period is applied or if patients migration to the study site is acceptable as per local regulation, 
outpatients will perform a D7 visit on-site, and the same examinations as hospitalized patients will be performed. 
At randomization visit, all patients must have been diagnosed for SARS-CoV-2 infection by PCR or Rapid Antigen 
tests either performed on site or in a private laboratory prior to the visit. The time between PCR or Rapid Antigen 
tests diagnosis and first study drug intake should not exceed 48 hours. A long-term follow-up is scheduled as an 
onsite visit for patients having been hospitalized during the course of the study. This follow-up will be performed 3 
months after the last study drug intake and will consist of a respiratory function exploration. In addition, investigators 

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will report the disease severity rating using a 7-point ordinal scale. 
3.2. 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 the study Data and Safety Monitoring Board 
(DSMB) as probably or definitely related to study treatment.  
Every grade 3 or higher adverse event will be immediately (within 24 hours) reported to the DSMB for causality 
assessment. 
In case of a life threatening (grade 4) adverse reaction probably or definitely related to study treatment, all safety 
data will be reviewed by DSMB members within 7 days of first notification of the event by the investigating site. 
In that case, new enrolment and treatment of ongoing patients will be discontinued and will re-start upon DSMB 
recommendation and after regulatory approvals are obtained. 
3.3. Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB), with expertise and experience in virology, immunology, 
and biostatistics, 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.  
The DSMB will meet first after the 20 first patients are enrolled and treated for at least 4 weeks (D28) and then every 
month after this first meeting.  
The DSMB will oversee the adequate balance of baseline characteristics (i.e. gender, disease duration, previous 
and concomitant CD medication) among the treatment groups and will review safety and efficacy data. 
Furthermore, all potential causally-related Serious Adverse Events within 7 days of the initial notification by an 
investigating site. Every grade 3 or higher adverse event will be reported within 24 hours to the DSMB for causality 
assessment. 
The DSMB has a consultative role. It will inform the Sponsor who will decide whether the DSMB recommendation 
will be followed. Besides, the DSMB may recommend the early termination of the trial at any time if an unacceptable 
toxicity occurs.  
A DSMB charter must be available upon submission of the trial (initial protocol) to the respective competent 
authorities. 
3.4. Steering Committee 
A study steering committee will oversight the practical aspects of the study especially with regards to the evolving 
nature of the COVD-19 infection. 
The Steering Committee will work in conjunction with the DSMB. Specific responsibilities of the Steering Committee 
include, but are not limited to, the following: ensure the overall supervision of the Mir-Age study, take actions to 
reduce deviations from the protocol to a minimum, review of the progress of the study, make any recommendations 
for modifications to the protocol that might be medically or ethically relevant during the course of the study.  
The Steering Committee will be able to terminate the trial if the medical relevance of the MiR-Age is substantially 
modified during its execution. ABIVAX and principal investigator will agree, in writing prior to the start of the study, 
to the charter of the Steering Committee. 
3.5. Duration of study participation 
There is no screening visit in the present protocol. 
After the collection of the signed informed consent, patients will be treated for 28 days, then will go through a 21-
days safety follow-up period. 
Finally, an exploration of the pulmonary function will take place 3 months after the last treatment dose intake for 
patients with at least 1 hospitalization during the study. For outpatients, a remote contact will be performed 3 months 
after the last treatment dose intake to collect their survival status. 
Therefore, the total study duration for a given participant is up to 4 months. 

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4. STUDY POPULATION 
4.1. Number of Patients/Centers 
Approximately 800 patients will take part in this study with a maximum number of patients of 1034 following the 
interim analysis. These patients will be enrolled in approximately 75 sites located in Europe and Latin America (i.e. 
France, Germany, Belgium, Italy, Spain, United Kingdom, Brazil, Mexico, Chile, Peru). 
4.2. Eligibility Criteria 
4.2.1. Inclusion Criteria 
A patient will be eligible to participate in this study if ALL the following criteria are met: 
1. Adult (≥ 18 years old) men or women, hospitalized or not hospitalized, diagnosed for SARS-CoV-2 infection by 
PCR or Rapid Antigen tests (approximately 48 hours prior to randomization), with at least one associated risk 
factor. Considered risk factors are: 
• 
Age ≥ 65 years 
• 
Obesity defined as BMI ≥ 30 
• 
Recent history of uncontrolled High Blood Pressure 
• 
Treated diabetes (type I or II) 
• 
History of ischemic cardiovascular disease  
2. Symptomatic patients must present at least 1 of the following symptoms at enrollment: fever or perceived fever 
for more than 24 hours, headache, sore throat, dry cough, fatigue, chest pain or choking sensation (with no 
associated respiratory distress), myalgia, anosmia, ageusia, or gastro-intestinal symptoms. 
3. Patients with pulse oximetry arterial saturation (SpO2) ≥ 92 % on room air at enrolment. 
4. Patients with the following hematological and biochemical laboratory parameters obtained within 7 days prior 
to D0: 
• 
Hemoglobin > 9.0 g dL-1 
• 
Absolute Neutrophil Count ≥ 1000 mm-3; 
• 
Platelets ≥ 100,000 mm-3; 
• 
Creatinine clearance ≥ 50 mL min-1 by the Cockcroft-Gault formula  
• 
Total serum bilirubin < 2 x ULN 
• 
Alkaline phosphatase< 2 x ULN, AST (SGOT) and ALT (SGPT) < 3 x ULN; 
5. Women of childbearing potential and men receiving the study treatment and their partners must agree to use a 
highly effective contraceptive method during the study and for 6 months (180 days) after end of study or early 
termination. Contraception should be in place at least 2 weeks prior to enrolment. 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 during the trial and for 6 months post 
completion of their participation in the trial. In addition, male patients should use condom during the trial and for 
6 months (180 days) post completion of their participation in the study. Male patients must not donate sperm 
as long as contraception is required. For the purpose of this protocol, a woman is considered of childbearing 
potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently 
sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 

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post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Finally, a 
man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
6. Patients must understand, sign and date the written voluntary informed consent form at the visit prior to any 
protocol-specific procedures. 
7. Patients able and willing to comply with study visits and procedures as per protocol. 
8. Patients should be affiliated to a social security regimen (for French sites only). 
4.2.2. Exclusion Criteria 
Patients who meet any of the following exclusion criteria will be excluded from the study: 
1. Patients with moderate or severe acute respiratory failure or requiring non-invasive ventilation or oxygen or with 
SpO2 < 92% or tachypnea (respiratory rate ≥ 30 breaths/min). 
2. Patients treated with immunosuppressors and/or immunomodulators (cf. Appendix #2). 
3. Engrafted patients (organ and/or hematopoietic stem cells). 
4. Patients with uncontrolled auto-immune disease. 
5. Patients with known or suspected active (i.e. not controlled) bacterial, viral (excluding COVID-19) or fungal 
infections. 
6. Patients with preexisting, severe and not controlled organ failure. 
7. History or active malignancy requiring chemotherapy or radiation therapy (excluding 2 years disease free 
survivor patients). 
8. Pregnant or breast-feeding women. 
9. Illicit drug or alcohol abuse or dependence that may compromise the patient's safety or adherence to the study 
protocol. 
10. Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, 
whichever is longer. 
11. Hypersensitivity to ABX464 and/or its excipients. 
12. 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.  
  
TREATMENT PERIOD 
UNSCH. 
VISIT 
FOLLOW-UP PERIOD 
V113 
Remote 
Medical 
Monitoring 
of 
Outpatients 
to be done 
every 2 days 
between D0 
and D14 
V2 
V3 
V4 
V5 - End of 
treatment 
V6 - Safety 
follow-up  
V7 – 
long-term 
Fup  
D0 
D7 for hosp. 
Patients/and 
potentially 
outpatients 
D14 
D21 
D28 
D48 
3 months 
post last 
SD intake 
GENERAL 
  
 
Signed inform consent form collection 
X 
  
  
  
  
  
  
  
 
Check of IN/EX Criteria  
X 
  
  
  
  
  
  
  
 
Demographic data collection 
X 
  
  
  
  
  
  
  
 
Medical History  
X 
  
  
  
  
  
  
  
 
Current medications  
X 
X 
X 
X 
X 
X 
X 
X 
 
7-point Ordinal scale 
X 
 
X 
X 
X 
X 
 
X 
X 
PHYSICAL EXAMS 
  
 
  
 
Physical Examination (including vital 
signs) 1 
X 
  
X 
X 
X 
X 
X 
X 
 
Oxymeter and patient diary 
dispensation/collection 
X 
  
  
X  
  
  
  
  
 
Remote monitoring of body temperature, 
SPO2 and Clinical Signs of COVID-19 
 
Monitoring 
every 2 days 
between D2 
and D14 
  
  
  
  
 
  
 
Outpatients mortality status12 
 
 
 
 
 
 
 
 
X  
(remote) 
Body Weight (kg) & Height (cm) 
measurements 2 
X 
  
  
  
  
  
 
  
 
ECG 3 
X 
  
X 
X 
X 
X 
X 
X 
 
ANALYSIS TO BE PERFORMED LOCALLY 
  
 
Blood Pregnancy test (WOCBP) 4 
X 
  
  
  
  
  
  
X 
 
Hematology + Biochemistry 5 
X 
  
X 
X 
X 
X 
X 
X 
X 10  
(Hb only) 
BIOBANKING 
  
 
Plasma (CRP, Troponin I & T, D-Dimer 6) 
X 
  
X 
X 
X 
X 
X 
 
 
Immunophenotyping and cells activation 
markers7 
X 
  
  
X 
  
X 
X 
 
 
Blood sample Cytokines8 
X 
  
  
X 
  
X 
X 
 
 
Nasopharyngeal and blood samples for 
viral load assessment 
X 
  
X 
X 
X 
X 
X 
  
 
Samples for miRNA-124 (Blood PAXgene 
tube) 
X 
  
X 
  
  
X 
 
  
 
Haemostasis function exploration 
X 
 
X 
X 
X 
X 
X 
 
 
IMAGING 
  
 
Chest CT-SCANS 9 
(X) 
  
For hospitalized patients only – to be performed at discharge 
 
RESPIRATORY FUNCTION EVALUATION 10 
 
Medical Research Council Dyspnea scale 
For hospitalized patients only – to be performed at discharge 
X 
Spirometry 
(For hospitalized patients only – to be performed at discharge) 
(X) 
CMDC 
(For hospitalized patients only – to be performed at discharge) 
(X) 
TREATMENT ALLOCATION 
  
 
Randomization 
X 
  
  
  
  
  
  
  
 
ABX464/placebo treatment dispensation 11 
X 
  
  
  
  
  
  
  
 
ABX464/placebo treatment accountability 
  
  
  
  
  
X 
  
  
 
SAFETY 
  
 
Adverse Events recording  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1 Physical examinations: a complete physical examination will be performed at D0, at the End of treatment visit (EoT), and at D48. Only 
differences from baseline will be reported at every other visit 
2 Body Weight and Height: Body weight and height will be measured at D0 for BMI assessment. 
3 ECG: A 12-Leads ECG will be performed at every on-site study visit. 

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4 Blood pregnancy test: Applicable to all women of childbearing potential at D0 and at D48. In order not to limit the patient enrollment a urine 
pregnancy test can be performed in addition if the blood test result is not available at the time of randomization. 
5 Hematology + Biochemistry: samples to be taken at every on-site study visit (except D7 for outpatients if not possible) and analyzed locally.  
6 CRP, Troponin I & T and D-Dimer: samples to be taken at every on-site study visit (except D7 for outpatients if not possible) and sent to central 
laboratory for biobanking purpose.  
7 Immunophenotyping and cells activation markers: samples will be taken in selected sites and for approximately 100 patients. 
8 Blood sample Cytokines: samples will be taken in all sites for all patients. 
9 Chest CT-scan: procedure concerns hospitalized patients only (whenever the hospitalization occurs during the course of the study). Images 
taken at discharge (± 7 days) will be assessed locally, then collected and sent to a blinded central reader for descriptive analysis of the lesions. If 
available at D0, Baseline CT scans of hospitalized patients will be sent to Central Reader for comparison purpose.  
10 Respiratory function evaluation: This evaluation will be performed only in patients who were hospitalized during the course of the study. For 
these patients the MRC Dyspnea assessment scale must be used at discharge and 3 months after last study drug intake 
For sites having adequate facilities a PFT (FEV1 and slow and forced Vital Capacity) and a Carbon Monoxide Diffusing Capacity (CMDC ) 
evaluation will be performed at discharge and 3 months after last study drug intake (optional assessments). For this last test, a blood sample for 
hemoglobin assessment must be taken within 48hrs prior to the CMDC test. 
11 ABX464/placebo treatment dispensation: treatment dispensation will be allowed once all the selection criteria are confirmed, including 
laboratory assessments for patients’ eligibility confirmation. 
12Outpatients mortality status: For patients not hospitalized during the course of the study, a phone contact will be done 3 months after 
the last study drug intake to collect their mortality status.  
13 V1: Visit 1 can be splitted into 2 separated visits for outpatients to follow site organization and quarantines requirement. However, the 
interval between these 2 visits cannot exceed 48 hours to ensure patients start the study treatment at an early stage of the disease. Date 
of first intake of study drug will be considered as D0. 
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. Visit 1 – Day 0 (D0 / Baseline) 
Patient with a PCR or Rapid Antigen tests diagnosis of COVID-19 will be informed about the general aspects of the 
study and will sign and date the informed consent form. Only when patient written informed consent has been 
collected may further study procedures be carried out. 
The patient number will be allocated once the patient is created in the eCRF.  
At baseline, the following assessments will be performed: 
 All inclusion/exclusion criteria will be verified, 
 Collection of the signed informed consent form, 
 Demographic data collection: year of birth, gender and ethnicity, 
 Medical history documentation including comorbidities or associated risks, 
 Start date (Onset) of COVID-19 symptoms and contamination date if known, 
 All current medications must be recorded and all changes must be documented during the course of the study, 
 Complete physical examination, 
 Vital signs, body weight and height measurement, 
 Record a 12 leads ECG, 
 Report the disease severity rating using the 7-point ordinal scale (i.e. Not hospitalized, no limitations on 
activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; 
Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen 
devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death); 
 Supply outpatients with oximeter, and explain purpose and how to use it 
 Collect samples for  
o 
Analysis performed by local lab: Hematology, biochemistry, serum pregnancy test for women of 
child-bearing potential (- an additional urine pregnancy test can be done if the result of the serum 
test is not available at the time of the study drug dispensation) 
o 
Biobanking purposes:  
 
Viral load testing (nasopharyngeal and blood), 
 
CRP, Troponin I & T and D-dimer,  
 
Cytokines testing, 

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 
Immunophenotyping and cells activation markers (samples will be taken in selected sites 
and for approximately 100 patients) 
 
Hemostasis function exploration 
o 
miRNA124 assessment (Blood PAXgene® tubes), 
 Patient randomization, 
 Dispensation of study treatment allocated to the patient once all the selection criteria have been confirmed 
(including laboratory assessments for patients’ eligibility) 
 Administration of the first intake on site for safety purpose; Instruct the patient how to take the study drug once 
at home. 
 Record all adverse event (if any) starting from the informed consent signature, 
 Schedule next on-site visit and/or remote medical monitoring. 
Since COVID-19 positive patients are invited to take part to the study and considering sites potential organization 
and the quarantines requirements in participating countries, randomization visit can be splitted into 2 separated 
visits. However, the interval between these 2 visits cannot exceed 48 hours to ensure patients start the study 
treatment at an early stage of the disease.  
Performing the visits at the patient’s home is allowed as long as authorized as per local requirements and 
adequately organized with the site staff to ensure patients safety (i.e. visit to be performed by a physician and/or a 
nurse depending on the examinations left to be done at the patient’s home, and both trained to the study protocol). 
Besides, for patients not diagnosed yet but with a high suspicion of COVID-19 (i.e. showing symptoms and who 
went in contact with infected people) and with at last one risk factor, the PCR or Rapid Antigen tests can be 
performed as part as the study visit. Nevertheless, the randomization procedure must not be done until the COVID 
positive status of the patients is confirmed.  
5.2.2. Follow-up of out-patients between D0 and D14 
After D0, outpatients will be contacted every other day by the investigator or his/her designee. 
During this remote medical monitoring, outpatients will be questioned on their state of health, including body 
temperature, SPO2, clinical signs and occurrence of any potential adverse events as well as any change in the 
current medication will be checked. Data will be recorded in the patient’s medical chart and in the dedicated page 
of the eCRF.  
In case of any sign of worsening, outpatients will be asked to come back to the study site for an unscheduled visit 
where additional examinations will be performed. 
During the last daily contact, the D14 onsite visit will be confirmed to the patient. Patients will be asked to bring back 
the oximeter provided at D0. 
If no quarantine period is applied or if patient migration to the study site is acceptable as per local country regulation, 
outpatients will perform a D7 visit on-site where the same examinations as hospitalized patients will be done. 
In case of quarantine policy, sites should organize home care settings to collect samples at D7 at patients’ home. 
5.2.3. Visit 2 – Day 7 (+/- 2 days)  
For Patients hospitalized at D7 (or since D7), the following assessments will be performed: 
 Change in current medication will be checked and recorded, 
 Complete physical examination and only changes from last visit will be recorded, 
 Vital signs measurement, 
 Record a 12-leads ECG, 
 Report the disease severity rating using the 7-point ordinal scale (i.e. Not hospitalized, no limitations on 
activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; 
Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen 
devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death); 
 Collect samples for  
o 
Analysis performed by local lab: Hematology, biochemistry 

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o 
Biobanking purposes:  
 
Viral load testing (nasopharyngeal and blood), 
 
CRP, Troponin I & T and D-dimer, 
 
Hemostasis function exploration 
o 
miRNA124 assessment (Blood PAXgene® tubes), 
 Adverse Event and follow-up and reporting (if any). 
NB: At any visit, for hospitalized patients: collect chest CT scan at discharge (± 7 days) and send to central reader 
for analysis. In addition, an evaluation of dyspnea severity will be done at discharge using the Medical Research 
Council (MRC) dyspnea scale. 
5.2.4. Visit 3 & 4 – Day 14 & 21 (+/- 2 days)  
At D14 and D21, the following assessments will be performed: 
 Change in current medication will be checked and recorded, 
 Complete physical examination and only changes from last visit will be recorded, 
 Vital signs measurement, 
 Record a 12-leads ECG, 
 Report the disease severity rating using the 7-point ordinal scale (i.e. Not hospitalized, no limitations on 
activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; 
Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen 
devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death); 
 Collect samples for  
o 
Analysis performed by local lab: Hematology, biochemistry 
o 
Biobanking purposes:  
 
Viral load testing (nasopharyngeal and blood), 
 
CRP, Troponin I & T and D-dimer,  
 
Cytokines testing, 
 
Immunophenotyping and cells activation markers (samples will be taken in selected sites 
only for Visit 3 (Day 14) for the same patients as at Visit 1  
 
Hemostasis function exploration 
 Adverse Event and follow-up and reporting (if any), 
 Schedule next visit and during D21 visit, instruct the patient to bring back the treatment kit for accountability 
purpose. 
NB: At any visit, for hospitalized patients: collect chest CT scan at discharge (± 7 days) and send to central reader 
for analysis. In addition, an evaluation of dyspnea severity will be done at discharge using the Medical Research 
Council (MRC) dyspnea scale 
5.2.5. Visit 5 / End of Treatment visit (EoT) – Day 28 (+/- 2 days)  
At Day 28, the following assessments will be performed: 
 Change in current medication will be checked and recorded, 
 Complete physical examination and only changes from last visit will be recorded, 
 Vital signs measurement, 
 Record a 12-leads ECG,  
 Report the disease severity rating using the 7-point ordinal scale (i.e. Not hospitalized, no limitations on 
activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; 
Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen 
devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death); 
 Collect samples for  
o 
Analysis performed by local lab: Hematology, biochemistry, 
o 
Biobanking purposes:  
 
Viral load testing (nasopharyngeal and blood), 

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 
CRP, Troponin I & T and D-dimer,  
 
Immunophenotyping and cells activation markers (samples will be taken in selected sites 
and for the same patients as at Visit 1  
 
Hemostasis function exploration 
o 
miRNA124 assessment (Blood PAXgene® tubes), 
 Adverse Event and follow-up and reporting (if any), 
 Collect the treatment kit dispensed at D0 for drug accountability and check patients’ compliance, 
 Schedule D48 visit. 
 
After this visit, should a patient still need to be treated for COVID-19, the sites standard of care will be applied. 
 
NB: At any visit, for hospitalized patients: collect chest CT scan at discharge (± 7 days) and send to central reader 
for analysis. In addition, an evaluation of dyspnea severity will be done at discharge using the Medical Research 
Council (MRC) dyspnea scale 
5.2.6. Visit 6 – Day 48 (+/- 2 days) 
At Day 48 visit, the following assessments will be performed: 
 Change in current medication will be checked and recorded, 
 Complete physical examination, 
 Vital signs, 
 Record a 12 leads ECG, 
 Report the disease severity rating using the 7-point ordinal scale (i.e. Not hospitalized, no limitations on 
activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; 
Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen 
devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death); 
 Collect samples for  
o 
Analysis performed by local lab: Hematology, biochemistry, serum pregnancy test for all women 
of childbearing potential 
 Adverse Event follow-up and reporting (if any). 
5.2.7. Visit 7 – 3-months follow-up visit (+/- 7 days) 
A long-term follow-up will be performed 3 months after the last study drug intake to explore the respiratory 
function of patients who have been hospitalized during the study. 
Patients having been hospitalized during the course of the study will come back for an on-site visit to perform a 
respiratory function assessment and a long-term survival evaluation as described below: 
 Report the disease severity rating using the 7-point ordinal scale (i.e. Not hospitalized, no limitations on 
activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; 
Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen 
devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death); 
 Evaluation of the dyspnea severity using the Medical Research Council (MRC) Dyspnea scale 
 Optional procedures for sites with adequate facilities and resources:  
o 
PFT (FEV1 and Slow and Forced Vital Capacity) 
o 
CMDC assessment (optional procedures) 
o 
Blood sample taken within 48 hours prior the visit for hemoglobin assessment. 
For outpatients, mortality status will be collected (phone contact) 3 months after the last study drug intake. 
5.2.8. Unscheduled visit 
An on-site visit is defined as unscheduled if occurring between 2 on-site visits. 
During such visit, the following examination will be performed:  
Change in current medication will be checked and recorded, 

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 Complete physical examination, 
 Vital signs, 
 Record a 12 leads ECG, 
 Report the disease severity rating using the 7-point ordinal scale (i.e. Not hospitalized, no limitations on 
activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; 
Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen 
devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death); 
 Collect samples for  
o 
Analysis performed by local lab: Hematology, biochemistry 
o 
Biobanking purposes:  
 
CRP, Troponin I & T and D-dimer, 
 
Cytokines testing, 
 
Immunophenotyping and cells activation markers (samples will be taken in selected 
sites)  
 
Hemostasis function exploration 
5.3. Detail of the study assessments  
5.3.1. Physical Examination and Vital Signs 
A complete physical examination will be performed at D0, at the End of treatment visit (EoT), and at D48. Only 
differences from baseline will be reported at every other visit (except at D7 for outpatients due to quarantine 
measures). 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 recorded in the dedicated section of the eCRF 
and documented as an adverse event (AE) when clinically significant in the investigator’s judgment. Patients weight 
will be measured at D0 only.  
Measurements of vital signs will be done at each visit (blood pressure, heart rate, body temperature). The patient 
should rest for at least 5 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 excursion assessed clinically significant, the investigator must document the change as an adverse event 
in the eCRF dedicated pages.  
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/she considers the change to be clinically significant, even if the absolute value is within the alert limit or 
reference range. 
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 skin lesions. To collect information regarding this Adverse Event 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, etiology (i.e. consequence of SARS-CoV-2 infection or 
not) and relationship to the study treatment. An anonymized medical report shall be provided to the Sponsor. 
5.3.3. Pregnancy 
For all female patients of childbearing potential, a blood pregnancy test (beta human chorionic gonadotropin [β-
HCG]) will be performed at baseline and at EoS. In case of positive pregnancy testing, detailed procedures can be 
found in section 8.3.3. 
In addition, a urine pregnancy test can be performed at D0 provided that the β-HCG testing has been done but the 
result is not available at the time of the first ABX464 or matching placebo administration. 

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Should the partner of a male patient become pregnant, investigators will also collect pregnancy information while 
the patient is participating in this study. A specific informed consent will be collected from the pregnant partner to 
allow data collection. 
5.3.4. ECG 
Electrocardiograms will be performed at all study visits. 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 in a resting position. Prior to the recording 
the patient should be at rest for five minutes minimum. Resting ECG should be performed before any examinations. 
The ECG printout will be reviewed by the Investigator, then signed, dated and attached to the medical file. 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 e-CRF. Any clinically relevant findings compared to ECG done at 
Day 0 must be documented as adverse events. 
5.3.5. Chest CT-Scans 
During the course of the study, should a patient be hospitalized as a consequence of Covid-19 infection, a chest 
CT scan will be obtained at discharge (± 7 days) and sent to a blinded Central Reader provider for assessment. If 
a CT scan was done at D0 as per site standard of care, the baseline CT scan will be collected and sent to the 
Central Reader for comparison purpose. Presence or absence of infiltrates or lesions will be described in the 
analysis. 
5.3.6. Respiratory function exploration 
A respiratory function exploration will be performed in patients having been hospitalized during the course of the 
study and who received an oxygen supplementation during their hospitalization. 
5.3.6.1. Medical Research Council (MRC) Dyspnea scale 
The first part of the respiratory function exploration consists in the evaluation of the dyspnea severity using the 
Medical Research Council (MRC) dyspnea scale.  
This scale is an easy tool which provides a baseline assessment of functional impairment attributable to dyspnea 
from respiratory diseases and which correlates with healthcare-associated quality of life, morbidity, and possibly 
mortality for patients with respiratory diseases (particularly COPD). It has been commonly used in clinical practice 
for almost two decades in multiple different heterogeneous patient populations, and correlates with other clinical 
and research dyspnea indices, with a high inter-rater reliability.  
This scale counts 5 severity grades from 0 to 4 as followed: 
• 
Grade 0 : Dyspnea only with strenuous exercise; 
• 
Grade 1:  Dyspnea when hurrying or walking up a slight hill; 
• 
Grade 2:  Walks slower than people of the same age because of dyspnea or has to stop for breath when 
walking at own pace; 
• 
Grade 3: Stops for breath after walking 100 yards (91 m) or after a few minutes; 
• 
Grade 4: Too dyspneic to leave house or breathless when dressing. 
The test will be performed at discharge and repeated 3 months after the last study drug intake.  
5.3.6.2. PFT and CMDC assessment (optional procedures) 
These assessments will be only performed in site with ad-hoc facilities and resources. 
In addition to the MRC Dyspnea scale, a Pulmonary Function Tests (PFT) (Forced Expiratory Volume (FEV) and 
slow and forced Vital Capacity (VC)) and a Carbon Monoxide Diffusing Capacity (CMDC) evaluation will be 
performed at discharge and 3 months after the last study drug intake.  

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For an appropriate lecture of this test a blood sample for hemoglobin assessment must be taken within 48hrs prior 
to the CMDC test. 
5.3.7. Laboratory parameters 
Parameters will be assessed either by the site local laboratory (for routine analysis) or a central laboratory (for 
specific analysis). 
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. 
Table 2 lists all the clinical laboratory parameters that must be measured and the central laboratory in charge of 
their analysis. 
Table 2: Laboratory Tests 
LABORATORY 
ANALYSIS 
PARAMETERS 
Local Lab 
HEMATOLOGY 
Hemoglobin, Hematocrit, WBC (Absolute & differential), Platelet Count, 
Prothrombin time or INR 
BIOCHEMISTRY 
Sodium, Potassium, Chloride, Calcium, Phosphate,  
Glucose, BUN or urea, Creatinine, AST / ALT, Lipase, Alkaline 
phosphatase, gGT, Total bilirubin, Total protein, Albumin, LDH, CRP, β-
hCG, Fibrinogen, 
Hematology 
Department of 
H.E.G.P. 
Haemostasis function 
exploration 
BIOBANKING antiphospholipid antibody (aPL), Coagulation inhibition, Fibrine 
(Monomer), von Willebrand factor (VWF) 
 
Cytokines 
(All patients) 
BIOBANKING MCP-1, MIP-1 α, G-CSF, IL-1b, IL-2, IL-6, IL-7, IL-10, IL-17, INFg, IP-10, 
RORᵞt and TNFa but not limited to 
Immunophenotyping and 
cells activation markers 
(Approx. 100 patients in 
selected sites) 
BIOBANKING CD11b, CD15+, CD24+, CD114+, CD182+, CD66b, CD3; CD4; CD8; 
CD19; CD16/CD56, CD161, CCR6, IL-23R but not limited to 
Nasopharyngeal and blood 
samples for viral load 
determination 
BIOBANKING SARS-CoV-2 quantitative PCR 
Plasma 
BIOBANKING Troponin I & T, CRP, and D-dimer 
Acobiom 
Samples for miRNA-124  
microRNA-
124 
miR-124 
 
5.3.7.1. miRNA-124 modulation 
ABX464 up-regulates miRNA-124 in PBMCs, making of this micro-RNA a potentially useful biomarker for ABX464 
treatment monitoring. Determination of miRNA-124 level in total blood will be performed in order to assess treatment 
effect by comparing before and after treatment. Assays for miRNA-124 determination will be conducted at the end 
of the study. 
5.3.7.2. Viral load assessment 
Viral load will be assessed by a central laboratory at each on-site study visit from D0 to D28 by qPCR performed 
on nasopharyngeal and blood samples. 
5.3.7.3. Lymphocyte Phenotyping, Cytokine Serum Concentrations  
Blood and serum samples will be collected at D0 in every site, and then at specified timepoints during the study. 

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Samples for Immunophenotyping assessment will be taken from selected sites only and for approximately 100 
patients, to document effects of ABX464 on T cell, NK and dendritic cell concentrations as well as on cytokines (as 
described in table 1: Laboratory tests).  
Cytokines serum concentrations will be tested in all treated patients at specified timepoints. 
These determinations will be performed by a central laboratory. 
5.3.8. Volume of blood sampling. 
The table 3 below summarizes the volume of blood to be sampled at each study visit. The total (maximal) volume 
of blood taken from a participating patient is 321 mL to 392 mL (including samples taken during an unscheduled 
visit). 
Table 3: Blood Volume 
 
 
D0 
D7 
D14 
D21 
D28/EOT 
UNSCH 
D49 
4M FUp 
Hematology 
2 
2 
2 
2 
2 
2 
2 
2 
Biochemistry  
10 
10 
10 
10 
10 
10 
10 
0 
Immunophenotyping & cells activation 
marker 
24 
0 
24 
0 
24 
24 
0 
0 
Cytokines 
6 
0 
6 
0 
6 
6 
0 
0 
miRNA-124 
5 
5 
0 
0 
5 
0 
0 
0 
Viral load  
2,5 
2,5 
2,5 
2,5 
2,5 
2,5 
0 
0 
Plasma (Troponin I & T, CRP, and D-
dimer) 
17  
17  
17  
17  
17  
17  
0 
0 
Haemostasis 
9 
9 
9 
9 
9 
9 
0 
0 
TOTAL PER VISIT 
75,5 
45,5 
70,5  
40,5 
75,5 
70,5 
12 
2 
 

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6. 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. 
6.1. Description of investigational treatment 
The study treatment that will be administrated to patients enrolled in this Phase 2/3 study consists of capsules 
containing ABX464 or its matching placebo given orally once daily with food for 28 days. 
6.2. Description of investigational Product 
6.2.1. 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 50mg of ABX464 drug substance in 
the form of granulate prepared with several common excipients (microcrystalline cellulose, polyvinylpyrrolidone, 
magnesium stearate and colloidal silica). 
It is supplied in study specific high-density polyethylene bottles containing 30 capsules. 
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 Clinical Supplies 
Z.A. Air Space 
Avenue de Magudas CS 2007 
33187 Le Haillan Cedex France  
Storage conditions: Do not store above 30°C (86°F). Do not refrigerate or freeze. 
6.2.2. 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 and containing 30 capsules. 
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: 
Creapharm Clinical Supplies 
Z.A. Air Space 
Avenue de Magudas CS 2007 
33187 Le Haillan Cedex 
Storage conditions: Do not store above 30°C (86°F). Do not refrigerate or freeze. 
 

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6.3. Administration and dosing 
6.3.1. Administration of the investigational product 
Depending on the randomization, patients will be treated with a daily dose of 50mg of ABX464 or its matching 
placebo. All patients regardless of the treatment group will receive 1 capsule every day. 
Patients will be orally dosed in a fed condition (e.g. regular breakfast or snack) with a glass of water.  
Should a patient be intubated during the study, it’s allowed to administer the study treatment through the feeding 
tube.  
Should a patient be hospitalized during the course of the study, every effort should be made to ensure treatment 
compliance. 
The minimum delay between 2 doses is 12 hours. Should a patient skip a dose s/he should take the next dose on 
the next morning. 
6.3.2. Guidelines for treatment postponement and dose modifications 
No dose escalation/dose adjustments are allowed.  
6.4. 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: 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 across the study according 
to a 2:1 ratio to ABX464 50mg : placebo treatment arms. 
Patients will be stratified according to:  
- 
Age ≥ 65 years or < 65 years (with at least one risk factor) 
- 
Inpatient or outpatient, at the time of enrolment 
Randomization will be performed via IWRS. Treatment numbers will be allocated as per randomization list. 
In all cases at the end of treatment visit, all patient should return the bottle dispensed at D0 for a compliance check. 
6.5. Blinding and breaking the study blind 
Study drug will be packaged in blinded high-density polyethylene 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 patients 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 patient number but NOT the result. The details 
shall be included in the statistical report. 

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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 treatment 
phase. 
6.6. Packaging 
The IMP consists in hard gelatin, powder-filled capsules (size 01) containing 50 mg of ABX464 supplied in study 
specific high-density polyethylene bottles. 
6.7. Storage 
ABX464/Placebo capsules will be shipped to the investigational site at a temperature not above 30°C (86°F). 
Storage conditions: do not store above 30°C (86°F).  
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. 
6.8. 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. 
6.9. Prior and Concomitant Medication 
6.9.1. Allowed concomitant treatment 
Are allowed all medications related to patient’s current affection (i.e. medical history). 
This study aims to enroll patients that are newly diagnosed with COVID-19, without sign of respiratory distress.  
The standard of care in non-hospitalized patients, according the WHO recommendations, consists mainly of 
symptomatic treatments and antibiotic therapies as appropriate at the physician’s discretion. The use of concomitant 
medications will be recorded in the eCRF. 
The standard of care in hospitalized patients may vary between sites and depends upon patient status and will 
remain at the physician’s discretion. 
Concomitant treatment with either corticosteroids (e.g. dexamethasone) or remdesivir is allowed providing they are 
part of a Standard of Care duly authorized in the respective countries where the study is conducted.  
6.9.2. Prohibited concurrent medications 
The following drugs are prohibited at enrollment and during the study:  
 
all immunosuppressor or immunomodulator agents (cf. appendix #2) 
 
Use of any investigational or non-registered product within 3 months or within 5 half-lives before 
enrollment, whichever is longer. 
The following drugs are prohibited during the study: 
 
Drugs that could interact with ABX464 should be avoided especially the CYP1A2 substrates (cf. Appendix 
#1). The following CYP1A2 substrates with a narrow therapeutic margin are prohibited during the whole 
course of the study (clozapine, theophylline, ropinirol, warfarin and methadone). In case of concomitant 
treatment with ondansetron the maximal daily dose must be limited to 8 mg. 
 
Inhibitors or inducers of the CYP1A2 (cf. Appendix #1). 

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7. STUDY COMPLETION  
7.1. Patient Completion 
Treatment with ABX464/Placebo shall continue until D28, except if a patient fulfils a premature discontinuation 
criterion (defined below). 
Patients should be instructed to take their last study drug dose until the day before D28 visit. Should a patient start 
to take the treatment at D1, s/he will be instructed to take the last dose on D28. 
After D28, patients will come back 21 days after the last study drug intake to perform an onsite safety follow-up visit 
at D48. 
Following this visit, long-term follow-up for respiratory function exploration will be performed on-site for patients 
having been hospitalized during the study. This follow-up will take place 3 months after the last study drug intake. 
For outpatients, a remote telephone follow-up will be performed 3 months after the last study drug intake. 
Then, patients will exit the study and will be treated/follow-up according to the site standard of care. 
Given the fact that the pulmonary function follow-up is exploratory and depends on the patient status during the 
study, a patient status is COMPLETE when the treatment period of 28 days is fulfilled, and the safety follow-up of 
21 days is performed. 
7.2. Patient Premature trial discontinuation 
A patient can be withdrawn at any time from the study. Premature trial discontinuation could occur for the following 
reasons: 
 
Investigator’s decision. 
 
An Adverse Event or an intercurrent condition that preclude continuation of treatment. 
Specifically, an elevation ≥ 3.0 x ULN in liver transaminases (AST/SGOT and/or ALT/SGPT) or Alkaline 
phosphatase or in total bilirubin compared to baseline requires close observation with repeating liver 
enzymes and serum bilirubin tests every 2 days. Discontinuation of the study treatment should occur if: 
 
ALT or AST > 8xULN 
 
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%). 
 
Alkaline Phosphatase ≥ 2.0 x ULN 
 
Serious adverse event with suspected causal relationship to the IMP 
 
Any relevant toxicity or negative change in the risk/benefit assessment leading to an unacceptable risk for 
the patient (i.e. occurrence of adverse events which character, severity or frequency is new in comparison 
to the existing risk profile), or any data deriving from other clinical trials or toxicological studies which 
negatively influence the risk/benefit assessment.  
 
Major protocol violation. 
 
Withdrawal of consent. 
 
Administrative reasons from Sponsor. 
A patient who prematurely exits the study will not be replaced.  
All patients, regardless of the completion or premature discontinuation, should come back for an on-site safety follow-
up visit 21 days after the last study drug intake, and all examinations must be performed according to the study flow-
chart. 
The same long-term follow-up will be performed as described in section 7.1 providing the reason for premature 
discontinuation is not “withdrawal of consent”. 
7.3. Baseline Failures 
A patient who does not fulfil the randomization criteria will be considered as baseline failure. All patient data should 
be entered in the eCRF including the failure data. Based on the investigator evaluation and sponsor prior approval, 
a non-randomized patient case can be re-evaluated for randomization. This re-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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All potential patients who are assessed for enrolment in this study will be listed on the patient Log/Identification List. 
Reasons for exclusion will be recorded for potential patients who do not enter the study. 
 
7.4. Study Discontinuation 
The 50 mg QD dose is well tolerated. Some patients are being treated for more than 2 years at that dose. No DLT 
has been reported. The study protocol plans some early discontinuation criteria and specifically in case of 
modification of LFTs in accordance to the pre-clinical findings.  
In addition, all safety data will be thoroughly reviewed by the DSMB. Part of the DSMB duties is to review occurrence 
of adverse events which character, severity or frequency is new in comparison to the existing risk profile. In such 
case, recommendations from the DSMB may lead the either additional stopping rules up to study discontinuation. 
7.5. End of Trial 
In the frame of the ABX464-401 study, the end of trial will occur once the last randomized patient has performed at 
least the safety follow-up visit of 21 days after the last study drug intake, and depending on their status during the 
study, the 4 months follow-up visit/call. 
Then all data will be analyzed and embed in a clinical study report. 
 
 

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8. 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.  
All adverse events (Serious  and non-serious) will be collected from the time of signing of ICF and until D48 visit.  
Any disease progression will be both reported in the eCRF as an adverse event and documented in the efficacy 
section. 
8.1. Definitions 
8.1.1. Definition of an Adverse Event (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 start 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. 
8.1.2. Definition of an Adverse Drug Reactions (ADR) 
A response to a medicinal product which is noxious and unintended.  
Suggesting that there is at least a reasonable possibility or suspicion of a causal relationship between the medicinal 
product and an adverse event. 
8.1.3. Definition of a Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) 
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 Covid-19 infection consequences will be reported as a Serious Adverse Event. 
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 

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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 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. 
8.1.4. Definition of a Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A Suspected Unexpected Serious Adverse Reaction (SUSAR), is a serious adverse reaction (SAR) for which a 
reasonable causal relationship with the medicine use is suspected but not confirmed. Unexpected in this context 
means not consistent with the applicable product information (e.g. investigator’s brochure for an unapproved 
investigational product or summary of product characteristics (SmPC) for an authorised product). 
8.2. 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).  
8.3. Events or Outcomes Qualifying as AEs or SAEs 
8.3.1. COVID-19 related AE/SAEs 
All COVID-19 related AE/SAEs will be recorded. 
8.3.2. 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 section 8.1. 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 will be recorded as medical 
history and will be reported as AEs or SAEs in case of worsening. 
8.3.3. 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 ABIVAX or its designee 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 ABIVAX or its designee. Follow-up will 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. 

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The time period for collecting pregnancy information is identical to the time period for collecting AEs, as stated in 
Section 8.4, Time Period, Frequency, and Method of Detecting AEs and SAEs.  
8.4. Adverse events from previous clinical trials 
More than 300 patients have already received ABX464 at different dose levels and for different durations. ABX464 
is generally well-tolerated. The most frequently reported side effects with ABX464 treatment are: 
• 
Occuring in more than 10% of the patients: headache, nausea, vomiting, gastrointestinal tract disorders 
(upper abdominal pain). 
All these adverse reactions were either mild or moderate and only 2 led to treatment stop. The frequency of these 
adverse events seemed to be dose-related, starting from 75mg and higher.  
• 
Ocurring in less than 10% of the patients: Diarrhea, Fatigue, Edema, Muscle and joint pain, Dizziness, 
Fever, Skin rash, Pruritus, Conjunctivitis. 
8.5. 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 21 days 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. 
IntuVigilance Limited 
UK: 
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. 
8.6. 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 (Most recent version), 
 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); 

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 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 anew each time. 
8.7. 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 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. 
8.8. 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.  

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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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9. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
A summary of the principal features of the statistical analysis of the data are described in this section. A more 
technical and detailed elaboration of the principal features stated in the protocol will be given in 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. 
9.1. Statistical and Analytical Plans 
9.1.1. 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 primary efficacy endpoint. The following 
deviations will be considered as major (non-exhaustive list):  
 
Non compliance with the inclusion or exclusion criteria; 
 
Non compliance with the study treatment; 
 
Intake of prohibited medication (see section 6.9.2); 
 
Noncompliance with time window. 
9.1.2. Definition of study analysis sets 
The following datasets will be defined and used for the analyses: 
 
Enrolled Analysis Set: All patients enrolled in the study will comprise of enrolled analysis set. There will be 
no safety or efficacy analysis performed on this set. 
 
Safety Analysis Set: The Safety analysis set will include all the patients randomized in the study and who 
have received at least one dose of study medication. The safety analysis will be based on the actual 
treatment received. 
 
The Full Analysis Set:  FAS is defined as all the patients randomized in the study.The efficacy analysis will 
be based on FAS. The treatment groups will be compared basis the randomized treatment rather than the 
actual treatment. 
 
The per protocol (PP) Set: The Per Protocol analysis set will consist of all patients in the FAS without any 
major protocol deviation (see section 9.1.1). The PP Analysis Set will be used for sensitivity efficacy 
analyses. 
9.1.3. 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. 
9.1.4. 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. 
9.1.5. Treatment compliance 
Number of daily doses will be presented on the FAS population. 
9.2. 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) including serious adverse drug reactions (SARs) and suspected unexpected serious 
adverse reactions (SUSARs), death, any grade 3 or higher adverse events from baseline to the end of Study.  

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Two periods will be defined for TEAE: 
 Any adverse event which occurs or worsens from first dosing to Day 28; 
 Any adverse event which occurs after Day 28. 
TEAEs 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 study treatment discontinuation; 
 TEAE of grade 3 or 4; 
 TEAE for which relationship with the study treatment is recorded as possible or probable. 
The 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 (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]. 
Clinical laboratory parameters, vital signs, ECG will be summarized by using descriptive statistics (n, mean, SD, 
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 study treatment group. 
9.3. Efficacy Analysis 
9.3.1. Generalities 
Descriptive statistics will be presented by treatment arm for all primary and secondary efficacy variables for each 
measurement timepoint. 
Continuous variables: mean, standard deviation, minimum and maximum and Confidence intervals (CI), median 
and quartiles will be presented when considered relevant.  
Categorical variables: Counts, rates and Confidence intervals (CI) with confidence level appropriately adjusted 
confidence intervals will be calculated.  
Time-to-event variables will be analyzed by Kaplan-Meier plots. 
Mixed model analysis of covariance will be conducted on changes from baseline in specifically chosen 
measurements defined in the SAP. In this model, treatments and visit will be fixed effect, patients 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. 
Additional sensitivity analysis will be performed on PP analysis set.  
9.3.2. Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint, response defined as  
• 
no use of  
o 
high-flow oxygen (use of high-flow oxygen being defined as settings of 3 L/min or greater AND with at least 
one SpO2 measurement < 92%, with or without O2 supplementation)  
o 
or non-invasive mechanical ventilation (IMV and NIV, respectively)  
within 28 days  
• 
and alive at the end of the 28 days period,  
will be analyzed by the Mantel–Haenszel (MH) approach stratified for factors used in the randomization (see section 
6.4).  
Intercurrent events: 
The following intercurrent events are expected to occur during the study 
IC1: Study Discontinuation for any reasons prior to Day 28.  
 
The estimand attributes for the primary analysis are as follows: 

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Criteria 
Description 
Treatment Condition  
Treatment conditions: 
• 
condition of interest: randomized to standard of care + Standard of Care + 
ABX464 50mg QD 
• 
alternative condition: randomized to Standard of Care + ABX464 50mg QD 
Patient population: 
As defined by protocol eligibility criteria, randomized and treated. 
Variable  
Binary response variable indicating response/failure [refer to primary endpoint derivation] at 
Day 28. 
Population level summary 
Estimated response probability in each treatment group separately (descriptive summaries 
may be complicated by subjects with missing primary efficacy endpoint data) 
Main estimator for primary estimand: common response probability difference across strata used in the 
randomization (see section 6.4). 
Treatment policy will be applied for all the intercurrent events (IC1), i.e., their occurrence will not lead to an exclusion 
from the analysis. 
Missing primary endpoint data will be imputed by multiple imputation assuming mechanism of missingness as 
missing at random (MAR).  
A sensitivity analysis using MNAR assumption will be performed. 
In addition, tipping point analysis will also be performed. 
The number and percentage of patients without respiratory failure or death prevented (RFDP), estimate of common 
risk difference, the corresponding CI and the p-value will be presented. The primary endpoint will also be analyzed 
using logistic regression analysis with all stratification factors and treatment. 
In addition, sensitivity analysis will be performed using logistic regression analysis with multiple factors like Age, 
BMI, Diabetes, History of ischemic cardiovascular disease, spO2, WHO Ordinal Scale etc. 
Additional details will be elaborated in the Statistical Analysis Plan (SAP). 
9.3.3. Analysis of Secondary Efficacy Endpoints 
The following secondary endpoints will be analyzed. The analysis will be done on FAS population 
• 
Rate of patients hospitalized  
• 
Percentage of patients reporting each severity rating on a 7-point ordinal scale at each study visit (i.e. 
Not hospitalized, no limitations on activities; Not hospitalized, limitation on activities; Hospitalized, not 
requiring supplemental oxygen; Hospitalized, requiring supplemental oxygen; Hospitalized, on non-
invasive ventilation or high flow oxygen devices; Hospitalized, on invasive mechanical ventilation or 
ECMO; Death) 
• 
Change in the ranking on an ordinal scale from baseline to days 7, 14, 21, 28, 48 and at 3 months after 
the last study drug intake 
• 
% change and AUC over time of oxygen saturation measured by daily pulse oximetry before 
hospitalization 
• 
Rate of patients with SpO2 ≤94% and rate of patients with SpO2 ≤92% at Day 28 
• 
Change from enrolment in inflammatory markers in plasma (i.e. MCP-1, MIP-1 α, G-CSF, IL-1b, IL-2, 
IL-6, IL-7, IL-10, IL-17, INFg and TNFa) and in immune phenotype and assessment of cell-activation 
markers in PBMCs at D14, D28 for hospitalized patients only 
• 
Rate of patients requiring oxygen supplementation 
• 
Time to hospitalization (log rank) from baseline 
• 
Time to assisted ventilation and oxygen supplementation (log rank) from baseline 
• 
Number of days of assisted ventilation 
• 
Number of days of oxygen supplementation 
• 
Number of days at the hospital from admission to discharge ps 
• 
Change from baseline in microRNA-124 levels in total blood (PAXgene®) at D0, D7 and 
• 
AUC and % of change from enrolment in CRP, Troponin I & T and D-dimer levels 
• 
Time to death and mortality rate (all causes, and Covid-19 related) 
• 
Time to improvement of one level in the 7-point ordinal scale 
• 
SARS-CoV-2 virus in nasopharyngeal sample and/or in blood at Day 0, 7 (hospitalized patients), 14, 
21, and 28 
• 
Change in SpO2 values from D0 to D14 in the outpatient’s population 
In addition, exploratory analysis to assess the radiological findings for patients hospitalized because of Covid-19 
infection consequences will be performed. 

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Central blinded review of the hospitalization discharge CT-Scans for descriptive analysis with regards to the disease 
severity and outcomes. 
Additional details will be elaborated in the Statistical Analysis Plan (SAP). 
9.4. Clinical laboratory evaluation 
Descriptive statistics for laboratory parameters will be computed at each scheduled assessment. If relevant for some 
parameter, descriptive statistics of change from baseline will also be presented. 
In addition, shift tables from baseline will also be presented. 
9.5. Determination of Sample Size 
For the sample size calculation, the following assumptions will be made: 
• 
Response rate (ABX464): 84 % 
• 
Response rate (placebo): 75 %  
• 
Type 1 error: 2.5% one-sided.  
• 
2:1 (ABX464 50mg: placebo) study treatment allocation ratio.  
• 
One futility interim analysis after approximately 300 patients complete Day 28 assessment or reach end of 
study: non-binding futility criterion is a conditional power (calculated under observed effect) ≤ 10%. 
If the above assumptions hold true, then an initial total sample size of 800 patients will lead to a power of 78%. 
Sample size re-assessment and potential increase to 1034 patients is described below in section 9.7. 
All sample size / power calculations were performed using EAST 6.5.  
9.6. Multiplicity adjustment:  
Not applicable. 
9.7. Interim analysis and sample size reassessment: 
One interim analysis is planned after approximately 300 of randomized patients’ complete day 28 assessment or reach 
end of study. Potential early stopping for futility will be based on a boundary defined by conditional power (see details 
below).  It is a non-binding futility approach so that it may be overruled by the DSMB or the Sponsor. 
The purposes for the interim analysis are to: 
• 
assess the safety of the study treatment; 
• 
potentially stop the study early for futility; 
• 
re-assess the total sample size and potentially increase it from 800 to 1034 patients. 
Interim analysis will be performed without unblinding the sponsor.  
Sample size re-assessment will be performed according to rules described in the table below. The scenarios are 
defined by conditional power for the primary efficacy endpoint calculated under the effect observed at the interim 
analysis. 
Scenario 
DSMB Recommendation to Sponsor 
Conditional power ≤ 10% 
Stop study for futility 
Conditional Power is between 10% and 80%  
Continue study, increase total sample size to 1034 
Conditional Power ≥ 80%  
Continue study with initially planned total sample size 
800 
If the total sample size is kept to 800, then the final analysis of the primary efficacy endpoint will be performed by a 
conventional CMH test (with MI handling of missing values) including all data from patients in the FAS and a one-
sided significance level of 0.025. 
If the total sample size is increased to 1034, then the final analysis of the primary efficacy endpoint will be performed 
by a weighted test statistic combining 

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the test statistic Z1 from the CMH test (with MI handling of missing values) based on primary efficacy 
endpoint data from n1 FAS patients included in the interim analysis  
 
and the test statistic Z2 from the CMH test (with MI handling of missing values) based on primary efficacy 
endpoint data from FAS patients not included in the interim analysis  
using pre-specified weights per the Cui, Hung, Wang (1999) method: 
• 
𝑤𝑤1 = ට
𝑛𝑛1
800  
• 
𝑤𝑤2 = ට800−𝑛𝑛1
800   
as 𝑍𝑍𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓= 𝑤𝑤1 ∙𝑍𝑍1 + 𝑤𝑤2 ∙𝑍𝑍2 (note that n1 is planned to be 300 and 800 is the initially planned total sample size). The 
null hypothesis of equal primary efficacy response probabilities in both study treatment groups will be rejected if 
𝑍𝑍𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 < 1.96 which corresponds to a one-sided significance level 0.025. 

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10. STUDY CONDUCT CONSIDERATION 
10.1. Regulatory and Ethical Considerations 
10.1.1. 
General Requirements 
The study will be conducted in compliance with the study protocol, ABIVAX / CRO 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 2005/28/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. 
10.1.2. 
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. 
10.1.3. 
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 also informed of his rights related to the processing of his personal data and must acknowledge that. 
The patient must be informed of and consent in writing that personal data relating to the trial may be subject 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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10.1.4. 
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, imaging, pharmacokinetics 
samplings…) 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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11. STUDY MANAGEMENT 
11.1. 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 an "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 associate's (CRA) disposal for review. 
11.2. 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.  
11.3. 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. 
11.4. Randomization 
Randomization will be centrally managed. It will be performed via the IWRS. The bottle numbers to be used for a 
specific patient will be assigned according to a pre-defined randomization list by the vendor in charge of drug 
supplies. This information will be provided to the site by fax or by email.  
11.5. 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. 
 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; 

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 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 the 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. 
During the Covid-19 outbreak, on-site monitoring visits might be postponed and delayed due to national contingency 
measures. Remote monitoring will be preferred during this period. 
11.6. 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. 
11.7. 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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11.8. 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. 
11.9. 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.  
11.10. 
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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12. REFERENCES  
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Scherrer D, Rouzier R, Noel Barrett P, Steens JM, Gineste P, Murphy RL, Tazi J, Ehrlich HJ. 12. Pharmacokinetics and tolerability of ABX464, a novel 
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Steens JM, Scherrer D, Gineste P, Barrett PN, Khuanchai S, Winai R, Ruxrungtham K, Tazi J, Murphy R, Ehrlich H. Safety, Pharmacokinetics, and 
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Agents Chemother. 2017 Jun 27;61(7). pii: e00545-17. doi: 10.1128/AAC.00545-17. 
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Rutsaert S, Steens JM, Gineste P, Cole B, Kint S, Barrett PN, Tazi J, Scherrer D, Ehrlich HJ, Vandekerckhove L Safety, tolerability and impact on viral 
reservoirs of the addition to antiretroviral therapy of ABX464, an investigational antiviral drug, in individuals living with HIV-1: a Phase IIa randomised 
controlled study.. J Virus Erad. 2019 Jan 1;5(1):10-22. 
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Vautrin A, Manchon L, Garcel A, Campos N, Lapasset L, Laaref AM, Bruno R, Gislard M, Dubois E, Scherrer D, Ehrlich JH, Tazi J. Both anti-inflammatory 
and antiviral properties of novel drug candidate ABX464 are mediated by modulation of RNA splicing. Sci Rep. 2019 Jan 28;9(1):792. doi: 
10.1038/s41598-018-37813-y. 
8. 
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–233 
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Koukos G, Polytarchou C, Kaplan JL, Morley-Fletcher A, Gras-Miralles B, Kokkotou E, et al. microRNA-124 regulates STAT3 expression and is down-
regulated in colon tissues of pediatric patients with ulcerative colitis. Gastroenterology (2013) 145(4):842.e–52.e.10.1053/j.gastro.2013.07.001 
10. Qin Z, Wang PY, Su DF, Liu X. miRNA-124 in Immune System and Immune Disorders. Front Immunol (2016) 7:406. 
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of the Rheumatic Diseases 2011;70:i88-i91. 
12. Veremeyko T, Siddiqui S, Sotnikov I, Yung A, Ponomarev ED. IL-4/IL-13-dependent and independent expression of miR-124 and its contribution to M2 
phenotype of monocytic cells in normal conditions and during allergic inflammation. PLoS One (2013) 8(12):e81774.10.1371/journal.pone.0081774 
13. Chebli K, Papon L, Paul C, Garcel A, Campos N, Scherrer D, J Ehrlich H, Hahne M, Tazi J. The Anti-Hiv Candidate Abx464 Dampens Intestinal 
Inflammation by Triggering Il-22 Production in Activated Macrophages. Sci Rep. 2017 Jul 7;7(1):4860. doi: 10.1038/s41598-017-04071-3. 
14. Manchon L, Chebli K, Papon L, Paul C, Garcel A, Campos N, Scherrer D, Ehrlich H, Hahne M, Tazi J. RNA sequencing analysis of activated macrophages 
treated with the anti-HIV ABX464 in intestinal inflammation. Sci Data. 2017 Oct 17;4:170150. doi: 10.1038/sdata.2017.150. 
15. Harriet A. Purvis, Amy E. Anderson, David A. Young, John, D. Isaacs and Catharien M. U. A Negative Feedback Loop Mediated by STAT3 Limits Human 
Th17 Responses.. J of Immu 2014; 193:1142-1150 
16. Hautefort A, Girerd B, Montani D, Cohen-Kaminsky S, Price L, Lambrecht BN, Humbert M, Perros F. T-helper 17 cell polarization in pulmonary arterial 
hypertension. Chest. 2015 Jun;147(6):1610-1620. doi: 10.1378/chest.14-1678. 
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18. Lai W, Huang L, Ho P, Montefiori D, Chen CH. The role of dynamin in HIV type 1 Env-mediated cell-cell fusion. AIDS Res Hum Retroviruses. 
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13. APPENDICES 
13.1. APPENDIX 1: CYPIA2 SUBSTRATES  
CYPIA2 substrates/inhibitors/inducers (in bold: prohibited concomitant medications) 
Substrates: 
Alosetron, Duloxetine, Ramelteon, Tasimelteon, Amitriptyline, Clomipramine, Imipramine, 
Agomelatine, Clozapine, Olanzapine, Haloperidol, Ropivacaine, Theophylline, Zolmitriptan, 
Tamoxifen, Erlotinib, Cyclobenzaprine, Mexiletine, Naproxen, Ondansetron, Phenacetin, Paracetamol, 
Propranolol, Tacrine, Tizanidine, Verapamil, Warfarin, Zileuton, Ropinirole, Methadone. 
Inhibitors: 
Artemisinin, Atazanavir, Ciprofloxacin, Enoxacin, Ethinyl Estradiol, Fluvoxamine, Mexiletine, 
Tacrine, Thiabendazole, Zileuton 
Inducers: 
Montelukast, Phenytoin, Rifampin, Ritonavir, Teriflunomide 
 
13.2. APPENDIX 2: IMMUNOSUPPRESSORS AND/OR IMMUNOMODULATORS 
Abatacept, Abetimus, Adalimumab, Afelimomab, Alefacept, Alemtuzumab, Anakinra, Apremilast, Azathioprine, 
Baricitinib, Basiliximab, Begelomab, Belatacept, Belimumab, Briakinumab, Brodalumab, Canakinumab, 
Certolizumab pegol, Cladribine, Cyclosporine, Daclizumab, Dimethyl fumarate, Eculizumab, Efalizumab, 
Emapalumab, Etanercept, Everolimus, Fingolimod, Glatiramer, Golimumab, Guselkumab, Gusperimus, 
Infliximab, Interferon, Ixekizumab, Leflunomide, Lenalidomide, Methotrexate, Muromonab, Mycophenolic acid, 
Natalizumab, Ocrelizumab, Ozanimod, Pirfenidone, Pomalidomide, Rilonacept, Sarilumab, Secukinumab, 
Siltuximab, Sirolimus, Sirukumab, Tacrolimus, Teriflunomide, Thalidomide, Tildrakizumab, Tocilizumab, 
Tofacitinib, Ustekinumab, Vedolizumab, Voclosporin.