Phase 2, Randomized, Double-blinded, Placebo-controlled, Multicenter Study to Assess Efficacy and Safety of Reparixin as add-on Therapy to SoC in Acute Respiratory Distress Syndrome (RESPIRATIO)
Phase: PHASE2
Conditions: Acute Respiratory Distress Syndrome, Adult
Sponsor: Dompé Farmaceutici S.p.A

REP0122  
Reparixin in ARDS  
Page 1 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Title:  Phase 2, proof-of-concept, randomized, double-blinded, placebo-controlled, multicenter 
study to assess efficacy and safety of reparixin as add-on therapy to standard of care in adult 
patients with Acute Respiratory Distress Syndrome (RESPIRATIO) 
 
Short title:  
 
 
Add-on reparixin in adult patients with ARDS 
 
 
Study Number:  
 
REP0122 
 
 
IND/EudraCT number:  
161827 / 2022-001612-25 
 
Investigational Product: 
Reparixin 
 
 
Phase of the study:  
Phase 2 proof-of-concept 
 
 
Protocol Version, Date: 
Version 3.0, February 8, 2024 
 
Amendment number:  
Substantial Amendment # 2, Global 
 
 
 
 
 
D Dompd

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 2  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
S T U D Y C O N T A C T I N F O R M A TI O N  
 
S P O N S O R  
D o m pé far mace utici s. p.a. [ D o m pé] 
Via Sa nta L ucia 6 , 2 0 1 2 2 Mila n, Ital y  
 
Me dic al E x pert  
 –  Ass ociate Direct or, Cli nical De vel o p me nt  
  
 
 
 
Cli nic al O per ati o n M a n a ger  
–  Site E n ga ge me nt a n d Trial Ma na ger  
 
 
 
De vel o p me nt Direct or  
  
 - Hea d of Cli nical De vel o p me nt  
 
 
 
 
C O N T R A C T R E S E A R C H O R G A NI Z A TI O N ( C R O ) 
 
Cli nic al:  
 
 
   
  
   
 
 
Bi o metrics a n d st atistics:     
 
   
 
 
 
P H A R M A C O VI GI L A N C E ( Seri o us A d verse E ve nts re p orti n g):  
 
D o m pé P har mac o vi gila nce, Safet y a n d S ur veilla nce 
e-mail: far mac o vi gila nza @ d o m pe.c o m; 
F a x: + 3 9 0 2 3 6 0 2 6 9 1 3  
 
 
  
 
 
 
C O O R DI N A TI N G I N V E S TI G A T O R S A N D I N V E S TI G A TI O N A L SI T E S  
F ull list of c o or di nati n g i n vesti gat ors a n d i n vesti gati o nal sites f or eac h c o u ntr y i n v ol ve d will be ke pt i n t he 
Trial Master File. U p date d versi o ns will be file d c hr o n ol o gicall y. C o pies will be pr o vi de d t o t he sites.  
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

REP0122  
Reparixin in ARDS  
Page 3 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
AMENDMENT DETAILS 
 
 
History of Amendments 
 
Document 
Sponsor Approval Date 
(dd/mmm/yyyy) 
Approximate {(#/%)} Enrolled 
Amendment #2 – Protocol version 3,0 
08 FEB 2023 
66, 100% 
Amendment #1 – Protocol version 2.0 
15 SEP 2022 
20, 30% 
Original Protocol version 1.0 
26 APR 2022 
0, 0% 
 

REP0122  
Reparixin in ARDS  
Page 4 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
Table of Contents 
1. 
STUDY SYNOPSIS 
9 
2. 
SCHEDULE OF EVALUATION 
16 
2.1. 
BACKGROUND INFORMATION 
18 
2.2. 
RELEVANT NON-CLINICAL STUDIES 
18 
2.3. 
SUMMARY OF TOXICOLOGY DATA 
20 
2.4. 
PHARMACOKINETICS AND PRODUCT METABOLISM 
20 
2.5. 
SUMMARY OF CLINICAL DATA 
21 
2.5.1. 
Efficacy in patients with acute lung injury due to COVID-19 
21 
2.5.2. 
Safety 
22 
2.6. 
DISEASE REVIEW AND STUDY RATIONALE 
24 
2.6.1. 
Alternative treatments 
24 
2.6.2. 
Risk – benefit evaluation 
25 
2.6.3. 
Description of the Investigational Product 
26 
3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN 
27 
3.1. 
STUDY OBJECTIVES 
27 
3.2. 
STUDY ADMINISTRATIVE STRUCTURES, STAFF AND RESPONSIBILITY 
27 
3.3. 
OVERALL STUDY DESIGN 
27 
3.3.1. 
Rationale for Selection of dose, control group and treatment schedule in the study 
28 
3.4. 
STUDY TIME_TABLE 
28 
4. 
SELECTION OF STUDY POPULATION 
29 
4.1. 
INCLUSION CRITERIA 
29 
4.2. 
EXCLUSION CRITERIA 
29 
4.3. 
ASSIGNMENT OF PATIENT NUMBER 
30 
5. 
STUDY MEDICATION 
31 
5.1. 
PRESENTATION, PACKAGING AND LABELING, SUPPLY, AND STORAGE OF THE 
INVESTIGATIONAL MEDICINAL PRODUCT 
31 
5.1.1. 
Presentation of the Investigational Medicinal Product 
31 
5.1.2. 
Manufacturing, Packaging and Labeling of IMP 
31 
5.1.3. 
Supply, Storage and Handling of IMP 
32 
5.1.4. 
Unblinding 
32 
5.2. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION 
32 
5.3. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION OR 
DISCONTINUATION OF THE IMP 
32 
5.3.1. 
Criteria for schedule adjustment/dose-modification 
33 
5.3.2. 
Criteria for discontinuation of the IMP 
33 
5.3.3. 
Criteria for temporary withholding of the IMP  
33 
5.4. 
ACCOUNTABILITY OF THE IMP 
34 
5.4.1. 
Assessment of compliance 
34 
5.5. 
PRIOR AND CONCOMITANT MEDICATIONS 
34 
5.5.1. 
Reporting of prior and concomitant medications 
34 
5.5.2. 
Medications to be used with caution 
35 
6. 
STUDY PROCEDURE AND ASSESSMENT 
36 
6.1. 
STUDY VISITS AND STUDY EVENTS/PROCEDURES DETAILS 
36 
6.1.1. 
Screening Procedures 
36 

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 5  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
6. 1. 2.  
Ra n d o mizati o n  a n d Baseli ne assess me nts  
3 6  
6. 1. 3.  
Treat me nt  a n d p ost -treat me nt h os pital sta y u p t o da y 6 0 
3 7  
6. 2.  
E A R L Y P A TI E N T WI T H D R A W A L  
3 8  
6. 2. 1.  
Wit h dra wal criteria  
3 8  
6. 2. 2.  
Re place me nt  pr oce d ures  
3 8  
6. 3.  
E N D O F S T U D Y  
3 8  
6. 4.  
P A TI E N T M A N A G E M E N T A F T E R S T U D Y C O M P L E TI O N O R T E R MI N A TI O N  
3 9  
6. 5.  
A S S E S S M E N T S A N D C LI NI C A L D E FI NI TI O N S  
3 9  
7.  
S T U D Y E N D P OI N T S  
4 1  
7. 1.  
E F FI C A C Y E N D P OI N T S  
4 1  
7. 2.  
S A F E T Y E N D P OI N T S  
4 1  
7. 3.  
P H A R M A C O KI N E TI C E N D P OI N T  
4 2  
8.  
A D V E R S E E V E N T S  
4 3  
8. 1.  
D E FI NI TI O N S  
4 3  
8. 2.  
M O NI T O RI N G F O R A D V E R S E E V E N T S  
4 4  
8. 3.  
R E C O R DI N G O F A D V E R S E E V E N T S  
4 4  
8. 3. 1.  
F oll o w -u p of patie nts wit h A Es  
4 4  
8. 3. 2.  
Relati o ns hi p of A Es t o t he I n vesti gati o nal Me dici nal Pr o d uct  
4 5  
8. 3. 3.  
Se verit y of a d verse e ve nts  
4 5  
8. 4.  
S E RI O U S  A D V E R S E E V E N T R E P O R TI N G  
4 6  
8. 4. 1.  
Re p orti n g Pr oce d ure t o D o m pé/ C R O  
4 6  
8. 4. 2.  
C o n diti o ns t hat s h o ul d n ot be re p orte d as seri o us a d verse e ve nts  
4 6  
8. 4. 3.  
A d verse e ve nts e xe m pti o n  
4 6  
8. 4. 4.  
Re p orti n g Pr oce d ure t o I E C a n d t o Re g ulat or y A ut h orities i n t he E ur o pea n U ni o n  
4 6  
8. 4. 5.  
Re p orti n g Pr oce d ures t o I R B a n d t o t he F D A i n t he U nite d States  
4 7  
8. 4. 6.  
E X P O S U R E T O I M P D U RI N G P R E G N A N C Y  
4 8  
8. 4. 7.  
A D V E R S E E V E N T S C A U SI N G T R E A T M E N T DI S C O N TI N U A TI O N  
4 8  
8. 4. 8.  
O V E R D O S E  
4 8  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
4 9  
9. 1.  
S A M P L E SI Z E  
4 9  
9. 2.  
R A N D O MI Z A TI O N  
4 9  
9. 3.  
O V E R VI E W O F P L A N N E D S T A TI S TI C A L A N A L Y SI S  
4 9  
9. 4.  
A N A L Y SI S P O P U L A TI O N  
4 9  
9. 5.  
S T A TI S TI C A L M E T H O D O L O G Y  
5 0  
9. 5. 1.  
A nal ysis of efficac y varia bles  
5 0   
9. 5. 2.  
A nal ysis of safet y varia bles  
5 1  
9. 5. 3.  
S pecificati o n of s u b gr o u ps f or a nal ysis  
5 1  
9. 5. 4.  
I nter me diate a nal yses f or t he D M C 
5 1  
 
5 1  
9. 5. 6.  
Missi n g data  
5 2  
 
1 0.  E T HI C A L C O N SI D E R A TI O N S  
5 3  
1 0. 1.  
 I N D E P E N D E N T E T HI C S C O M MI T T E E (I E C) / I N S TI T U TI O N A L R E VI E W B O A R D 
(I R B) 
5 3  
1 0. 2.  
 E T HI C A L C O N D U C T O F T H E S T U D Y  
5 3  
1 0. 2. 1.  
I D E N TI FI C A TI O N O F L E G A L L Y A U T H O RI Z E D R E P R E S E N T A TI V E S 
5 4   
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 6 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
10.2.2. 
RETROSPECTIVE SUBJECT INFORMED CONSENT 
54  
10.3. 
 SUBJECT INFORMATION AND CONSENT 
55 
10.4. 
 CONFIDENTIALITY 
55 
10.5. 
 COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 55 
11. DATA HANDLING AND RECORD-KEEPING 
56 
11.1. 
 CASE REPORT FORM (CRF) 
56 
11.2. 
 DATA MANAGEMENT 
56 
11.3. 
 DOCUMENTATION REQUIRED PRIOR TO INITIATION AND DURING THE STUDY 
 
 
 
 
 
 
 
      
 
 
 
      56 
11.4. 
 ESSENTIAL DOCUMENT RETENTION 
57 
12 STUDY MANAGEMENT 
58 
12.1 
REGULATORY BODY OF APPROVAL 
58 
12.2 
SERIOUS BREACHES MANAGEMENT  
58 
12.3 
MONITORING 
58 
12.4 
ACCESS TO RECORD 
58 
12.5 
AUDIT AND INSPECTION 
59 
12.6 
PROTOCOL AMENDMENTS 
59 
12.7 
DATA MONITORING COMMITTEE 
59 
12.8 
DISCONTINUATION OF THE STUDY 
59 
 
13. REFERENCES 
61 
14. APPENDICES 
63 
14.1. 
APPENDIX 1 - SPONSOR APPROVAL PAGE 
63 
14.2. 
APPENDIX 2 - INVESTIGATOR’S SIGNATURE PAGE 
64 
14.3. 
APPENDIX 3 - PACKAGING AND LABELING DETAILS 
65 
14.4. 
APPENDIX 4 - METHODOLOGICAL DETAILS 
66 
14.4.1. 
Calculation of Oxygenation Index 
66 
14.4.2. 
SOFA score 
66 
14.4.3. 
RALE score 
67 
14.4.4. 
Ventilatory ratio (VR) 
67 
14.4.5. 
Acute lung Injury Score 
68 
14.4.6. 
Norepinephrine equivalents 
68 
14.4.7. 
Suggested ventilation protocol 
68 
14.4.8. 
Formula for calculation of predicted body weight 
69 
14.4.9. 
Formula for calculation of eGFR 
69 
14.4.10. 
Handling of samples for assays 
69 
14.4.11. 
Ventilator-free days (VFDs) 
70 
14.5. 
APPENDIX 14.5 - CLINICAL TRIALS SUBJECT TO TRANSITION FROM EUROPEAN 
DIRECTIVE 2001/20/EC TO CLINICAL TRIAL REGULATION EU NO 536/2014 71 
14.6. 
SUMMARY OF CHANGES 
72

REP0122  
Reparixin in ARDS  
Page 7 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
List of Abbreviations and Definitions of Terms 
 
ABG 
Arterial Blood Gas analysis 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALI 
Acute Lung Injury 
ALT 
Alanine Aminotransferase 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BAL 
Broncho-Alveolar Lavage 
CBC 
Complete Blood Count 
CDE 
Cat Dander Extract 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum concentration 
COVID 
CoronaVirus Disease 
CPAP 
Continuous Positive Airway Pressure 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
Css 
Concentration, steady state 
CT 
Computerized Tomography 
CXR 
Chest X-Rays 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
electronic Case Record Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIO2 
Fraction of inspiration oxygen 
GCP 
Good Clinical Practice 
HR 
Heart Rate 
ICAM-1 
Intercellular Adhesion Molecule-1 
GI 
Gastrointestinal 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IMV 
Invasive Mechanical Ventilation 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
ITT 
Intention to Treat 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
KM 
Kaplan-Meier 
LD50 
Lethal Dose 50% 
LDH 
Lactate Dehydrogenase 
LR 
Legal Representative 
LTAC 
Long Term Acute Care 
MAP 
Mean Arterial Pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram (s) 
ml 
Milliliter (s) 
mcg 
Microgram (s) 
ng 
Nanogram (s) 

REP0122  
Reparixin in ARDS  
Page 8 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
NET 
Neutrophils Extracellular Traps 
NSAIDs 
Non Steroidal Anti Inflammatory Drugs 
OI 
Oxygenation index 
PaO2 
Partial pressure of oxygen 
PaCO2 
Partial pressure of carbon dioxide 
PAI-1 
Plasminogen Activator Inhibitor-1 
PCR 
Polymerase Chain Reaction 
PEEP 
Positive End Expiratory Pressure 
PI 
Principal Investigator 
PIP 
Peak Inspiratory Pressure 
pg 
Picogram (s) 
PK 
Pharmacokinetic 
PMN 
Polymorphonuclear cell (s) 
PP 
Per Protocol 
RAGE 
Receptor for Advanced Glycation End products 
RALE 
Radiographic Assessment of Lung Edema 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcriptase-Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
Peripheral Capillary Oxygen Saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
TID 
Three times a day 
TNFr1 
Tumor Necrosis Factor receptor 1 
TV 
Tidal Volume 
ULN 
Upper Limit of Normal 
VFDs 
Ventilatory-free days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 9  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
1.  
S T U D Y S Y N O P SI S  
 
C LI NI C A L S T U D Y S Y N O P SI S:  
St u d y C o de  
R E P 0 1 2 2  
 
Title of St u d y  
P hase 2, pr o of -of -c o nce pt, ra n d o mize d, d o u ble -bli n de d, place b o -
c o ntr olle d , m ultice nter st u d y t o assess efficac y a n d safet y of re pari xi n 
as a d d -o n t hera p y t o sta n dar d of care i n a d ult patie nts wit h Ac ute  
Res pirat or y Distress S y n dr o me ( R E S PI R A TI O)  
S h ort title  
Re pari xi n i n Ac ute Res pirat or y Distress S y n dr o me ( A R D S ) 
I N D/ E u dra C T N o. 
1 6 1 8 2 7/ 2 0 2 2 -0 0 1 6 1 2 -2 5  
St u d y Ce ntres ( C o u ntr y)  
U S, Ger ma n y, Ital y  
De vel o p me nt P hase  
P hase 2, pr o of -of c o nce pt st u d y  
 
 
 
 
O bjecti ves  
1.  T o c haracterize t he efficac y of re pari xi n i n a meli orati n g l u n g 
i nj ur y a n d s yste mic i nfla m mati o n a n d e x pe diti n g cli nical rec o ver y 
a n d li berati o n fr o m mec ha nical ve ntilati o n i n a d ult patie nts wit h 
m o derate t o se vere A R D S ( Pa O 2/ FI O 2 rati o ≤ 2 0 0). F urt her m ore,  
t o assess t he effect of re pari xi n o n s yste mic bi o mar kers li n ke d t o 
a h y per -i nfla m mat or y A R D S p he n ot y pe. 
2.  
3.  T o e val uate t he safet y of re pari xi n vs. place b o i n patie nts e nr olle d 
i n t he st u d y. 
 
 
 
Desi g n a n d Met h o d ol o g y  
P hase 2, pr o of -of -c o nce pt, ra n d o mize d,  d o u ble -bli n de d, place b o -
c o ntr olle d , m ultice nter st u d y. 
All patie nts will recei ve t hera p y i n li ne wit h c urre nt sta n dar d -of -care 
as it pertai ns t o 
A R D S 
ma na ge me nt ( pr ot oc olize d ve ntilat or 
ma na ge me nt will be ma de a vaila ble t o all sites i n acc or da nce wit h 
c urre ntl y acce pte d sta n dar d of care). Patie nts will be ra n d o mize d 
( 1: 1) t o eit her re pari xi n or place b o. D urati o n of treat me nt will be 1 4 
da ys wit h t he o pti o n t o e xte n d t o 2 1 da ys if t he patie nt is still i nt u bate d 
o n Da y 1 4.  
 
 
   St u d y pr oce d ures  
T he st u d y will c o nsist of 4 st u d y peri o ds:  
Scree ni n g  
R a n d o miz ati o n a n d B aseli ne assess me nts  
Tre at me nt ( 1 4 da ys,  wit h t he o pti o n of e xte nsi o n u p t o 2 1 da ys if t he 
patie nt is still i nt u bate d o n Da y 1 4)  
F oll o w -u p ( u p t o 2 8 da ys a n d h os pital disc har ge if later t ha n 2 8 
da ys; a n d t he n u p t o da y 6 0).  
 
Scree ni n g : P ote ntial st u d y patie nts wit h c o nfir me d A R D S will be 
i de ntifie d fr o m t h ose h os pitalize d at t he partici pati n g cli nical sites f or 
disease 
ma na ge me nt. Scree ni n g will be perf or me d i n c o nse nte d 
patie nts f or assess me nt of eli gi bilit y a n d will i ncl u de : 
● De m o gra p hic data, past me dical hist or y, aller gies t o me dicati o ns, 
disease -s pecific cli nical i nf or mati o n 
● C o nc o mita nt me dicati o ns  
● Hist or y of si de effects relate d t o pri or use of N o n -Ster oi dal A nti - 
I nfla m mat or y Dr u gs (N S AI Ds ) s uc h as gastr oi ntesti nal ( GI ) 
blee di n g or ot her f or m of blee di n g, pe ptic ulcer disease  
● Bl o o d sa m pli n g f or meas ure me nt of he mat ol o g y/ bi oc he mistr y 
( Safet y 
La b orat or y 
Tests) 
a n d 
deri ve d re nal [ Esti mate d 
Gl o mer ular Filtrati o n rate ( e G F R) e val uati o n b y 2 0 2 1 C K D -E PI] 
a n d he patic f u ncti o n [ A L T/ A S T a n d bilir u bi n deter mi nati o n] 
( u nless alrea d y c ollecte d f or cli nical care) 
● Pre g na nc y test ( uri ne test is acce pta ble) i n w o me n of c hil d beari n g  
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 10 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
potential; positive urine test results will be confirmed with a serum 
pregnancy test 
● 12-lead ECG performed using local equipment (unless already 
collected for clinical care) 
● PaO2 and FIO2 
● Chest imaging [either chest x-ray (CXR) or computerized 
tomography (CT) scan] 
 
Randomization and Baseline assessments: Patients successfully 
completing the screening process and confirmed eligible for the study 
will be randomized to either reparixin or placebo within 24 hours and 
as soon as possible from screening assessment. They then will 
proceed to the following baseline assessments, before start of 
treatment (day 1): 
● PaO2, PaCO2 and FIO2  
● Vital signs: respiratory rate (RR), heart rate (HR), mean arterial 
pressure (MAP) 
● Invasive mechanical ventilation (IMV) parameters [tidal volume 
(TV), positive end expiratory pressure (PEEP), mean airway 
pressure, plateau airway pressure) 
● Use of neuromuscular blocking agents and inhaled vasodilators 
● Prone positioning 
● Vasoactive 
medications 
(drug 
and 
dose 
calculated 
in 
norepinephrine equivalents) 
● Sequential organ failure assessment (SOFA) score 
● Blood sampling for measurement of IL-6, IL-8, PAI-1, TNFr-1, 
ICAM-1, RAGE 
● CXR (screening values, if any, will be considered if screening 
was within 24 hours) 
 
Treatment and post-treatment hospital stay assessments: 
After the baseline assessments have been completed, patients will 
start receiving the IMP. 
 
The following data will be collected daily from day 1 until extubation: 
● PaO2, PaCO2 and FIO2 
● Vital signs: RR, HR, MAP 
● IMV parameters (TV, PEEP, mean airway pressure, plateau 
airway pressure) 
● Use of neuromuscular blocking agents and inhaled vasodilators 
● Prone positioning 
● Transition to Extracorporeal membrane oxygenation (ECMO) 
● Vasoactive medications (drug and dose calculated in 
norepinephrine equivalents) 
● SOFA score 
● Number of attempts at weaning defined as continuous positive 
airway pressure (CPAP) trial (CPAP 5 cmH2O plus PEEP 5 
cmH2O) of 2 hours duration 
 
If an initial extubation is followed by reintubation, the above 
parameters will be collected daily for each subsequent re-intubation 
period. 
 
At days 2(±8h), 3(±8h), 7±1 and 14±2 a CXR will be performed 
[CXR performed for routine clinical care in intensive care unit (ICU) 
patients will be accepted]. 

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 1 1  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
 
 
O n da ys 3( ± 8 h), 7 ± 1, 1 4 ± 2 bl o o d sa m ples will be o btai ne d f or 
meas ure me nt of t he f oll o wi n g plas ma bi o mar kers: I L -6, I L -8, P AI -1, 
T N Fr -1, I C A M -1, R A G E  
 
Bet wee n e xt u bati o n  a n d da y 2 8 or h os pital disc har ge (if it occ urs 
bef ore da y 2 8) t he f oll o wi n g data will be c ollecte d e ver y 4 8 ± 8 h o urs:  
● Vital si g ns: R R, H R, M A P  
● Pa O 2 ( or S p O2) a n d FI O2 
● T y pe of o x y ge n s u p p orti ve t hera pies use d, if a n y  
● Nee d f or rei nt u bati o n (after i nitial e xt u bati o n) 
 
 
At da y 2 8 a n d at h os pital disc har ge, t he f oll o wi n g data will be 
c ollecte d: 
● Pa O 2 ( or S p O2) a n d FI O2 
● T y pe of o x y ge n s u p p orti ve t hera pies use d, if a n y  
● D urati o n of I M V  
● I C U le n gt h of sta y 
● Nee d f or rei nt u bati o n (after i nitial e xt u bati o n)  
● H os pital le n gt h of sta y  
● Perf or ma nce of trac he ost o m y  
● Tra nsfer t o l o n g ter m ac ute care ( L T A C ) facilit y 
 
S afet y : T he f oll o wi n g safet y assess me nts will be perf or me d o n da y 
3( ± 8 h), 7 ± 1, 1 4 ± 2, 2 1 ± 2 (if re pari xi n  is still a d mi nistere d o n da y 2 1) 
a n d at da y 2 8 ± 2 a n d h os pital disc har ge  
● Safet y La b orat or y Tests ( He mat ol o g y/ bi oc he mistr y)  
● Esti mate d Gl o mer ular Filtrati o n rate ( e G F R) e val uati o n 
● He patic f u ncti o n e val uati o n ( A L T/ A S T a n d bilir u bi n)  
● 1 2 lea d E C G a n d r h yt h m a nal ysis 
 
P ost -h os pit al disc h ar ge f oll o w -u p : O n da y-6 0,  t he patie nts will be 
c o ntacte d b y p h o ne f or e val uati o n of vital stat us, A Es.  
 
N u m ber of patie nts  
6 0 e val ua ble patie nts. Ass u mi n g t hat 1 0 % of e nr olle d patie nts will 
n ot be e val ua ble f or pri mar y a nal ysis, a p pr o xi matel y 6 6 patie nts will 
be e nr olle d  
 
C CI
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 12 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and Main 
Criteria for 
Inclusion/Exclusion 
Inclusion criteria 
1. 
Signed Informed Consent, according to local guidelines and 
regulations. 
2. 
Male and female adults (>18 years old) 
3. 
Mechanically ventilated (invasive) patients with PaO2/FIO2 ratio 
≤200 in the presence of PEEP of ≥5 cm H2O. 
4. 
Respiratory failure not fully explained by cardiac failure or fluid 
overload (if acute Congestive Heart Failure exacerbation is 
identified as part of the clinical picture, this should be addressed 
effectively and as soon as possible before the patient can be 
enrolled). 
5. 
Bilateral radiologic opacities consistent with pulmonary edema 
on the frontal chest x-ray (CXR) radiograph, or bilateral ground 
glass opacities on a chest CT scan. 
6. 
≤48 hours from fulfilling above ARDS criteria (if a patient is 
transferred from a non-participating hospital to a participating site, 
a 12-hour period beyond the 48 hours is allowed) 
7. 
Females of child-bearing potential who are sexually active must 
be willing not to get pregnant within 30 days after the last 
Investigational Medicinal Product (IMP) dose and must agree to 
at least one of the following reliable methods of contraception: 
• Hormonal contraception, systemic, implantable, transdermal, 
or injectable contraceptives from at least 2 months before 
the screening visit until 30 days after the last IMP dose; 
• A sterile sexual partner; 
• Abstinence. 
For patients unable to personally consent to the above, due to 
complications of acute illness and/or its treatment, assurances for 
the above must be given by LR and reiterated by the patient when/if 
she is able to do so. 
Female participants of non-child-bearing potential or in post-
menopausal status for at least 1 year will be admitted. For all 
female subjects with child-bearing potential, pregnancy test results 
must be negative before first drug intake. 
 

REP0122  
Reparixin in ARDS  
Page 13 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
 
Exclusion criteria 
1. 
Moderate-Severe chronic hepatic disease (as verified by a 
previously known Child-Pugh score ≥7). If baseline Child-Pugh 
score is not known, it should not be calculated while the patient 
is acutely ill. In that case, the patient is excluded on the basis of: 
ALT/AST ≥ 3x ULN and total bilirubin > 2x ULN or ALT/AST 
≥ 5x ULN.   
2. 
Severe chronic renal dysfunction: eGFR (2021 CKD-EPI) < 30 
mL/min/1.73m2. If baseline (chronic) renal function is not 
known, the patient is only excluded if in need of acute renal 
replacement therapy (currently on RRT or to be imminently 
placed on RRT). 
3. 
Participation in another interventional clinical trial. 
4. 
Patients that are clinically determined to have a high likelihood 
of death within the next 24 hours based on PI’s estimation. 
5. 
Currently receiving ECMO or high frequency oscillatory 
ventilation. 
6. 
Anticipated extubation within 24 hours of screening. (In such 
cases, re-screening is allowed if the patient is within the 
enrollment window).  
7. 
Evidence of GI dysmotility as demonstrated by presence of all 
the following: persistent gastric distention and enteral feeding 
intolerability and persistent gastric residuals >500 ml). 
8. 
Anticipated transfer to a hospital not participating in the trial 
within 72 hours of screening. 
9. 
Decision to withhold or withdraw life-sustaining treatment 
(patients may still be eligible however if they are committed to 
full support except cardiopulmonary resuscitation if cardiac 
arrest occurs). 
10. History of: 
a) Documented 
allergy/hypersensitivity 
to 
sulfonamides, 
ibuprofen and other COX-1 and 2 inhibitors, and to the study 
product and/or its excipients. 
b) Lactase deficiency, galactosemia or glucose-galactose 
malabsorption. 
c) History of peptic ulcer, GI bleeding or perforation due to 
previous NSAID therapy. 
11. Active bleeding (excluding menses) from an uncontrolled site that 
cannot be definitively resolved prior to enrollment. 
12. Pregnant or lactating women. 
13. Women of childbearing potential and fertile men who do not agree 
to use at least one primary form of contraception during the study 
and up to 30 days after the last IMP dose.  
 
For patients unable to personally consent to above due to 
complications of acute illness and/or its treatment, assurances for the 
above must be given by LR and reiterated by the patient when/if he/she 
is able to do so. 

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 1 4  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
 
Test Pr o d uct, D osa ge a n d 
M o de of A d mi nistrati o n  
Re pari xi n  6 0 0 m g ta blets, a d mi nistere d cr us he d t hr o u g h nas o gastric 
t u be at t he d ose of 1 2 0 0 m g TI D ( 2 ta blets TI D) as a d d-o n t o t he  
sta n dar d of care. After e xt u bati o n a n d if t he patie nt ca n s wall o w, 
re pari xi n ma y be a d mi nistere d orall y 
D urati o n of Treat me nt  
1 4 da ys wit h t he o pti o n t o c o nti n ue u p t o 2 1 da ys, if t he patie nt is still  
i nt u bate d o n Da y 1 4 
Refere nce pr o d uct, D osa ge 
a n d 
M o de of A d mi nistrati o n  
Place b o ta blets. A d mi nistere d cr us he d t hr o u g h nas o gastric t u be wit h 
t he 
sa me sc he d ule as re pari xi n as a d d-o n t o t he sta n dar d of care. After 
e xt u bati o n a n d if t he patie nt ca n s wall o w place b o ma y be a d mi nistere d 
orall y  
 
Pri mar y efficac y e n d p oi nts  
- C ha n ge i n o x y ge nati o n i n de x ( OI ) fr o m baseli ne t o da y 7 of 
treat me nt. T he OI is defi ne d as: 
% mea n air wa y press ure x 
FI O 2/ Pa O2  
- Ve ntilat or free da ys ( V F D ) at da y 2 8 
 
 
 
 
 
 
 
 
 
 
Sec o n dar y e n d p oi nts  
- 
C ha n ge i n OI fr o m baseli ne t o da y 4  
- 
Ac ute l u n g i nj ur y sc ore [c o m p osite of Pa O 2/ FI O2 rati o, P E E P, 
l u n g c o m plia nce ( platea u air wa y press ure mi n us P E E P/ T V) a n d 
e xte nt of p ul m o nar y i nfiltrates] at 2, 3, 7, 1 4 da ys (if still 
i nt u bate d) 
- 
S O F A sc ores at 2, 3, 7, 1 4 da ys (if still i nt u bate d)  
- 
Ve ntilat or y rati o ( pr o d uct of mi n ute ve ntilati o n a n d Pa C O 2) at 
2, 3, 7, 1 4 da ys (if still i nt u bate d) 
- 
I nci de nce of E C M O b y da y 1 4 
- 
Use of vas oacti ve me dicati o ns b y da y 1 4  
- 
C X R assess me nt of p ul m o nar y e de ma b y “ra di o gra p hic 
assess me nt of l u n g e de ma” ( R A L E ) sc ore at 2, 3, 7, 1 4 da ys 
- 
Perce nta ge of patie nts ac hie vi n g press ure s u p p ort ve ntilati o n 
e q ual t o 5 c m H 2O  wit h P E E P e q ual t o 5 c m H 2O  f or 2 h o urs 
( meas ure of wea ni n g) b y da y 2 8 a n d at h os pital disc har ge 
- 
I C U-free da ys b y da y 2 8 a n d h os pital disc har ge 
- 
H os pital -free da ys b y da y 2 8 a n d h os pital disc har ge 
- 
I nci de nce of trac he ost o mies b y da y 2 8 a n d h os pital disc har ge 
- 
I nci de nce of tra nsfer t o l o n g ter m ac ute care (L T A C ) facilit y b y 
da y 2 8 a n d h os pital disc har ge  
- 
All -ca use m ortalit y b y da y 2 8  
- 
H os pital disc har ge b y da y 2 8  
- 
All -ca use m ortalit y b y da y 6 0  
- 
C ha n ge fr o m baseli ne t o da y 3, 7 a n d da y 1 4 i n plas ma le vels of 
I L- 6, I L -8, P AI -1, T N Fr -1, I C A M -1 R A G E  
 
 
 
 
  
 
 
  
  
  
 
 
 
 
 
 
 
 
 
Safet y e n d p oi nts  
● 
I nci de nce of Treat me nt E mer ge nt A Es (T E A Es ) a n d S A Es 
(T E S A Es ) fr o m t he be gi n ni n g of st u d y treat me nt t o u p t o t he 
e n d of st u d y partici pati o n.  
● 
He mat ol o g y/ bi oc he mistr y val ues c ha n ge fr o m scree ni n g t o da y 
3( ± 8 h), 7 ± 1, 1 4 ± 2, 2 1 ± 2 (if still recei vi n g re pari xi n), 2 8 ± 2 a n d 
h os pital disc har ge.  
● 
e G F R, a bs ol ute val ue a n d c ha n ge fr o m scree ni n g t o da y 3( ± 8 h), 
7 ± 1, 1 4 ± 2, 2 1 ± 2 (if still recei vi n g re pari xi n), 2 8 ± 2 a n d h os pital 
disc har ge.  
● 
He patic f u ncti o n ( A L T/ A S T, t otal/ direct bilir u bi n), a bs ol ute 
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 15 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
values and change from screening to day 3(±8h), 7±1, 14±2, 
21±2 (if still receiving reparixin), 28±2 and hospital discharge.  
● 
ECG/rhythm analysis changes from screening to day 3±8h, 7±1, 
14±2, 21±2 (if still receiving reparixin), 28±2 and hospital 
discharge. 
● 
Incidence of secondary infections by day 28±2 or hospital 
discharge. 
 
Statistical Methods 
A sample size of 60 evaluable subjects is considered adequate for 
descriptively assessing the difference between groups in primary 
endpoints, i.e. change from baseline in OI at day 7 and VFD at day 
28 Assuming equal size groups (1:1), the given sample size will 
provide a reasonable precision in the estimation of group differences 
in primary endpoints to an expected margin of error for a 95% one-
sided confidence interval of at most 46.5% the standard deviation, 
whatever it is. Consequently, assuming a standard deviation of 11.5 
points for OI and of 8 days for VFD (based on literature), the 95% 
one-sided confidence intervals for the differences between groups 
will have a width of 5.35 points and 3.75 days, respectively. 
Assuming that 10% of enrolled patients will not be evaluable for 
primary analysis, the total number of patients to be enrolled will be 
approximately 66. 
Appropriate descriptive statistics will be produced by treatment arms 
according to the nature of the variable. For continuous data, number 
of observations, mean, standard deviation, median, range (minimum 
and maximum) and 95% confidence intervals will be presented. For 
categorical data, frequency distributions and percentages with 95% 
confidence intervals (Wilson method) per category will be presented. 
The Safety and the Full Analysis Set (FAS) populations will consist 
of all patients who will be randomized and received at least one dose 
of the investigational product. Safety population will be analyzed 
according to the actual treatment received; FAS population will be 
analyzed according to the Intention To Treat principle, i.e. by 
treatment allocation. 
All secondary endpoints will be analyzed at each available time point 
by means of summary statistics and by appropriate parametric or non-
parametric tests depending on the nature of the variable and its 
distribution. All analyses will be descriptive in nature. 
TEAEs and TESAEs will be presented in terms of the number and 
incidence of TEAEs and TESAEs. Other safety parameters will be 
summarized by treatment at each available time point by means of 
descriptive statistics. 
The Study Statistical Analysis Plan with more technical and detailed 
elaboration of the principal features of statistical analyses will be 
finalized before database lock. Any deviation from the original 
statistical plan will be described in the Clinical Study Report. 

REP0122  
Reparixin in ARDS  
Page 16 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
2. 
SCHEDULE OF EVALUATION 
The grid below summarizes the study schedule of the trial. For all measurements, the actual date and time 
of assessment, including date of sampling, will be recorded in the Source Document and/or eCRFs. 
Timeframe for each assessment is also shown in the grid below. 
 
Days  
(windows) 
Screening (day-1 or 1) 
Randomization and 
baseline assessments1 
Day 1 
Day 2 (±8h) 
Day 3 (±8h) 
Day7 (±1) 
Day 14 (±2) 
End of Treatment21 
Extubation to 
Hospital Discharge 
(every 48h±8h) 
Day 28 (±2) and 
Hospital 
Discharge19 
Day 60 
ELIGIBILITY 
Informed consent 
signed 
X 
 
 
 
 
 
 
 
 
 
 
Demo- 
graphics, Medical 
History, Disease-
Specific 
Information, 
allergies 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
IMP 
administration3 
 
 
 
Daily through day 14 with the option to 
extend to day 21 
 
 
 
STUDY PROCEDURES 
Vital signs (RR, 
HR, MAP) 
 
Daily through extubation 
X 
 
 
PaO2 (or SaO2), 
FIO2 
X 
Daily through extubation 
X 
X 
 
PaCO2 
 
Daily through extubation 
 
 
 
Mechanical 
ventilation 
parameters4 
 
 
Daily through extubation 
 
 
 
SOFA score 
 
Daily through extubation 
 
 
 
Neuromuscular 
blocking agents, 
inhaled 
vasodilators6 
 
 
Daily through extubation 
 
 
 
Prone positioning6 
 
Daily through extubation 
 
 
 
Vasoactive 
medications7 
 
Daily through extubation 
 
 
 
ECMO8 
 
Daily through extubation 
 
 
 
CPAP attempts 9 
 
Daily through extubation 
 
 
 
Chest imaging10 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Biomarkers11 
 
X 
 
 
X 
X 
X 
 
 
 
 
Reintubation12 
 
 
 
 
 
 
 
 
 
X 
 
Other clinical 
events13 
 
 
 
 
 
 
 
 
 
X 
 
Follow up14 
 
 
 
 
 
 
 
 
 
 
X 
SAFETY TESTS 
Adverse events 
 
Concomitant 
medications 
 
Safety 
hematology 
and 
X 
 
 
 
X 
X 
X 
X 
 
X 
 

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 1 7  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
Da ys  
( wi n d o ws) 
Scree ni n g ( da y -1 or 1)  
Ra n d o mizati o n a n d 
baseli ne assess me nts 1 
D a y 1  
D a y 2 ( ± 8 h)  
D a y 3 ( ± 8 h)  
D a y 7 ( ± 1)  
D a y 1 4 ( ± 2)  
E n d of Treat me nt 2 1 
E xt u bati o n  t o 
H os pital Disc har ge 
(e ver y 4 8 h ± 8 h)  
D a y 2 8  ( ± 2) a n d 
H os pital 
Disc har ge 1 9 
Da y 6 0  
bi o c he mistr y 1 5  
e G F R 1 6  
X  
 
 
 
X  
X  
X  
X  
 
X  
 
He patic 
f u ncti o n1 7  
X  
 
 
 
X  
X  
X  
X  
 
 
 
E C G  
X  
 
 
 
X  
X  
X  
X  
 
X 2 1 
 
 
1.  Baseli ne a n d i nitiati o n of I M P ( da y 1) ma y c oi nci de  
2.  I n fe males of c hil d beari n g p ote ntial, o nl y date will be re q uire d 
3.  St u d y pr o d uct will be a d mi nistere d e v er y 8 h o urs ( q 8 h) f or 1 4 da ys, a n d o pti o nall y u p t o 2 1 da ys  
4.  M o de of ve ntilati o n, T V, mea n air wa y press ure, platea u air wa y press ure, P E E P  
5.  Use or n ot of ne ur o m usc ular bl oc ki n g me dicati o ns a n d/ or i n hale d vas o dilat ors  
6.  Use or n ot of t he m o dalit y of pr o ne p ositi o ni n g  
7.  T y pe a n d d ose of vas oacti ve me dicati o ns meas ure d i n n ore pi ne p hri ne e q ui vale nts  
8.  Tra nsiti o n or n ot t o E C M O  
9.  Defi ne d as use of press ure s u p p ort v e ntilati o n e q ual t o 5 c m H 2O wit h P E E P e q ual t o 5 c m H 2O f or 2 h o urs  
1 0.  C hest i ma gi n g at scree ni n g will be i n t he f or m of C X R or C T sca n base d o n i nstit uti o nal prefere nces a n d 
res o urces. C X R will be perf or me d at ot her ti me p oi nts. If n o m ore t ha n 2 4 h o urs ha ve ela pse d fr o m a scree ni n g 
C X R, baseli ne C X R will be deferre d.  
1 1.  I L-6, I L -8, P AI -1, T N Fr -1, I C A M -1, R A G E  
1 2.  De n otes re p eat i nt u bati o n at least 2 4 h o urs after a s uccessf ul e xt u bati o n  
1 3.  De n otes: D urati o n of I M V, I C U le n gt h of sta y, nee d f or rei nt u bati o n (after i nitial e xt u bati o n, o ver le n gt h of 
h os pitalizati o n), H os pital le n gt h of sta y, perf or ma nce of trac he ost o m y, tra nsfer t o L T A C facilit y * 
1 4.  Verificati o n of vital stat us a n d i n q uir y a b o ut A E ( p h o ne i nter vie w)  
1 5.  I ncl u des He m at ol o g y ( R B B, he mat ocrit, he m o gl o bi n, 
W B C, ne utr o p hils a n d l y m p h oc ytes a bs ol ute c o u nt, 
platelets c o u nt) a n d Bi oc h e mistr y (s o di u m, p otassi u m, c hl ori de, calci u m, gl uc ose, creati ni ne, al b u mi n, A S T, 
A L T, t otal a n d direct bilir u bi n). Res ults o btai ne d at t he h os pital i n t he pre vi o us 4 8 h o urs ca n be acce pte d as 
scree ni n g val ues. 
1 6.  Esti mate d gl o mer ular filtrati o n rate (e G F R) deter mi ne d b y 2 0 2 1 C K D -E PI  
1 7.  He p atic f u ncti o n is e v al uate d base d o n A L T/ A S T a n d t otal/ direct bilir u bi n le vels –  da y 1 4 assess me nt re q uire d 
if treat me nt is pr ol o n ge d u p t o da y 2 1 
  
 
1 9.  If h os pital disc h ar ge occ urs < 2 8 d, a 2 8-d f oll o w -u p i n -pers o n visit s h o ul d be perf or me d. If t his is n ot feasi ble, 
a p h o ne f oll o w -u p will be pla n ne d t o c ollect: D urati o n of I M V, I C U le n gt h of sta y, nee d f or rei nt u bati o n, 
H os pital le n gt h of sta y, perf or ma n ce of trac he ost o m y, tra nsfer t o L T A C * facilit y, or m ortalit y. 
2 1.  O nl y at h os pital disc h ar ge  
 
 
* A n L T A C is a L o n g Ter m Ac ute Care H os pital, i.e., a facilit y t hat s pecializes i n t he treat me nt of patie nts 
wit h seri o us me dical c o n diti o ns, i ncl u di n g patie nts wit h o n g oi n g nee ds f or mec ha nical ve ntilati o n, b ut w h o 
n o l o n ger re q uire i nte nsi ve care or e xte ns i ve dia g n ostic pr oce d ures. T he patie nts i n L T A C are tra nsferre d 
t here directl y fr o m t he i nte nsi ve care u nit beca use t he y re q uire m ore care t ha n t he y ca n recei ve i n a 
re h a bilitati o n ce nter, s kille d care facilit y or at h o me.
C CI
C C
I
C CI
C CI
C CI
C CI
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 18 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
2.1. BACKGROUND INFORMATION 
Reparixin is a specific inhibitor of the two receptors for IL-8 (CXCL8), i.e., CXCR1 and CXCR2, stemming 
from a program of drug design of molecules intended to modulate chemokine activity. Reparixin is the first 
low molecular weight blocker of IL-8 biological activity in clinical development. It has been shown to inhibit 
polymorphonuclear leukocytes (PMN) chemotaxis in animal and human studies. Early, pre-clinical 
characterization of reparixin was specifically targeted on the prevention of ischemia/reperfusion injury during 
solid organ transplantation which is known to be due to PMN recruitment in the transplanted organ. In this 
field, reparixin received orphan drug designation in EU in September 2001 and in USA in January 2003 for 
prevention of delayed graft dysfunction after solid organ transplantation. More recently, orphan drug 
designation was granted in EU (September 2011) for the “prevention of graft loss in pancreatic islet 
transplantation” and in the US (September 2012) for the “prevention of graft loss in islet cell transplantation”. 
The recent COVID-19 epidemic provided a unique opportunity to evaluate the role of IL-8 inhibition in 
severe lung injury induced by SARS-COV2. Initial compassionate use of reparixin, in the form of IV infusion, 
in 4 patients with COVID-19 induced Acute Respiratory Distress Syndrome (ARDS) led to clinical 
improvement and was subsequently followed by phase II and  phase III studies which verified the salutary 
effect of reparixin in preventing disease progression. The insights gained from these studies will be further 
expanded in our proposed study of reparixin in ARDS.  
 
2.2. RELEVANT NON-CLINICAL STUDIES 
Reparixin is a potent and specific inhibitor of CXCL8 biological activity. In vitro experiments have shown 
that reparixin inhibits CXCL8-induced chemotaxis of human PMN in the low nanomolar range. Studies to 
elucidate the mechanism of action have shown that reparixin is a non-competitive allosteric inhibitor of the 
CXCL8 receptors CXCR1 and CXCR2. Interaction of reparixin with CXCL8 receptors inhibits the 
intracellular signal transduction events activated by binding of CXCL8 to CXCR1 and CXCR2 1,2. 
Ischemia/reperfusion 
In vivo, in a rat model of lung transplantation, reparixin improved graft oxygenation, decreased pulmonary 
oedema, and significantly reduced neutrophil infiltration into the transplanted lung. Moreover, reparixin 
prevented PMN infiltration and tissue damage in other animal models of ischemia/reperfusion injury of liver, 
brain, intestine, heart and spinal cord. In these models, in vivo inhibition of PMN recruitment ranged from 40 
to 90%, and inhibition of tissue damage ranged from 50 to 80%.  
LPS induced Acute Lung Injury (ALI) 
In a murine model of LPS-induced ALI, reparixin (15 μg/g) reduced neutrophil recruitment in the interstitial 
pulmonary compartment by approximately 50% and ameliorated vascular permeability. Both prophylactic 
and therapeutic application of reparixin improved gas exchange and reduced neutrophil recruitment and 
vascular permeability in a clinically relevant model of acid-induced ALI3. 
Allergen induced airway inflammation 
In the cat dander extract (CDE) single challenge model, administration of reparixin (15 mg/kg) suppressed 
neutrophil recruitment into the lungs. In the CDE multiple challenge model, reparixin decreased eosinophils, 
neutrophils, and total cell numbers in bronchoalveolar lavage (BAL) fluid, serum levels of total IgE and CDE-
specific IgE, airway epithelial mucin secretion, levels of Th2 inflammation associated genes periostin and 
muc5ac, and BAL fluid levels of IL‐ 4, IL‐ 13, IL‐ 33, and TSLP. Pharmacological inhibition of CXCR1/2‐ 
axis by administration of reparixin inhibited allergen induced airway inflammation in mice4. 
Bleomycin model of pulmonary fibrosis 
In a murine model of pulmonary fibrosis induced by exposure to a combination of bleomycin and particulate 
matter, inhibition of CXCR2 with reparixin reduced neutrophil number and neutrophil elastase concentration 
in BAL fluid. Moreover, reparixin improved lung function and reduced extent of pulmonary fibrosis, as 
assayed by total lung collagen content and histochemical stains of fibrosis markers, on day 14 lung tissues5. 
Pneumococcal and influenza pneumonia 

REP0122  
Reparixin in ARDS  
Page 19 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
The role of CXCR1/2 inhibition during influenza, pneumococcal, and post-influenza pneumococcal 
infections was also investigated. Most experiments were conducted using DF2162, a reparixin analogue, 
belonging to the same family of non-competitive allosteric inhibitors of CXCR1 and CXCR2. Reparixin and 
DF2162 exhibit similar potency in the inhibition of the target receptors CXCR1 and CXCR2 (IC50s for IL- 
8-induced chemotaxis in the range of 1 nM). The molecular mechanism of action has been characterized by 
point-mutagenesis studies on CXCR1 and CXCR2 showing that reparixin and DF2162 bind the receptors in 
the same allosteric site of the trans-membrane region, which is highly conserved between the two receptor 
subtypes. DF2162 was used to assess the role of CXCR1/2 in influenza (IAV), pneumococcal, and post-
influenza pneumococcal infections in mice. Mice were infected with IAV or Streptococcus pneumoniae and 
then treated daily with DF2162. To simulate secondary pneumococcal infection, mice were infected with a 
sublethal inoculum of IAV followed by infection with S. pneumoniae 14 days later. DF2162 was given in a 
therapeutic schedule from day 3 to day 6 after influenza infection. Lethality, weight loss, inflammation, 
viral/bacterial counts, and lung injury were assessed. CXCL1 and CXCL2 (the functional murine analogues 
of CXCL8) were produced at high levels during IAV infection. DF2162 treatment decreased morbidity, and 
this was associated with decreased lung neutrophil infiltration and reduced pulmonary damage and viral titers. 
During S. pneumoniae infection, DF2162 treatment decreased neutrophil recruitment, pulmonary damage, 
and mortality, without affecting bacterial burden. Treatment with DF2162 during sublethal IAV infection 
followed by infection with S. pneumoniae reduced the morbidity associated with the viral infection and also 
decreased the magnitude of inflammation, lung damage, and bacterial titers in mice subsequently infected 
with S. pneumoniae. These data suggest that modulation of the inflammatory response through blockade of 
CXCR1/2 improves disease outcome during 
influenza and pneumococcal infections, without compromising the ability of the murine host to deal with 
infection6. To determine if reparixin would replicate the effect of DF2162 in influenza infection, mice were 
infected with 1 × 104 PFU of IAV and then treated three times a day (from day 0 i.e., time of infection, to 
day 5 post-infection) with reparixin at 15 mg/kg. As with DF2162, treatment with reparixin decreased 
morbidity, as seen by the reduction in weight loss, suppressed the pro-inflammatory cytokines TNF-α and 
CXCL1 as well as the leukocytic, and in particular, neutrophilic infiltration into the airways and improved 
the histopathologic lung injury score. 
COVID-19 
During COVID-19 neutrophils undergo IL-8-induced degranulation that drives a systemic prothrombotic 
phenotype. Therapeutic blockade of IL-8 by reparixin reduced COVID-19-associated human neutrophil 
activation in vitro and attenuated pulmonary capillary micro-thrombosis in vivo in the transgenic hACE2 
mouse model of COVID-19 associated respiratory failure where reparixin treatment led to decreased 
fibrinogen binding by intravascular neutrophils7.

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 2 0  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
2. 3.  S U M M A R Y O F T O XI C O L O G Y D A T A  
Re pari xi n  was teste d f or t o xicit y i n r o de nt a n d n o n -r o de nt a ni mal s pecies after si n gle a n d re peate d I V d oses. 
T he re peate d d ose a d mi nistrati o n st u dies were c o n d ucte d b y I V c o nti n u o us i nf usi o n, acc or di n g t o t he 
i nte n de d h u ma n a d mi nistrati o n r o ute. T he ge neral t o xic ol o gical pr ofile of I V re pari xi n, i n t he st u dies 
c o n d ucte d t o date, is c haracterize d b y a l o w t o xicit y after si n gle or re peate d d ose a d mi nistrati o ns i n rats 
 
 
. C o nti n u o us I V i nf usi o n of re pari xi n t o male a n d fe male rats at d ose le vels of u p t o  
 
 di d n ot ha ve a n y si g nifica nt a d verse effects o n mati n g perf or ma nce a n d fertilit y. Re pari xi n p oses 
n o ge n ot o xic hazar d f or h u ma ns.  
Re pari xi n l ysi ne salt, at d oses i n e xcess of t h ose i nte n de d f or use i n h u ma ns, has a safe p har mac ol o g y pr ofile 
i n t he re nal, car di o vasc ular a n d res pirat or y s yste ms of rats a n d d o gs. T he l ocal t olera bilit y of re pari xi n l ysi ne 
salt was assa ye d i n t he ra b bit ear lateral vei n. T he c o m p o u n d was well t olerate d i n c o nce ntrati o ns u p t o  
 
 i nf use d o ver o ne mi n ute. I n or der t o pr o vi de e vi de nce of t he safet y of D F 2 2 4 3 Y, t he mai n 
meta b olite of re pari xi n e xcrete d i n uri ne i n h u ma ns, safet y, p har mac ol o g y, a n d t o xicit y st u dies ha ve bee n 
perf or me d at d oses 2 t o 3 ti mes hi g her t ha n t h ose reac he d i n ma n, as ma y occ ur d uri n g t he treat me nt of 
patie nts recei vi n g ki d ne y tra ns pla ntati o n.  
I n t he precli nical setti n g, re pari xi n has s h o w n a n e xcelle nt safet y pr ofile as de m o nstrate d wit h ver y 
c o m pre he nsi ve t o xic ol o gical st u dies i n vitr o a n d i n a ni mal s pecies.  
 
 
2. 4.  P H A R M A C O KI N E TI C S A N D P R O D U C T M E T A B O LI S M  
P har mac o ki netic ( P K ) st u dies b y I V i njecti o n re veale d t hat re pari xi n is ver y ra pi dl y eli mi nate d i n rats a n d 
h u ma ns ( T 1/ 2 0. 5 -3 hrs a n d 1. 0 -1. 5 hrs, res pecti vel y) w hereas eli mi nati o n is sl o wer i n d o gs ( 1 2 -2 8 hrs). T he 
P K of re pari xi n was li near i n rats a n d i n d o gs , b ut li nearit y was less e vi de nt i n h u ma ns. Re pari xi n u n der g oes 
c o m plete meta b olis m ( o xi dati o n + c o nj u gati o n) i n all t he s pecies teste d. T he i n vitr o h u ma n he patic, p hase I 
meta b olis m of re pari xi n is catal yze d b y C Y P 2 C 9 a n d t o a lesser e xte nt b y C Y P 2 C 1 9. D F 2 2 4 3 Y, D F 2 1 8 8 Y, 
met ha nes ulf o na mi de a n d i b u pr ofe n are t he meta b olites detecte d i n h u ma n plas ma a n d uri ne, wit h D F 2 2 4 3 Y 
bei n g t he maj or meta b olite. T he  plas ma le vels of i b u pr ofe n after a d mi nistrati o n of re pari xi n 2. 7 7 m g/ k g/ h f or 
4 8 hrs (t he hi g hest d ose teste d i n h u ma ns) were si milar or l o wer t o t h ose o btai ne d after a sta n dar d t hera pe utic 
si n gle d ose of i b u pr ofe n ( 3 0 0 m g). Preli mi nar y P K data o btai ne d i n  a fe w patie nts u n der g oi n g islet 
tra ns pla ntati o n s h o we d t hat plas ma le vels of re pari xi n (t otal a n d u n b o u n d) a n d its maj or meta b olite D F 2 2 4 3 Y 
were wit hi n t he e x pecte d ra n ge acc or di n g t o t he d ose a d mi nistere d. D ue t o e xte nsi ve meta b olis m, u nc ha n ge d 
re pari xi n was mi ni mall y or n ot at all o bser ve d i n t he uri ne of rats, d o gs a n d h u ma ns,  s u g gesti n g t hat t he P K 
pr ofile of re pari xi n is n ot i nfl ue nce d b y re nal i m pair me nt. I n vitr o pr otei n bi n di n g of [ 1 4 C] - re pari xi n s h o we d 
t hat re pari xi n is hi g hl y b o u n d (a p pr o xi matel y 9 9 %) t o plas ma pr otei ns i n rats, d o gs, ra b bits, c y n o m ol g us 
m o n ke ys a n d h u ma ns. Al b u mi n is li kel y t o be t he maj or bi n di n g pr otei n i n plas ma i n all s pecies, acc o u nti n g 
for 9 9. 2 % i n h u ma ns. 
I n cli nical trials wit h oral ta blets, re pari xi n was a d mi nistere d f or 2 1 c o nsec uti ve da ys f oll o we d b y 7 da ys of 
dr u g h oli da y bef ore t he ne xt c ycle. Re pari xi n was ra pi dl y a bs or be d ( me dia n T ma x 1 hr). Re pari xi n s yste mi c 
e x p os ure ( C ma x a n d A U C last) di d n ot c ha n ge fr o m da y 1 t o da y 2 1, i n dicati n g t he a bse nce of acc u m ulati o n 
o ver t he d osi n g peri o d. Als o, T 1/ 2 di d n ot c ha n ge fr o m da y 1 t o da y 2 1, wit h a me dia n val ue of a b o ut 2 hrs. 
O nce a bs or be d, re pari xi n is hi g hl y b o u n d t o pr otei ns as o nl y < 0. 1 % t o 0. 2 % of t otal re pari xi n is a vaila ble as 
u n b o u n d (free) dr u g. Re pari xi n was ra pi dl y meta b olize d t o D F 2 2 4 3 Y, D F 2 1 8 8 Y a n d i b u pr ofe n. F or all t hree 
meta b olites s yste mic e x p os ure was si milar o n b ot h da y 1 a n d da y 2 1 wit hi n t he o bser ve d i nter -s u bject 
varia bilit y. T he T 1/ 2 of all t hree meta b olites a p peare d t o re mai n a b o ut t he sa me fr o m da y 1 t o da y 2 1.  
T o i n vesti gate t he P D c haracteristics of re pari xi n, t he effect of t he dr u g i n i n hi biti n g I L -8 - me diate d 
Ne utr o p hils E xtracell ular Tra ps ( N E T ) release b y h u ma n P M N i n t he w h ole bl o o d of healt h y v ol u nteers was 
assesse d. Re pari xi n bl oc ke d I L -8 -i n d uce d N E T f or mati o n i n a c o nce ntrati o n de pe n de nt ma n ner, wit h t he 
i n hi biti o n ( 4 0 %) bec o mi n g statisticall y si g nifica nt at 5 µ g/ m L a n d reac hi n g near c o m plete ness (a b o ut 9 0 %) 
at 2 5 µ g/ m L w hic h c orres p o n ds t o t he t otal bl o o d c o nce ntrati o n (e q ui vale nt t o a free u n b o u n d c o nce ntrati o n 
of 1 0 0 n M) t hat is reac he d at t he stea d y state ( Css ) b y I V i nf usi o n or b y re peate d oral a d mi nistrati o n. 
Re pari xi n has s o me p ote ntial i n vitr o f or a n o n-c o m petiti ve i n hi biti o n of t he h u ma n he patic e nz y me C Y P 3 A 4 
t hat is i n v ol ve d i n t he meta b olis m of c ycl os p ori ne A, tacr oli m us a n d ra pa m yci n. H o we ver, si nce i n hi biti o n 
C CI
C CI
C CI

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 2 1  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
is e vi de nt at c o nce ntrati o ns far hi g her t ha n t he free plas ma c o nce ntrati o n of re pari xi n at stea d y state i n 
h u ma ns, it is pre dicte d t hat t he cli nical rele va nce of s uc h i n hi biti o n is mi n or. I n dee d, re pari xi n d oes n ot 
affect, t o a cli nicall y rele va nt e xte nt, t he acti vit y of C Y P 3 A 4 a n d C Y P 2 C 9 (e nz y me i n v ol ve d i n re pari xi n 
meta b olis m), as re veale d b y a n i nteracti o n st u d y w here t he P K of mi daz ola m a n d t ol b uta mi de ( pr o be 
s u bstrates f or t hese e nz y mes) was e val uate d i n healt h y s u bjects recei vi n g si n gle oral d oses of  t he pr o bes 
al o ne or i n c o m bi nati o n wit h re pari xi n.  
 
 
2. 5.  S U M M A R Y O F C LI NI C A L D A T A  
 
A t otal of 1. 0 5 0 s u bjects ha ve bee n treate d i n p hase 1, p hase 2 a n d p hase 3 c o m plete d ( C S R iss ue d) cli nical 
st u dies. A m o n g t hese, 6 6 6 ha ve bee n e x p ose d t o re pari xi n.  
D uri n g t he p hase 1 st u dies a t otal of 1 6 6 s u bjects of w h o m 1 0 3 n or mal v ol u nteers (i ncl u di n g 3 fe males) a n d 1 7 
patie nts wit h differe nt gra de of re nal i m pair me nt (i ncl u di n g 5 fe males), 1 6 patie nts u n der g oi n g car di o p ul m o nar y 
b y pass (i ncl u di n g 6 fe males) a n d 3 0 patie nts wit h metastatic breast ca ncer were e x p ose d t o re pari xi n. A t otal of 
6 5 s u bjects were treate d wit h place b o.  
I n p hase 2 a n d 3 st u dies, a t otal of 2 8 2 patie nts, 4 6 u n der g oi n g l u n g tra ns pla ntati o n ( 2 3 M a n d 2 3 F), 4 8 patie nts 
u n der g oi n g ki d ne y tra ns pla nt (i ncl u di n g 1 7 fe males), 2 0 patie nts wit h earl y breast ca ncer ( 2 0 F), 6 1 fe male 
patie nts wit h metastatic T N B C, 8 5  patie nts u n der g oi n g i ntra he patic islet tra ns pla ntati o n ( 3 2 M a n d 5 3 F) a n d 2 2 
( 1 8 
M a n d 4 F) u n der g oi n g ort h ot o pic li ver tra ns pla ntati o n, were treate d wit h re pari xi n. I n t he islet 
tra ns pla ntati o n st u dies, 2 2 patie nts recei ve d re pari xi n t wice. A t otal of 21 2 s u bjects were treate d wit h place b o.  
O ut of t he 1 6 6 s u bjects e x p ose d t o re pari xi n i n p hase 1 st u dies, 3 0 fe male patie nts wit h metastatic breast 
ca ncer recei ve d re pari xi n oral ta blets i n c o m bi nati o n wit h paclita xel i n a p hase 1 b cli nical trial. I n t he p hase 
2 earl y breast ca ncer st u d y, 2 0 fe ma le patie nts recei ve d re pari xi n oral ta blets al o ne. I n t he ra n d o mize d, p hase 
2 st u d y 6 1 metastatic T N B C patie nts recei ve d re pari xi n oral ta blets i n c o m bi nati o n wit h paclita xel.  
I n all st u dies, re pari xi n s h o we d a g o o d safet y pr ofile wit h b ot h I V a n d oral a d mi nistrati o n. 
 
2. 5. 1.  Effic ac y i n p atie nts wit h ac ute l u n g i nj ur y d ue t o C O VI D -1 9  
T o date 3 st u dies were perf or me d wit h re pari xi n i n C O VI D -1 9 patie nts. T hese were:  
1.  C o m passi o nate use wit h re pari xi n I V i nf usi o n  
2.  P hase II o pe n -la bel st u d y 
) 
3.  P hase III d o u ble -bli n d st u d y ( 
 
I n partic ular: 
1.  I n Marc h 2 0 2 0, re pari xi n was use d i n I R C C S Os pe dale Sa n Raffaele, a refere nce ce nter  f or C O VI D-1 9 i n 
Ital y, u n der a c o m passi o nate use a p plicati o n. F o ur patie nts wit h A R D S ca use d b y C O VI D-1 9 p ne u m o nia 
were treate d wit h re pari xi n I V i nf usi o n 
 via hi g h-fl o w ce ntral vei n f or 
fi ve da ys. O ne o ut of t he 4 patie nts was ne ver i nt u bate d a n d disc har ge d fr o m t he h os pital, w hereas a m o n g 
t he 3 w h o were i nt u bate d 1 was i n sta ble c o n diti o n a n d 2 were gra d uall y i m pr o vi n g wit h c o nc o mita nt 
i m pr o ve me nt or sta bilizati o n of i nfla m mat or y mar kers ( C-reacti ve pr otei n, pr ocalcit o ni n, an d ferriti n) a n d 
tiss ue da ma ge mar kers ( L D H, A L T, A S T). As per t he last u p date of 
Marc h 2 0 2 1, all 3 patie nts 
were s uccessf ull y e xt u bate d a n d disc har ge d fr o m t he h os pital. 
2.  P hase II o pe n -la bel st u d y 
. I n 2 0 2 0 D o m pé c o ncl u de d a P hase II  ra n d o mize d, c o ntr olle d 
m ultice ntre st u d y o n t he efficac y a n d safet y of re pari xi n i n t he treat me nt of h os pitalize d patie nts wit h 
C O VI D -1 9 p ne u m o nia. Fift y -si x patie nts were ra n d o mize d 2: 1 t o recei ve 1 2 0 0 m g ( 2 x 6 0 0 m g ta blets) 
oral re pari xi n t hree ti mes dail y ( 3 7 pts) or sta n dar d of care ( 1 9 pts) f or u p t o 2 1 da ys. Res ults s u g geste d 
t hat re pari xi n ma y pre ve nt t he pr o gressi o n t o se vere disease, as it si g nifica ntl y decrease d t he i nci de nce of 
at least o ne cli nical e ve nt of t he c o m p osite e n d p oi nt i ncl u di n g s u p ple me ntal o x y ge n re q uire me nt, i n vasi ve 
mec ha nical ve ntilati o n use, a d missi o n t o I nte nsi ve Care U nit ( I C U), a n d use of a resc ue me dicati o n f or 
a n y reas o n. Treat me nt wit h re pari xi n was well t olerate d i n ter ms of treat me nt -e mer ge nt a d verse e ve nts.  
3.  P hase III d o u ble -bli n d st u d y  
 T he a b o ve res ults i nf or me d t he desi g n of a s u bse q ue nt d o u ble - 
bli n d, place b o -c o ntr olle d cli nical st u d y ( 
 a p pr o ve d i n Ital y ( E u dra C T N u m ber: 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 2 2  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
 a n d i n t he U S alt h o u g h, d ue t o late acti vati o n of t he t hree ce nters i n U S t hat c oi nci de d wit h a decli ne 
of ne w C O VI D -1 9 i nfecti o ns, t he st u d y e nr olle d o nl y i n Ital y.  
 was 
 
 
” a n d its o bjecti ve was t o e val uate efficac y a n d 
safet y of oral re pari xi n as c o m pare d t o place b o ( b ot h o n t o p of sta n dar d treat me nt). Fr o m F e br uar y 2 0 2 1 
t o J u ne 2 0 2 1, patie nts wit h R T-P C R -c o nfir me d se vere C O VI D -1 9 were ra n d o mize d i n a 2: 1 fas hi o n t o 
recei ve oral re pari xi n 1 2 0 0 m g ( 2 x 6 0 0 m g ta blets) t hree ti mes a da y (TI D ) or place b o f or 2 1 da ys. T he 
treat me nt sc he d ule a n d re gi me n were c o nsiste nt wit h t he pre vi o us trial. F oll o w-u p i nf or mati o n o n t he 
patie nts’ cli nical c o n diti o n a n d s ur vi val were c ollecte d u ntil da y 9 0. Briefl y, patie nts were c o nsi dere d f or 
i ncl usi o n if t hey ha d e vi de nce of res pirat or y fail ure re q uiri n g o x y ge n s u p p ort (i.e., Pa O 2/ Fi O 2 rati o 
bet wee n 1 0 0 a n d 3 0 0, S p O 2 < 9 5 % at r o o m air, or res pirat or y rate ( R R ) ≥2 4 breat hs/ mi n at r o o m air), 
a b n or mal c hest i ma gi n g, a n d la b orat or y si g ns of i nfla m mati o n ( L D H > n or mal ra n ge, C R P ≥1 0 0 m g/ L or 
I L-6 ≥4 0 p g/ m L, ser u m ferriti n ≥9 0 0 n g/ m L, X D P > 2 0 mc g/ m L). T he pri mar y efficac y o utc o me was t he 
pr o p orti o n of patie nts ali ve a n d wit h n o res pirat or y fail ure at da y 2 8, defi ne d as n o nee d f or i n vasi ve 
mec ha nical ve ntilati o n ( I M V), e xtrac or p oreal me m bra ne o x y ge nati o n ( E C M O ), or a d missi o n t o t he 
i nte nsi ve care u nit (I C U) d ue t o w orse ni n g res pirat or y stat us. A m o n g 2 7 9 ra n d o mize d patie nts, all e nr olle d 
i n E ur o pe, 1 8 2/ 1 8 5 ( 9 8. 4 %) i n t he Re pari xi n gr o u p a n d 8 8/ 9 4 ( 9 3. 6 %) i n t he place b o gr o u p recei ve d at 
least o ne d ose of t he i n vesti gati o nal pr o d uct. All partici pa nts ha d a p ositi ve R T-P C R assa y f or S A R S -
C o V -2 R N A fr o m t he u p per res pirat or y tract. At baseli ne, t he c o h ort was well -bala nce d acr oss t he t w o 
gr o u ps: mea n a ge 6 0. 8 ( S D = 1 1. 9) years, 7 3 % were males, 2 7 % were of His pa nic ori gi n, a n d 3 0 % ha d a 
B MI > 3 0 K g/ m 2. All partici pa nts ha d t he t y pical feat ures of ac ute res pirat or y fail ure i.e., nee d f or o x y ge n 
t hera p y eit her i n t he f or m of l o w fl o w s u p ple me ntal o x y ge n or hi g h fl o w nasal ca n n ula ( N H N C)/ n o n-
i n vasi ve ve ntilati o n ( 4 9. 2 % i n t he re pari xi n a n d 5 0. 0 % i n t he place b o gr o u p re q uire d H F N C/ NI V), wit h a 
mea n Pa O 2/ FI O 2 rati o of 2 0 0. 2 ( S D = 6 7. 5). T he treat me nt was disc o nti n ue d m ore fre q ue ntl y i n t he 
place b o gr o u p ( 3 4 patie nts [ 1 8. 4 %] vs. 2 0 [ 2 1. 3 %]), wit h g o o d c o m plia nce t o st u d y me dicati o n d uri n g 
treat me nt i n b ot h ar ms ( me dia n 9 7. 2 2 % i n t he re pari xi n gr o u p a n d 9 6. 8 5 % i n t he place b o gr o u p). 
Acc or di n g t o t he I nte nti o n -t o-Treat (I T T) pri nci ple, all ra n d o mize d a n d treate d patie nts were c o nsi dere d 
f or t he efficac y a nal ysis, usi n g retrie ve d dr o p o uts’ i nf or mati o n t o ha n dle missi n g data at Da y 2 8.  
 
 
 
 T he m ortalit y at 2 8 da ys was  
 i n 
t he place b o gr o u p a n d  
 i n t he re pari xi n gr o u p ( O R 0. 4 6 8, 9 5 % CI: 0. 1 5 8-1. 3 8 6, p = 0. 1 7 0). T he 
inci de nce of I C U a d missi o n d ue t o deteri orati o n of res pirat or y fail ure (f oll o we d b y I M V, or E C M O, or 
deat h) was: 1 0 patie nts ( 6. 1 %) i n t he re pari xi n gr o u p vs. 1 0 ( 1 2. 2 %) i n t he place b o gr o u p ( O R 0. 4 2 9, 9 5 % 
CI: 0. 1 6 7 -1. 1 0 0, p = 0. 0 7 8). A statisticall y si g nific a ntl y differe nce i n t he Pa O 2/ FI O2 rati o bet wee n gr o u ps, 
i n fa v o ur of t he re pari xi n gr o u p, was o bser ve d at Da y 3 ( p = 0. 0 0 2), w he n t he mea n ( ± S D) c ha n ges fr o m 
baseli ne were 1 3. 3 7 7 ± 3 6. 5 6 8 m m H g i n t he re pari xi n gr o u p a n d -5. 2 7 4 ± 4 1. 1 0 3 m m H g i n t he place b o 
gr o u p. O nce a gai n, t here was a st r o n g safet y si g nal wit h t he n u m ber of a d verse e ve nts bei n g stea dil y 
hi g her i n t he c o ntr ol gr o u p.  
 
 
2. 5. 2.  S afet y  
I n all st u dies, re pari xi n has s h o w n a g o o d safet y pr ofile wit h b ot h I V a n d oral a d mi nistrati o n.  
T he patie nt p o p ulati o n e x p ose d t o t he I V f or m ulati o n i ncl u des 1 0 3 a d ult healt h y s u bjects ( 1 0 0 M/ 3 F), 1 7 
patie nts wit h differe nt gra des of re nal i m pair me nt ( 1 2 M/ 5 F), 1 6 patie nts u n der g oi n g car di o p ul m o nar y b y - pass 
( 1 0 M/ 6 F), 4 6 patie nts u n der g oi n g l u n g tra ns pla ntati o n ( 2 3 M/ 2 3 F), 4 8 patie nts u n der g oi n g ki d ne y 
tra ns pla ntati o n ( 3 1 M/ 1 7 F), 2 2 u n der g oi n g li ver tra ns pla ntati o n ( 1 8 M/ 4 F) a n d 8 5 recei vi n g i ntra he patic 
pa ncreatic islet i nf usi o n ( 3 2 M/ 5 3 F), wit h 2 2 patie nts i n t his gr o u p recei vi n g re pari xi n t wice. E x p os ure  
i ncl u de d s h ort or pr ol o n ge d I V i nf usi o n u p t o  
 o ver 3 0 mi n or  
 o ver 4 8 h a n d, i n 
pa ncreatic islet a n d li ver tra ns pla ntati o n st u dies, 
 c o nti n u o us i nf usi o n f or 7 
da ys. O verall, re pari xi n was safe a n d well t ol erate d i n b ot h healt h y s u bjects a n d criticall y ill patie nts. I n p hase 
1 st u dies, n o deat hs, Seri o us A d verse E ve nts ( S A E ) or A d verse E ve nts (A E )-relate d wit h dra wals were 
re p orte d. T he maj orit y of A Es re p orte d were of mil d i nte nsit y. All s u bjects rec o vere d c o m pletel y or ha d 
o n g oi n g a d verse e ve nts of mil d i nte nsit y w he n t he y were disc har ge d. T he safet y of re pari xi n was als o 
c o nfir me d i n patie nts wi t h differe nt gra des of re nal i m pair me nt. I n t he i nteracti o n st u d y n o safet y c o ncer ns 
were raise d d uri n g c o -a d mi nistrati o n of mi daz ola m/t ol b uta mi de wit h re pari xi n. D uri n g p hase II a n d III 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 2 3  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
st u dies, A E a n d S A E pr ofile was si milar f or b ot h place b o a n d re pari xi n gr o u ps a n d n o partic ular safet y 
c o ncer ns were raise d. Data o btai ne d i n t he trials i n islet tra ns pla ntati o n f urt her s u p p ort t he safet y pr ofile of t he 
pr o p ose d d ose, e ve n after a 7 -da y a d mi nistrati o n, re peate d  
 i n se veral patie nts. M ost fre q ue nt A d verse 
Dr u g Reacti o ns ( A D Rs ) were na usea, hea dac he, a n d v o miti n g; t he great maj orit y of t hese were mil d t o 
m o derate i n nat ure a n d n o ne re q uire d disc o nti n uati o n of t he i n vesti gati o nal pr o d uct. Tac h ycar dia occ urre d i n 
o ne patie nt fr o m Da y 5 t o 3 8 after t he 1st islet i nf usi o n w hic h was  j u d ge d t o be pr o ba bl y relate d t o t he 
i n vesti gati o nal pr o d uct. V o miti n g, na usea a n d hea dac he o n Da y 5 a n d 6 after t he 2 n d islet i nf usi o n i n o ne 
patie nt a n d er yt he ma, na usea a n d hea dac he o n Da ys 2 t o 6 after t he 1st islet i nf usi o n i n a n ot her patie nt were 
j ud ge d as ver y li kel y relate d t o t he i n vesti gati o nal pr o d uct. Na usea, v o miti n g a n d se vere gastr oi ntesti nal 
blee di n g ass ociate d wit h a ne mia de vel o pe d earl y after t he be gi n ni n g of re pari xi n i nf usi o n i n a fe male patie nt 
w h o recei ve d a d ose of re pari xi n 3 ti mes as hi g h as t hat f oresee n i n t he pr ot oc ol ( me dical err or). T hese e ve nts 
were assesse d as seri o us b y t he i n vesti gat or a n d b y t he S p o ns or.  
T he m ost fre q ue nt ( > 1 0 %) A D Rs o bser ve d i n st u dies o n I V f or m ulati o n were:  
Gastr oi ntesti nal dis or ders  (a b o ut 2 8 %), i ncl u di n g a b d o mi nal pai n l o wer, a b d o mi nal pai n n ot ot her wise 
s pecifie d, a b d o mi nal pai n u p per, c o nsti pati o n, diarr hea, d ys pe psia, flat ule nce, gastr oes o p ha geal refl u x 
disease, gastr oi ntesti nal he m orr ha ge, i ntra -a b d o mi nal he m orr ha ge, na usea a n d v o miti n g.  
Ner v o us s yste m dis or ders  (a b o ut 1 6. 5 %), i ncl u di n g hea dac he, dizzi ness, h y p oaest hesia, s o m n ole nce. 
Ge neral dis or ders a n d a d mi nistrati o n site c o n diti o ns  (a b o ut 1 5 %), i ncl u di n g I V site i nserti o n reacti o ns 
i ncl u di n g he m orr ha ge, t hr o m b osis a n d l ocalize d e de ma, fati g ue, let har g y, malaise, peri p heral oe de ma, a n d 
p yre xia.  
T he patie nt p o p ulati o n e x p ose d t o re pari xi n oral ta blets i n t he o nc ol o gical pr o gra m, c o nsiste d of 1 1 1 fe male 
patie nts recei vi n g eit her si n gle a ge nt re pari xi n ( 
 o pera ble breast ca ncer: 2 0 patie nts) or t he 
c o m bi nati o n of re pari xi n a n d wee kl y paclita x el i n metastatic breast ca ncer ( 
 p hase I b: 3 0 patie nts; 
R E P 0 1 1 4, ra n d o mize d p hase II: 6 1 patie nts). I n t hese st u dies, re pari xi n was ge nerall y well t olerate d at all 
d oses st u die d. O verall, 5 0 5 A D Rs were re p orte d i n 7 8 patie nts i n t he safet y p o p ulati o n: 7 0. 9 % of t he A D Rs 
were gra de 1 ( mil d), 2 2. 9 % were gra de 2 ( m o derate) a n d 4. 3 % were gra de 3 (se vere). O ne gra de 4 A D R was 
re p orte d o verall ( 
 I n a d diti o n, o ne patie nt i n cli nical trial R E P 0 1 1 4 e x perie nce d seri o us A D Rs 
i ncl u di n g gra de 4 perit o nitis a n d gra de 5 i ntesti nal perf orati o n. 
T he m ost fre q ue nt ( > 1 0 %) A D Rs o bser ve d i n t he t he o nc ol o gical pr o gra m were:  
Gastr oi ntesti nal dis or ders  ( 3 2. 0 %), i ncl u di n g na usea, v o miti n g, c o nsti pati o n, diarr hea a n d d ys pe psia 
Ge neral dis or ders a n d a d mi nistrati o n site c o n diti o ns  ( 1 9. 5 %), i ncl u di n g fati g ue a n d peri p heral oe de ma. 
Ner v o us s yste m dis or ders  ( 9. 7 %) i ncl u di n g hea dac he as m ost fre q ue nt A D R. 
F urt her data ca n be f o u n d i n t he I n vesti gat or’s Br oc h ure.  
F urt her m ore, t he patie nt p o p ulati o n e x p ose d t o re pari xi n oral ta blets i n t he C o vi d -1 9 st u dies i ncl u des 2 1 8 
patie nts ( 3 6 i n t he P hase 2/ 3 
 st u d y a n d 1 8 2 i n t he P hase 3  
 trial). 
Safet y data fr o m st u d y 
, s h o w t hat treat me nt wit h re pari xi n was well t olerate d i n ter ms of 
treat me nt-e mer ge nt a d verse e ve nts, la b orat or y tests a n d vital si g ns para meters. Seri o us T E A Es (all u nrelate d) 
were re p orte d i n 2 patie nts ( 5. 6 %) i n t he re pari xi n gr o u p ( 2 T E A Es) a n d i n 4 ( 2 1. 1 %) i n t he sta n dar d of care 
gr o u p ( 4 T E A Es): a m o n g t hese, deat h o cc urre d i n 1 patie nt ( 2. 8 %) i n t he re pari xi n gr o u p a n d i n 3 ( 1 5. 8 %) i n 
t he sta n dar d of care gr o u p. N o A D R was re p orte d. 
I n t he st u d y  
 t he Safet y p o p ulati o n i ncl u de d 1 8 2 a n d 8 8 patie nts i n re pari xi n a n d place b o ar m, 
res pecti vel y. Treat me nt wit h oral re pari xi n was well t olerate d i n ter ms of T E A Es safet y la b orat or y tests a n d 
vital si g ns para meters. Seri o us T E A Es were r e p orte d i n 2 0 patie nts ( 1 1. 0 %) i n t he re pari xi n gr o u p ( 2 3 T E A Es) 
a n d i n 1 3 ( 1 4. 8 %) i n t he place b o gr o u p ( 1 6 T E A Es) a n d n o ne of t hese was relate d t o treat me nt. Te n T E A Es 
lea di n g t o deat h were re p orte d i n 1 0 patie nts ( 5. 5 %) i n t he re pari xi n gr o u p a n d 7 T E A Es lea di n g t o deat h were 
re p orte d i n 7 patie nts ( 8. 0 %) i n t he place b o gr o u p. A t otal of 1 3 A D Rs were re p orte d i n 1 0 patie nts ( 5. 5 %) i n 
t he re pari xi n gr o u p a n d 1 1 A D Rs were re p orte d i n 8 patie nts ( 9. 1 %) i n t he place b o gr o u p o n treat me nt or 
f oll o w-u p peri o d. I n s u m mar y, treat me nt wit h re pari xi n was ass ociate d wit h l o wer pr o p orti o ns of patie nts t hat 
re p orte d T E A Es (seri o us, se vere, lea di n g t o disc o nti n uati o n of I M P or ha vi n g a fatal o utc o me). 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 24 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
The SOC more frequently (>10%) involved in ADRs observed with oral tablets in COVID-19 pneumonia 
studies were: 
Infections and infestations (about 31% of the overall reported ADRs), including bacterial sepsis, lower 
respiratory tract infection fungal and pneumonia bacterial. 
Gastrointestinal disorders (15%), including abdominal pain upper and diverticulum intestinal haemorrhagic. 
Hepatobiliary disorders (15%), including hypertransaminasemia. 
 
 
2.6. DISEASE REVIEW AND STUDY RATIONALE 
ARDS is a heterogeneous syndrome of acute respiratory failure first described in 19678 and more recently 
defined by the clinical criteria of bilateral pulmonary opacities on chest radiograph, arterial hypoxemia 
(PaO2/FiO2 ratio < 300), on positive end-expiratory pressure (PEEP) ≥5 cm H2O, and exclusion of cardiac 
failure as the primary etiology of the syndrome9. The pathophysiology of the syndrome is characterized by 
pulmonary edema due to excessive alveolocapillary permeability associated with inflammatory injury to the 
alveolocapillary barrier, generated either locally in the lungs or systemically from extra- pulmonary sites. 
Examples of such injuries include pneumonia due to viral, bacterial or fungal pathogens, sepsis, aspiration of 
gastric contents, smoke inhalation, acute pancreatitis, severe trauma, drug overdose and ischemia-reperfusion 
injury10. By products generated by invading microorganisms called pathogen associated molecular patterns, 
in combination with damage associated molecular patterns released by damaged or dying cells interact with 
pattern recognition receptors on pulmonary vascular endothelial cells, epithelial cells, smooth muscle cells 
and resident innate immune cells leading to the release, from these cells, of inflammatory cytokines11,12 some 
of which act as chemoattractants for leukocytes (chemokines). Leucocyte chemokines are classified into 
several families based on the position of cysteine (C) residues: CXC, CC, C and CX3C13. CXC chemokines, 
and mainly CXCL8 (interleukin 8) in humans and its orthologs in mice are considered the prototypical 
neutrophil-specific chemokines that regulate neutrophil migration14. Neutrophil influx into the extravascular 
compartments of the lungs is a defining characteristic of ARDS15. Neutrophils retained within the pulmonary 
capillaries or migrating through the alveolocapillary barrier into the airspaces release oxidants and proteases 
whose primary role is the killing of pathogens16. However, when excessive, intrapulmonary accumulation 
and activation of neutrophils can cause disproportionate tissue injury. In fact, disease severity and mortality 
in ARDS correlates with the extent of neutrophilia in the lung15 as well as with the levels of CXC chemokines 
both in patients with ARDS17 and animal models of lung injury18,19 . Two CXC chemokine receptors, CXCR1 
and CXCR2, have been shown to mediate the response to CXC chemokines in human neutrophils. Whereas 
human CXCR1 binds to CXCL6 (IL-6) and CXCL8 (IL-8) with a high affinity, human CXCR2 binds also to 
IL-6 and IL-8 as well as several other CXC chemokines (GRO-α, GRO-β, GRO-γ, CXCL1, CXCL2, 
CXCL3), ENA-78 (CXCL5) and CXCL720. Binding of IL-8 to its receptors on neutrophils mediates not only 
recruitment of these cells but also their activation. Upon their activation neutrophils release neutrophil 
extracellular traps (NET) which are networks of extracellular fibers, primarily composed of DNA, embedded 
with histones, myeloperoxidase and neutrophil elastase (NE)21. Neutrophils release NETs in response to both 
infectious and non-infectious systemic inflammatory diseases, including sepsis, acute ischemia-reperfusion 
injury of the liver, and transfusion-related or LPS-induced acute lung injury22-24. NET release is associated 
with induction of alveolar-capillary barrier damage, platelet aggregation, and cytokine production and 
inhibition of NETs through inhibition of NE ameliorates acute lung injury in mouse models25,26. Strategies 
that would prevent excessive neutrophil accumulation in the injured lung through inhibition of the main 
neutrophilic chemotactic cytokine, i.e., IL-8, are intuitively attractive and, in fact, have been pursued with 
promising results as neutralization of CXCL8 by polyclonal antibodies has been shown to reduce the severity 
of ARDS in animal models27. 
Our experience with reparixin induced IL-8 inhibition in patients with ARDS due to COVID-19, obtained 
through the compassionate use of reparixin, as well as in the phase II and III trials in COVID-19 patients 
support the potential clinical efficacy of reparixin in ARDS of other etiologies. These findings, coupled with 
the safety shown in phase I to III clinical trials, provide strong rationale supporting further testing of reparixin 
in ARDS. 
 
2.6.1. Alternative treatments 
Currently the treatment of ARDS is mainly supportive and involves implementation of lung protective 

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 2 5  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
ve ntilati o n, pr o ne p ositi o ni n g, caref ul m o nit ori n g of fl ui d bala nce a n d treat me nt of t he u n derl yi n g eti ol o gic 
pat h ol o g y. All patie nts partici pati n g i n t he st u d y will recei ve t he sta n dar d of care f or A R D S as descri be d 
a b o ve. 
 
2. 6. 2.  Ris k –  be nefit e v al u ati o n  
2. 6. 2. 1.  Ris k relate d t o re pari xi n  
Res ults fr o m precli nical a n d cli nical st u dies j ustif y t he le vel of dr u g e x p os ure pla n ne d i n t his st u d y. T he 
safet y of re pari xi n was c o nfir me d i n t he p hase II a n d III trials usi n g t he sa me sc he d ule; i n dee d, n o safet y 
c o ncer ns were raise d i n C O VI D -1 9 patie nt s. A n y p ossi ble ris k deri ve d fr o m t he c o nti n u o us a d mi nistrati o n 
of re pari xi n i n t he s pecific p o p ulati o n i n v ol ve d i n t his st u d y will be mi ni mize d b y i nte grate d m o nit ori n g 
w hic h will i ncl u de la b orat or y tests a n d dail y cli nical o bser vati o ns.  
E ve n if re pari xi n mar gi nall y i n hi bits t he e nz y me C Y P 2 C 9 (I C 5 0 7 9 µ M) a n d sli g htl y i n hi bits C Y P 3 A 4 
(I C 5 0 8 µ M) i n vitr o, t his effect d oes n ot tra nslate i nt o cli nicall y si g nifica nt i n hi biti o n of eit her e nz y me as 
re veale d b y a n i nteracti o n st u d y w here t he P K of mi daz ola m a n d t ol b uta mi de ( pr o be s u bstrates f or t hese 
e nz y mes) was e val uate d i n healt h y s u bjects recei vi n g si n gle o ral d oses of t he pr o bes al o ne or i n c o m bi nati o n 
wit h re pari xi n ( Re pari xi n I n vesti gat or’s Br oc h ure, 2 0 2 1).  
T he A D Rs m ost fre q ue ntl y re p orte d f or t he oral f or m ulati o n use d i n o nc ol o g y st u dies (i n patie nts wit h 
metastatic diseases, u n der g oi n g c he m ot hera p y) were n ot differe nt fr o m S O C ( he patic e nz y mes ele vati o n). I n 
C O VI D -1 9 ( pr ot oc ol  
), A D Rs occ urre d i n fe w s u bjects wit h o ut a n y partic ular tre n d. Wit h refere nce 
t o c u m ulati ve A D Rs (irres pecti vel y of t he seri o us ness), t he S O Cs 
m ore fre q ue ntl y i n v ol ve d were 
Gastr oi ntesti nal dis or ders ( mai nl y na usea a n d v o miti n g), Ner v o us S yste m Dis or ders ( mai nl y hea dac he) a n d 
Ge neral dis or ders a n d a d mi nistrati o n site c o n diti o ns (fati g ue a n d peri p heral e de ma).  
I n re gar d t o seri o us e ve nts i n partic ular, t he si g nal detecti o n pr ocess f or si n gle Seri o us A d verse E ve nts a n d 
reacti o ns le d t o n o i m p orta nt ris k ha vi n g bee n i de ntifie d or s us pecte d s o far f or patie nts treate d wit h re pari xi n, 
re gar dless of t he f or m ulati o n an d t he i n dicati o n f or treat me nt. N o S A R was re p orte d i n t he C o vi d -1 9 st u dies.  
 
2. 6. 2. 2.  Bl o o d sa m pli n g  
Meas ure me nt of st u d y relate d para meters ca n ge nerall y be d o ne fr o m bl o o d sa m ples c ollecte d f or r o uti ne 
care of I C U patie nts. Partici pati o n i n t he st u d y mi g ht re q uire a d diti o nal bl o o d sa m pli n gs ot her t ha n t he r o uti ne 
o nes. I n partic ular:  
● bl o o d sa m ples f or i nfla m mat or y bi o mar kers (a p pr o x. 1 0 m L) will be c ollecte d at baseli ne as well as 
o n da ys 3, 7 a n d 1 4  
● 
 
Ve ni p u nct ure mi g ht ca use mi n or pai n, br uisi n g, i nfla m mati o n or e xcessi ve blee di n g at t he ve ni p u nct ure site 
a n d fai nt ness a n d/ or s welli n g, pai n, re d ness, or i nfecti o n (i nfecti o n rarel y ha p pe ns) at t he site w here t he nee dle 
is i nserte d. Rare ris ks i ncl u de hemat o ma, i nfecti o n, arterial p u nct ure. T he v ol u me of bl o o d a b o ve is a n 
a m o u nt t hat t he b o d y ca n safel y re place.  
I n t he a bse nce of a n i n d welli n g arterial cat heter ( w hic h is h o we ver c o m m o n i n I C U patie nts) arterial 
p u nct ure is re q uire d dail y f or assess me nt of Pa O 2 a n d Pa C O 2; a s mall s yri n ge a n d s mall nee dle (t o pical 1 % 
li d ocai ne, if a vaila ble) will be utilize d t o wit h dra w a p pr o xi matel y 1 m L ( mi ni m u m v ol u me 0. 2 ml) of bl o o d 
fr o m a n arter y ( prefera bl y ra dial). Arterial p u nct ure mi g ht ca use l ocal disc o mf ort, he m orr ha ge, t o pical 
he mat o ma, t o pical i nfecti o n a n d arterial occl usi o n lea di n g t o tiss ue h y p o perf usi o n i n t he distri b uti o n of t he 
arter y. 
 
2. 6. 2. 3.  P ote ntial be nefit  
T o t he patie nts: half of t he patie nts will be assi g ne d t o t he place b o ar m a n d will t heref ore o btai n n o be nefit. 
Patie nts recei vi n g re pari xi n treat me nt ma y p ossi bl y be nefit, b ut t his is t o be ascertai ne d.  
T o s ociet y: T his st u d y ma y i de ntif y a usef ul me dicati o n t hat ma y hel p li mit disease pr o gressi o n i n A R D S 
patie nts. C urre ntl y, A R D S is dia g n ose d i n 1 0 % of I C U patie nts a n d 2 3 % of mec ha nicall y ve ntilate d patie nts 
C CI
C CI
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 26 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
and has a disease-associated mortality which ranges from 27% to 45% based on severity28. Regimens that 
can inhibit disease progression and improve severity of disease can have significant effects on quality of life 
and healthcare related costs. 
In summary, given the cumulative knowledge for the safety profile of reparixin in patients with COVID-19 
and acute illness, and the significant unmet need for a treatment of ARDS, the benefit/risk balance for this 
study is assessed to be favorable. 
 
 
2.6.3. Description of the Investigational Product 
In this study the Investigational Medicinal Product (IMP) will be either reparixin 600 mg tablet or matched 
placebo. The proposed dose in this clinical study is 1200 mg oral reparixin TID for 14 days with optional 
continuation of treatment up to 21 days, if the patient is still intubated on Day 14. Placebo will be administered 
with the same schedule. 
The particular dose regimen has been selected based on the clinical data from previous clinical studies in 
patients with acute lung injury due to COVID-19. 
The 1200 mg TID dosage is supported by both preclinical studies and efficacy/safety results from phase I 
and phase II clinical studies already conducted. The resulting average steady state plasma concentration of 
the reparixin unbound fraction should ensure full inhibition of PMN migration, considering that the in vitro 
IC50 is in the range of 1 ng/mL. 
The toxicity studies conducted to date support the dose regimen proposed for this study, which has already 
been used for the previous phase II and phase III trials in COVID-19 adult patients.

REP0122  
Reparixin in ARDS  
Page 27 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN 
 
3.1. STUDY OBJECTIVES 
To characterize the efficacy of reparixin in ameliorating lung injury and systemic inflammation and 
expediting clinical recovery and liberation from mechanical ventilation of adult patients with moderate to 
severe ARDS (PaO2/FIO2 ratio ≤ 200). Furthermore, to characterize the PK of reparixin in this group of 
severely ill patients as well as the effect of reparixin on systemic biomarkers linked to a hyper-inflammatory 
ARDS phenotype29-31. 
Safety objectives: To evaluate the safety of reparixin versus placebo in the specific clinical setting, including 
the effect on the incidence of secondary infections. 
 
 
3.2. STUDY ADMINISTRATIVE STRUCTURES, STAFF AND RESPONSIBILITY 
This study will be performed at designated clinical spaces available for clinical studies, under the 
supervision and responsibility of the Principal Investigator (PI). The PI will be responsible for ensuring that 
the investigation is conducted according to the signed Investigator agreement, the protocol, Good Clinical 
practice (GCP) guidelines, institutional, federal, state and local regulations. 
The PI will be responsible for the management of the study, which will consist of maintaining the study file 
and the patient records, reporting SAEs within required timelines, completing the electronic case report form 
(eCRF) and any other study document. PI at US sites should also correspond with the Institutional Review 
Board (IRB). 
The PI is responsible for supervising any individual or party to whom (s)he delegates trial related duties and 
functions conducted at the trial site. The PI/institution should ensure that any individual or party that performs 
trial related duties and functions is qualified to perform those trial related duties and functions and should 
implement procedures to ensure the integrity of the trial related duties and functions performed and any data 
generated. Similarly, it is the responsibility of the PI to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study, including detailed knowledge of and training in all 
procedures to be followed. 
The PI will maintain a list of delegated responsibility detailing the various study tasks to be performed by 
each member of his/her study staff. Each staff member should sign the delegation of authority/activity log 
for their performing each of the tasks delegated to them on the list. Where reference is made in this protocol 
to the PI, either the PI and/or one or more delegated members of his/her staff are meant, according to the list 
of delegated responsibility. 
 
 
3.3. 
OVERALL STUDY DESIGN 
The study is an international, multicenter, 1:1 randomized, double-blind, placebo-controlled, phase II 
proof-of-concept trial. It will enroll approximately 66 adult patients hospitalized with ARDS that meet the 
inclusion criteria, randomly assigned at 1:1 ratio to receive either reparixin 1200 mg (treatment group) 
through a nasogastric tube or matched placebo (control group) TID for 14 days with optional continuation of 
treatment up to 21 days, if the patient is still intubated on Day 14. The IMP may be administered orally after 
extubation and between extubation and day 14 should the patient be able to swallow. In such cases the IMP 
may be administered either intact or crushed and mixed with a vehicle as per speech swallow evaluation. All 
patients must receive standard and supportive care according to their clinical status and local guidelines 
during the whole study period. Although the ventilatory strategy in both groups is in the discretion of the PI, 
physicians are encouraged to comply with the following ventilator strategy: tidal volume of 4-6 ml/Kg of 
predicted body weight, a plateau pressure < 30 cm H2O, driving pressure < 15 cm H2O to maintain arterial 
pH > 7.2 and FIO2/PEEP adjusted to keep SpO2 ≥ 88% or PaO2≥55 mmHg. 
Sedation, use of neuromuscular blocking agents or nitric oxide and other inhaled vasodilators, prone 
positioning, and use of ECMO are left to the PI’s discretion and are registered daily on the study’s electronic 
case report form. 

REP0122  
Reparixin in ARDS  
Page 28 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
Each patient will be involved in the study for up to 60 days. This period consists of informed consent 
acquisition and screening, randomization and baseline assessments, a post-randomization study period of up 
to 28 days from the first IMP dose or hospital discharge and a follow-up period of up to day-60. Patients will   
be assessed daily while hospitalized up to extubation from first IMP administration. The end of this study is 
defined as the end of follow up. 
 
3.3.1. 
Rationale for Selection of dose, control group and treatment schedule in the study 
The dose and dose regimen have been selected according to the rationale reported in Section 2.6.3. 
A double-blind, randomized study design including a placebo group is being adopted as the gold standard 
to minimize systematic bias and increase baseline comparability between treatment groups. Both groups of 
patients will receive the current standard of care for ARDS. 
 
 
3.4. 
STUDY TIME_TABLE 
Overall planned study timelines are reported below: 
Study period 
First Patient First Visit: February 2023 
Last Patient First Visit: December 2024  
Last Patient Last Visit: February 2025

REP0122  
Reparixin in ARDS  
Page 29 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
4. 
SELECTION OF STUDY POPULATION 
Number of patients: approximately 66 adult patients hospitalized with ARDS will be enrolled to target 60 
evaluable patients. A patient is considered enrolled if, after signature of consent and screening, it is 
determined that (s)he fully meets all the Inclusion Criteria and none of the Exclusion Criteria described in 
Sections 4.1. and 4.2. below. 
 
 
4.1. INCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must fulfill the following inclusion criteria: 
 
1. 
Signed Informed Consent, according to local guidelines and regulations. 
2. 
Male and female adults (>18 years old). 
3. 
Mechanically ventilated (invasive) patients with PaO2/FIO2 ratio 
≤200 in the presence of PEEP of ≥5 cm H2O. 
4. 
Respiratory failure not fully explained by cardiac failure or fluid overload (if acute Congestive Heart 
Failure exacerbation is identified as part of the clinical picture this should be addressed effectively and as 
soon as possible before the patient can be enrolled). 
5. 
Bilateral radiologic opacities consistent with pulmonary edema on the frontal chest x-ray (CXR) 
radiograph, or bilateral ground glass opacities on a chest CT scan. 
6. 
≤48 hours from fulfilling above ARDS criteria (if a patient is transferred from a non-participating hospital 
to a participating site, a 12-hour period beyond the 48 hours is allowed) 
7. 
Females of child-bearing potential who are sexually active must be willing not to get pregnant within 30 
days after the last Investigational Medicinal Product (IMP) dose and must agree to at least one of the 
following reliable methods of contraception: 
• Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives from at least 
2 months before the screening visit until 30 days after the last IMP dose; 
• A sterile sexual partner; 
• Abstinence. 
For patients unable to personally consent to the above, due to complications of acute illness and/or its 
treatment, assurances for the above must be given by LR and reiterated by the patient when/if she is able 
to do so. 
Female participants of non-child-bearing potential or in post- menopausal status for at least 1 year will be 
admitted. For all female subjects with child-bearing potential, pregnancy test results must be negative 
before first drug intake. 
 
 
4.2. EXCLUSION CRITERIA 
 
1. 
Moderate-Severe chronic hepatic disease (as verified by a previously known Child-Pugh score ≥7). If 
baseline Child-Pugh score is not known, it should not be calculated while the patient is acutely ill. In that 
case, the patient is excluded on the basis of: ALT/AST ≥ 3x ULN and total bilirubin > 2x ULN or 
ALT/AST ≥ 5x ULN.   
2. 
Severe chronic renal dysfunction: eGFR (2021 CKD-EPI) < 30 mL/min/1.73m2. If baseline (chronic) 
renal function is not known the patient is only excluded if in need of acute renal replacement therapy 
(currently on RRT or to be imminently placed on RRT). 
3. 
Participation in another interventional clinical trial. 
4. 
Patients that are clinically determined to have a high likelihood of death within the next 24 hours based 
on PI’s estimation. 
5. 
Currently receiving ECMO or high frequency oscillatory ventilation. 
6. 
Anticipated extubation within 24 hours of screening. (In such cases, re-screening is allowed if the patient is 
within the enrollment window).  
7. 
Evidence of GI dysmotility as demonstrated by presence of all the following: persistent gastric distention 
and enteral feeding intolerability and persistent gastric residuals >500 ml). 
8. 
Anticipated transfer to a hospital not participating in the trial within 72 hours of screening. 
9. 
Decision to withhold or withdraw life-sustaining treatment (patients may still be eligible however if they 

REP0122  
Reparixin in ARDS  
Page 30 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
are committed to full support except cardiopulmonary resuscitation if cardiac arrest occurs). 
10. History of: 
a) Documented allergy/hypersensitivity to sulfonamides, ibuprofen and other COX-1 and 2 inhibitors, 
and to the study product and/or its excipients. 
b) Lactase deficiency, galactosemia or glucose-galactose malabsorption. 
c) History of peptic ulcer, GI bleeding or perforation due to previous NSAID therapy. 
11. Active bleeding (excluding menses) from an uncontrolled site that cannot be definitively resolved prior to 
enrollment. 
12. Pregnant or lactating women. 
13. Women of childbearing potential and fertile men who do not agree to use at least one primary form of 
contraception during the study and up to 30 days after the last IMP dose.  
 
For patients non able to personally consent to above due to complications of acute illness and/or its treatment 
assurances for the above must be given by LR and reiterated by the patient when/if he/she is able to do so. 
 
4.3. ASSIGNMENT OF PATIENT NUMBER 
At screening, each patient will be assigned a unique sequential screening number. If the patient is 
randomized, the randomization number will be assigned in a sequential manner. This number will be used 
for identification throughout the study and will not be used for any other participant. 
If a patient is dropped from the study for any reason, the patient’s randomization number will not be 
reassigned.

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 3 1  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
5.  
S T U D Y M E DI C A TI O N  
5. 1.  
P R E S E N T A TI O N, P A C K A GI N G A N D L A B E LI N G, S U P P L Y, A N D S T O R A G E O F T H E 
I N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T 
5. 1. 1.  
Prese nt ati o n of t he I n vesti g ati o n al Me dici n al Pr o d uct  
I n t his st u d y t he I M P will be eit her re pari xi n or matc he d place b o, w hic h will be pr o vi de d i n t he f or m of 
ta blets t o be disi nte grate d f or nas o-gastric t u be a d mi nistrati o n or a d mi nistere d orall y after e xt u bati o n.  
A ta blet of re pari xi n has t he f oll o wi n g c o m p ositi o n:  
C o m p ositi o n of e ac h re p ari xi n u nit (t a blet)  
 
I n gre die nt 
A m o u nt per 
t a blet 
( m g) 
F u ncti o n  
Q u alit y st a n d ar d  
Re pari xi n ( D F 1 6 8 1 Y)  
6 0 0. 0  
Dr u g s u bsta nce  
I n-h o use s pecificati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
--- 
--- 
C o m p ositi o n of e ac h pl ace b o u nit (t a blet)  
 
 
Batc h release certificate will be pr o vi de d t o get her wit h t he I M P. Place b o ta blets are i de ntical i n a p peara nce 
t o t he acti ve f or m ulati o n. 
 
5. 1. 2.  M a n uf act uri n g, P ac k a gi n g a n d L a beli n g of I M P 
Ta blets will be ma n ufact ure d b y eit her 
 or 
. Pri mar y pac ka gi n g will be perf or me d b y eit her 
or 
. Sec o n dar y pac ka gi n g a n d la beli n g will be perf or me d b y 
 or, alter nati vel y, b y 
. 
T he st u d y me dicati o n will be pr o vi de d as a P atie nt Kit , c o ntai ni n g 
 
 
 
All la bels will be pre pare d t o meet l ocal re g ulat or y re q uire me nts. Details of pac ka gi n g a n d la beli n g are 
re p orte d i n A p pe n di x 1 4. 3 .
N a m e s of i n g r e di e nt s
F o r m ul a
%
A m o u nt p e r
t a bl et
F u n cti o n  of
i n g r e di e nt
R ef e r e n c e t o q u alit y
st a n d a r d s
R e p ari xi n
( D F 1 6 8 1 Y)
—
...
Di n g s u bst a n c e
I nt er n al m o n o gr a p h
P PI
P PI
P PI
P PI
P PI
P PI
P PI
P PI
C CI
C CI
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 32 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
5.1.3. 
Supply, Storage and Handling of IMP 
An appropriate number of packages will be initially sent to the site as soon as all essential documents and 
regulatory/ethics approvals have been obtained. IMP re-supply will be planned on demand, according to 
enrolment rate. 
The IMP must be kept at a temperature not exceeding 30°C and must not be frozen. 
A temperature probe will accompany the drug on shipment. Temperature range reached during shipment 
will be verified on receipt at site, so that potential stability concerns during shipment can be investigated and 
appropriate action taken. 
Once received at the site, the Pharmacist (or designee) will check the package for accurate delivery and 
acknowledge receipt; any deviations from expected package content (inconsistency, damages) should be 
immediately reported to Dompé (or appointed CRO) and the use of the drug suspended until authorization 
for its continued use has been given by Dompé (or appointed CRO). 
The IMP must be stored at site in a secure location, in a temperature-controlled room. Temperature records 
must be available for the clinical research associate (CRA) to review at monitoring visits; any deviations 
from the recommended storage conditions should be immediately reported to Dompé (or appointed CRO) 
and the use of the drug suspended until authorization for its continued use has been given by Dompé (or 
appointed CRO). 
 
 
5.1.4. Unblinding 
Appearance, including packaging and labeling, of the IMP will not allow recognition of the treatment arm 
(either reparixin or placebo). 
For each randomized subject, individual code breaks will be accessible in the event of a medical emergency 
requiring knowledge of the treatment assigned to the subject. Only the responsible investigator, or authorized 
delegates, can break the code via the Interactive Response System (IRS). 
Investigators will be allowed to unblind study medication directly through the IRT system; any unblinding 
must be notified to the CRO’s medical monitor. Training is provided to investigators prior to authorization 
to use the IRT system and the unblinding function is outlined in the study specific user guide. 
Dompé Pharmacovigilance, Safety and Surveillance Department shall break the treatment code for subjects 
who experience a potential Suspected Unexpected Serious Adverse Reaction (SUSAR), in order to determine 
if the individual case requires expedited regulatory reporting and fulfills expedited regulatory reporting 
requirements. Unmasked information will not be disclosed to Investigators and other Sponsor staff. 
With the exception of the above-mentioned episodes, the identity of the treatments will remain unknown to 
the subject, Investigator, site staff, CRO and Dompé’s personnel until the study completion and formal 
unmasking. Only the Data Monitoring Committee (DMC) will have access to group-unblinded and/or fully 
unblinded DMC reports. 
For analysis purposes, the randomization codes will be broken when the last enrolled patient has completed 
therapy, and once the database has been locked. 
 
 
5.2. DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION 
Reparixin will be administered through a nasogastric tube at the dose of 1200 mg (2 x 600 mg tablets) TID 
every 8 hours (6 tablets daily) for 14 days. If the patient becomes extubated prior to the end of treatment on 
day 14 and if swallowing ability has been restored as per clinical judgment, the IMP can be administered 
orally. In such cases the IMP may be administered either intact or crushed and mixed with vehicle as per 
speech swallow recommendation. The IMP may be administered for a total of 21 days if the patient is still 
intubated on Day 14. Placebo will be administered with the same treatment schedule. 
Administration of the study drug through a nasogastric tube should follow this procedure: for each 
administration, disperse two reparixin 600 mg tablets in 25 mL of drinking water in a suitable container (e.g., 
conical tubes for 50 mL Falcon centrifuge). Disintegrate the tablets (shaking manually or with the aid of a 

REP0122  
Reparixin in ARDS  
Page 33 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
planetary shaker or a rocker) until obtaining a homogeneous milky suspension (time required 7–10 minutes). 
Keep the prepared suspension at room temperature and protected from light for up to 24 hours. Immediately 
before administration, manually shake the suspension again until complete and homogeneous resuspension, 
withdraw using a 50 mL needle-free syringe and administer to the patient through the nasogastric tube. After 
administration, flush the gastric tube with 25 ml of water. 
 
5.3. CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION OR 
DISCONTINUATION OF THE IMP 
5.3.1. 
Criteria for schedule adjustment/dose-modification 
No schedule adjustment and/or dose modification is foreseen, except for discontinuation of IMP as detailed 
below. 
5.3.2. 
Criteria for permanent discontinuation of the IMP 
The IMP must be discontinued in the case: 
⮚ Upon initiation of renal replacement therapy; 
⮚ Upon increase of ALT and/or AST to≥ 3x ULN and total bilirubin > 2x ULN or upon increase of ALT 
and/or AST to ≥ 5x ULN 
⮚ The patient is discharged home; 
⮚ Withdrawal of informed consent by the patient or his/her legal representative (in this case, the patient / 
representative will be asked whether they consent to usage of the data already collected in the study; if 
not, the data will be deleted); 
⮚ Pregnancy occurs; 
⮚ Development of Serious AE probably or possibly related to IMP, as per PI’s judgment; 
⮚ Inadvertent missing of 3 or more consecutive doses of the IMP; 
⮚ Inability to resolve within 24 hours any medical condition/event that led to temporary withholding of the 
IMP (see also 5.3.3.); 
⮚ Recurrence of AE probably or possibly related to IMP upon re-introduction of the IMP. 
Occurrence of renal or hepatic dysfunction will be monitored as part of the biochemistry data set through 
safety laboratory tests obtained at day 3±8h, 7±1, 14±2, and 21 (if the IMP is meant to be administered up to 
21 days). The other criteria that qualify the patient to treatment discontinuation will be monitored daily. 
If the IMP administration is prematurely discontinued, the primary reason for discontinuation must be 
recorded in the eCRF. Patients who discontinue the treatment with the IMP will NOT be withdrawn from the 
study by default and will be asked to complete safety and efficacy observations as per the protocol unless 
they withdraw their consent. 
 
5.3.3. 
Criteria for temporary withholding of the IMP 
The IMP can be temporarily withheld upon: 
⮚ Development of AE (excluding Serious AE) probably or possibly related to IMP, as per PI’s judgment 
⮚ Any AE (including Serious AE) not thought to be related to IMP as per PI's judgment.  
⮚ Any medical condition that may threaten the safety of the patient if they continue to receive study 
treatment (as per investigator or Sponsor evaluation) 
 
Temporary withholding of the IMP should not exceed 24 hours during which time every effort should be made 
to resolve/stabilize conditions that led to IMP withholding. If this is not resolved within the allotted 24 hours the 

REP0122  
Reparixin in ARDS  
Page 34 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
IMP should be permanently discontinued.  
 
5.4. ACCOUNTABILITY OF THE IMP 
All supplies will be maintained under adequate security by the designated member of site staff, until they are 
dispensed to the patients. The Investigator will ensure that study treatment is only dispensed by designated 
staff within the study site. 
When the IMP is received at the site, the designated staff member will check for accurate delivery and 
acknowledge receipt by signing and dating the documentation provided by or on behalf of Dompé and 
returning it to Dompé or to the appointed CRO. A copy will be retained for the Investigator/Pharmacy file. 
The dispensing of the IMP will be carefully recorded on the eCRF and appropriate drug accountability forms; 
an accurate accounting will be available for verification by the CRA at each monitoring visit. 
Drug accountability records will include: 
1. 
the confirmation of receipt of the IMP at the trial site, 
2. 
the dispensing of the IMP to the patient, 
3. 
the disposition of unused product(s), 
4. 
accounts of any IMP accidentally or deliberately destroyed. 
 
They should include dates, quantities, batch numbers, expiration dates (if applicable), and any unique code 
numbers assigned to the IMP and/or patients. Investigators should maintain records which document 
adequately that: 
1. 
The patients were provided the doses specified by the protocol/amendment(s), 
2. 
The IMP provided was fully reconciled at the site. 
The administration of the IMP (date/time for each administration) will be recorded by the site staff in the 
eCRF. The CRA will review the drug accountability forms/eCRF and check all IMP (both unused and used) 
prior to deciding on their disposal. 
IMP which has been dispensed to a patient and was not used will not be re-dispensed to a different patient. 
Unused IMP (tablets) must remain in the Patient Kit and must not be discarded or used for any purpose. Any 
remaining test material at the end of the trial will be returned to Dompé or disposed of, as determined by 
Dompé. 
5.4.1. 
Assessment of compliance 
The actual doses of the study drugs received by each patient during the trial will be recorded. A reconciliation 
will be made by the study monitor between expected and actual administrations over the time between the 
start and the end of treatment. Discrepancies will be documented and justified. 
Compliance with the study product dosing schedule will be verified by the investigator and 
confirmed/checked by the delegated CRA during on-site monitoring visits, as per records in the specific study 
eCRF and actual tables remaining in the Patient Kits. Exposure, calculated on the 48h regimen, will be 
assessed based on the actual duration of treatment. 
 
 
5.5. 
PRIOR AND CONCOMITANT MEDICATIONS 
5.5.1. 
Reporting of prior and concomitant medications 
Prior and concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter drugs, 
vaccines) used by a patient in addition to the IMP from 7 days before the screening to the end of the study. 
All such medications will be reported in the appropriate section of the eCRF. 
All the details as per the eCRF fields (sequential number, drug name, indication, starting dose, start/stop date, 
route of administration) will be recorded. 
 

REP0122  
Reparixin in ARDS  
Page 35 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
5.5.2. Medications to be used with caution 
From an in vitro study, reparixin was found to slightly inhibit human CYP3A4, CYP2C9 and, in minor extent, 
CY2C19 isoenzymes. However, the results of a clinical study, investigating the interaction of reparixin with 
probe drugs for CYP2C9 and CYP3A4 showed that the concomitant administration of reparixin does not 
have a significant effect on PK of drugs metabolized by the above isoenzymes. Reparixin, in human 
hepatocytes, did not show induction of the CYP2C8, CYP3A4 and CYP3A5 mRNA levels at the tested 
concentration range. Furthermore, reparixin is not an inhibitor of docetaxel metabolism and inhibits paclitaxel 
metabolism with a non-clinical relevant IC50 value > 100 μM. Therefore, for the purposes of this study and 
taken under consideration the intended patient population, the following medications with a potential to alter 
CYP2C9 activity may be used if the clinical benefit is considered to be higher than the perceived risk 
according to the PI’s discretion: 
1) CYP2C9 inducers (rifampin, phenytoin, carbamazepine, aprepitant, bosentan, phenobarbital) 
2) CYP2C9 inhibitors (amiodarone, fluconazole, miconazole, oxandrolone, capecitabine, cotrimoxazole, 
etravirine, fluvastatin, fluvoxamine, metronidazole, sulfinpyrazone, tigecycline, voriconazole, zafirlukast).

REP0122  
Reparixin in ARDS  
Page 36 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
6. 
STUDY PROCEDURE AND ASSESSMENT 
During the course of the study, assessments will be performed as defined in the Schedule of Assessments 
(Section 2). 
For all measurements, the actual date and time of assessment, including date of sampling, will be recorded 
in the Source Document and in the eCRFs. 
 
6.1. STUDY VISITS AND STUDY EVENTS/PROCEDURES DETAILS 
The study will consist of 4 study periods: screening, randomization and baseline assessments, treatment (up 
to 21 days), and follow-up (up to 60 days). Potential participants will be identified from those hospitalized at 
the participating clinical sites with a diagnosis of ARDS. Patients under evaluation at the Emergency 
Department with an expected admission to the ward will be considered hospitalized for study purposes. 
 
6.1.1. Screening Procedures 
Informed consent must be documented before any study-specific screening procedure. Patients should not 
be screened if, for any reason, there is a high probability that they will be transferred during the treatment 
phase to another institution not belonging to the study network. 
Procedures included in the screening will include: 
● Demographic data, past medical history, allergies to medications, disease-specific clinical information 
● Concomitant medications 
● History of side effects related to prior use of NSAIDs such as gastrointestinal (GI) bleeding or other 
form of bleeding, peptic ulcer disease) 
● Blood sampling for measurement of hematology/biochemistry (Safety Laboratory Tests) and derived 
renal and hepatic function (unless already collected for clinical care) 
● Pregnancy test (either urine or serum test is acceptable) in women of childbearing potential; positive 
urine test results will be confirmed with a serum pregnancy test; 
● 12-lead ECG performed using local equipment (unless already collected for clinical care) 
● PaO2 and FIO2 
● Chest imaging (either CXR or CT scan). Imaging performed for diagnostic purposes prior to the 
informed consent process will be accepted if it is done within 24 hours from screening 
The overall eligibility of the subject to participate in the study will be assessed once all screening values are 
available. If a subject fails screening, he/she will be recorded as a screen failure. In that case the subject may 
be rescreened once (immediately or later as long as randomization can be accomplished within the 48 hour 
window from ARDS diagnosis as per inclusion criteria) if deemed appropriate by the investigator. In that 
case, the subject must be re-consented. A new rescreening period will start, all screening procedures must be 
repeated. 
 
6.1.2. Randomization and Baseline assessments 
Patients meeting all inclusion and none of the exclusion criteria will be enrolled (eligibility confirmed) and 
randomized (see sections 4.1 and 4.2) at the latest within 48 hours from ARDS diagnosis as described in 
inclusion criteria. Consecutive randomization numbers will be given to the subjects upon their confirmed 
eligibility for randomization. Subjects will be assigned to their treatment according to their randomization 
number. Patients will be randomized in a 1:1 fashion between reparixin and placebo using a computer-
generated randomization list generated in the study. Randomization will be performed through IRT. 
Investigators will have to remain blind throughout the whole study duration. Information for unblinding is 
provided in section 5.1. IMP will be administered TID for 14 days with the option of continuation to 21 days 
if the patient is still intubated on Day 14. 
Before starting the administration of the IMP, the following baseline data will be collected: 
● PaO2, PaCO2 and FIO2  
● Vital signs: respiratory rate (RR), heart rate (HR), mean arterial pressure (MAP) 
● IMV parameters [tidal volume (TV), PEEP, mean airway pressure, plateau airway pressure) 

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 3 7  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
● Use of ne ur o m usc ular bl oc ki n g a ge nts a n d i n hale d vas o dilat ors  
● Pr o ne p ositi o ni n g  
● Vas oacti ve me dicati o ns ( dr u g a n d d ose calc ulate d i n n ore pi ne p hri ne e q ui vale nts)  
● Se q ue ntial or ga n fail ure assess me nt ( S O F A ) sc ore 
● C X R (if n o m ore t ha n 2 4 h o urs ha ve ela pse d fr o m a scree ni n g C X R, baseli ne C X R will be deferre d)  
● Il-6, I L -8, P AI -1, T N Fr -1, I C A M -1, R A G E  
 
6. 1. 3.  Tre at me nt a n d p ost -tre at me nt h os pit al st a y u p t o d a y 6 0 
T he bel o w data will be c ollecte d dail y fr o m da y 1 u ntil e xt u bati o n:  
● Pa O 2, Pa C O2 a n d FI O 2 
● Vital si g ns: R R, H R, M A P  
● I M V para meters ( T V, P E E P,, mea n air wa y press ure, platea u air wa y press ure) 
● Use of ne ur o m usc ular bl oc ki n g a ge nts a n d i n hale d vas o dilat ors  
● Pr o ne p ositi o ni n g  
● Tra nsiti o n t o E C M O  
● Vas oacti ve me dicati o ns ( dr u g a n d d ose calc ulate d i n n ore pi ne p hri ne e q ui vale nts)  
● S O F A sc ore  
● N u m ber of atte m pts at wea ni n g defi ne d as c o nti n u o us p ositi ve air wa y press ure ( C P A P ) trial 
( C P A P 5 c m H2O pl us P E E P 5 c m H 2O) of 2 h o urs d urati o n  
 
If a n i nitial e xt u bati o n is f oll o we d b y re-i nt u bati o n t he a b o ve varia bles will be c ollecte d dail y f or eac h 
s u bse q ue nt i nt u bati o n. 
At da ys 2( ± 8 h), 3( ± 8 h), 7 ( ± 1 da y), a n d 1 4 ( ± 2 da y) a C X R will be perf or me d ( C X R perf or me d f or r o uti ne 
cli nical care i n I C U patie nts will be acce pte d) 
At da ys 3 ± 8 h, 7 ± 1, 1 4 ± 2 bl o o d sa m ples will be o btai ne d f or meas ure me nt of t he f oll o wi n g plas ma bi o mar kers: 
I L-6, I L -8, P AI -1, T N Fr -1, I C A M -1, R A G E  
Bet wee n e xt u bati o n a n d da y 2 8 or h os pital disc har ge (if it occ urs bef ore da y 2 8) t he f oll o wi n g data are 
c ollecte d e ver y 4 8 ± 8 h o urs:  
● Vital si g ns: R R, H R, M A P  
● Pa O 2 ( or S p O2) a n d FI O2 
● T y pe of o x y ge n s u p p orti ve t hera pies use d if a n y  
● Nee d f or rei nt u bati o n (after i nitial e xt u bati o n) 
At da y 2 8 a n d h os pital disc har ge, t he f oll o wi n g data will be c ollecte d: 
● Pa O 2 ( or S p O2) a n d FI O2 
● T y pe of o x y ge n s u p p orti ve t hera pies use d, if a n y  
● D urati o n of I M V  
● I C U le n gt h of sta y 
● Nee d f or rei nt u bati o n (after i nitial e xt u bati o n)  
● H os pital le n gt h of sta y  
● Perf or ma nce of trac he ost o m y  
● Tra nsfer t o l o n g ter m ac ute care ( L T A C * ) facilit y 
T he a b o ve i nf or mati o n, t o get her wit h m ortalit y, ma y be c ollecte d b y p h o ne f oll o w -u p . 
* L T A C : A n L T A C is a L o n g Ter m Ac ute Care H os pital, i.e., a facilit y t hat s pecializes i n t he treat me nt of patie nts wit h 
seri o us me dical c o n diti o ns, i ncl u di n g patie nts wit h o n g oi n g nee ds f or mec ha nical ve ntilati o n, b ut w h o n o l o n ger re q uire 
i nte nsi ve care or e xte nsi ve dia g n ostic pr oce d ures. T he patie nts i n L T A C are tra nsferre d t here directl y fr o m t he i nte nsi ve 
care u nit beca use t he y re q uire m ore care t ha n t he y ca n recei ve i n a re ha bilitati o n ce nter, s kille d care facilit y or at h o me.  
 
C CI
C CI

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 3 8  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
 
 
S afet y : T he f oll o wi n g safet y assess me nts will be perf or me d o n da y 3 ± 8 h, 7 ± 1, 1 4 ± 2, 2 1 ± 2 (if re pari xi n is 
still a d mi nistere d), 2 8 ± 2 a n d at h os pital disc har ge 
● 
Safet y La b orat or y Tests ( Hae mat ol o g y/ bi oc he mistr y)  
● 
Esti mate d Gl o mer ular Filtrati o n rate ( e G F R) e val uati o n 
● 
He patic f u ncti o n e val uati o n u p t o da y 1 4 or 2 1, de pe n di n g o n e n d of treat me nt  
● 
1 2 lea d E C G a n d r h yt h m a nal ysis  
 
P ost -h os pit al disc h ar ge f oll o w -u p : o n da y-6 0 t he patie nts will be c o ntacte d b y p h o ne f or e val uati o n of 
vital stat us a n d A Es . Patie nts will be c o nsi dere d l ost t o f oll o w u p w he n u na ble t o be c o ntacte d u p o n 3 
atte m pts ma de o n 3 se parate da ys a n d at 3 se parate ti mes.  
 
6. 2.  E A R L Y P A TI E N T WI T H D R A W A L  
6. 2. 1.  
Wit h dr a w al criteri a  
Patie nts will be i nf or me d t hat t he y ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me ( wit h dra wal of 
c o nse nt), wit h o ut prej u dice t o t heir me dical care, a n d are n ot o bli ge d t o state t heir reas o ns.  
T he pri mar y, act ual, reas o n f or wit h dra wal s h o ul d be rec or de d, es peciall y if t here is s us pici o n of wit h dra wal 
d ue t o a d verse e ve nts (“ wit h dra wal of c o nse nt” is a defi niti o n t o be use d if t he patie nt d oes n ot gi ve reas o ns). 
Safet y la b orat or y tests s h o ul d be perf or me d w he ne ver p ossi ble at patie nt wi t h dra wal. 
Patie nts w h o disc o nti n ue t he treat me nt wit h t he I M P ( Secti o n 5. 3. 2) will n ot be wit h dra w n fr o m t he st u d y  
b ut will be as ke d t o c o m plete o bser vati o ns as per t he pr ot oc ol, u nless t he y wit h dra w t heir c o nse nt. It is 
i m p orta nt t hat a n y ra n d o mize d patie nt re mai ns i n t he st u d y a n d is f oll o we d f or b ot h efficac y a n d safet y 
o utc o mes, re gar dless of w het her he/s he has c o m plete d or disc o nti n ue d t he st u d y treat me nt.  
I n vesti gat ors will be trai ne d o n t he i m p orta nce of patie nt rete nti o n t hr o u g h t he d urati o n of t he trial. 
I n case of pre g na nc y, t he patie nt will be wit h dra w n fr o m t he st u d y, b ut s he will be m o nit ore d f or safet y a n d 
pre g na nc y o utc o mes, u nless s he wit h dra ws her c o nse nt.  
A n y wit h dra wals m ust be f ull y d oc u me nte d i n t he e C R F.  
 
 
6. 2. 2.  Re pl ace me nt pr oce d ures  
T here are n o pla ns t o re place disc o nti n ue d s u bjects.  
 
 
6. 3.  
E N D O F S T U D Y  
F or t he p ur p ose of t his trial, t he E n d of St u d y is defi ne d as t he date of t he last assess me nt of t he last patie nt.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 39 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
6.4. 
PATIENT MANAGEMENT AFTER STUDY COMPLETION OR TERMINATION 
After completion of the 28-day assessment or at study termination (for any other reason), patients will receive 
post-study care as prescribed by their non-study health care provider. No post-study or post study-termination 
treatment will be provided by the study team or Dompé. 
 
6.5. 
ASSESSMENTS AND CLINICAL DEFINITIONS 
 
Assessment 
type 
Parameters to be analyzed 
(units) 
Demographic 
data 
- 
age (years); 
- 
date of birth (or only year of birth if full date of birth cannot be recorded, 
for local regulations); 
- 
sex (M/F); 
- 
self-reported race/ethnicity (Black / African American, White, Asian, 
Hispanic / Latino, multiple / other) 
- 
height (cm), also self-reported; 
- 
body weight (kg) 
Medical 
history 
- 
all relevant past and ongoing diseases and surgeries 
- 
allergies, with a particular focus on IMP-related allergy/intolerance (such as 
ibuprofen hypersensitivity, lactase deficiency, galactosemia, glucose-galactose 
malabsorption) 
- 
past (no / yes) or current tobacco use (no / yes, < or ≥ 10 cigarettes daily or 
equivalent) 
- 
past (no / yes) or current alcohol consumption (no / yes, < or ≥ one liter of 
wine daily, or equivalent) 
- 
recent test for influenza (no / yes, positive / negative) 
- 
vaccination for COVID-19 (no / yes: number of doses) 
- 
date of hospital/emergency department admission 
Chest 
imaging 
CXR/CT scan 
Findings to be recorded (multiple answers allowed): 
● Consolidation 
● Ground-glass opacities 
● Air bronchograms 
● Pleural and Interlobular septal thickening 
Safety 
Laboratory 
Tests 
Hematology 
● RBC count (n x106/µL), hematocrit (%), hemoglobin (g/dL) 
● WBC count and differential count: neutrophils, eosinophils, basophils, 
monocytes, lymphocytes (n x103/µL or percentages of WBC) 
● platelet count (n x103/µL) 
Biochemistry 
● albumin (mmol/L or g/dL) 
● AST (nkat/L or U/L) 
● ALT (nkat/L or U/L) 
● total and direct bilirubin (e.g., mg/dl or μmol/L) 
● creatinine (µmol/L or mg/dL) 
● estimated Glomerular Filtration Rate (eGFR; 2021 CKD-EPI formula) 
● serum glucose (mmol/L or mg/dL); specify if fasting or random 
● sodium (mmol/L or mEq/L), potassium (mmol/L or mEq/L), chloride 
(mmol/L or mEq/L), calcium (mmol/L or mg/dL)  
(units may change as per local lab standard) 

REP0122  
Reparixin in ARDS  
Page 40 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
Inflammatory 
markers 
● IL-6 (pg/ml) 
● IL-8 (pg/ml) 
● TNFr1 (pg/ml) 
● PAI-1 (ng/ml) 
● ICAM-1 (ng/ml) 
● RAGE (pg/ml) 
Prior and 
Concomitant 
medications 
At screening: recording of drug name, indication, total daily dose, dose unit, route, 
start and end dates 
During hospital stay: recording of any change of already recorded, or new 
concomitant medications 
Lung 
function 
- 
Peripheral arterial oxygen saturation (SpO2; %) 
- 
Partial pressure of oxygen (PaO2; mmHg) 
- 
Partial pressure of carbon dioxide (PaCO2; mmHg) 
- 
Mean airway pressure (cm H2O) 
- 
Plateau airway pressure (cm H2O) 
- 
PEEP (cm H2O) 
- 
Tidal volume (mL) 
- 
Fraction of inspired O2 (FIO2; 0.21 to 1) 
- 
PaO2/FIO2 (mmHg); SpO2 may be used in place of PaO2 if arterial sample is 
not available 
IMV/ECMO 
- 
Endotracheal intubation 
- 
Tracheostomy tube 
Extracorporeal Membrane Oxygenation Duration of IMV or ECMO to be recorded 
(days) 
SECONDA
RY 
INFECTIO
NS 
Defined as: 
1) New (occurring after the first IMP intake) infection in a previously 
known to be sterile site, including blood, body fluid or tissue. 
2) New pathogen isolated from cultures of biological samples known to 
be previously infected 
ECG 
ECG after the subject has been lying quietly for 5 minutes. 
The following to be recorded: 
- 
overall assessment for the presence of alterations (no / yes), 
- 
presence of: arrhythmia, conduction abnormalities; ST-segment 
elevation / depression; T-wave alterations; 
- 
HR (bpm) 
- 
PQ interval (msec); 
- 
QT/QTc (Bazett formula; msec) 
Clinically significant abnormalities should be marked in the ECG-CRF (no / yes, 
specify) and also reported as an AE 

REP0122  
Reparixin in ARDS  
Page 41 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
7. STUDY ENDPOINTS 
7.1. EFFICACY ENDPOINTS 
Primary endpoint: 
● Change in oxygenation index (OI) from baseline to day 7 of treatment. The OI is defined as: % 
mean airway pressure x FIO2/PaO2 
● Ventilator free days (VFD) at day 28 (see 14.4.11) 
Secondary endpoints: 
● Change in OI from baseline to day 4 
● Acute lung injury score [composite of PaO2/FIO2 ratio, PEEP, lung compliance (plateau airway 
pressure minus PEEP/TV) and extent of pulmonary infiltrates] at 2, 3, 7, 14 days (if still intubated) 
● SOFA scores at 2, 3, 7, 14 days (if still intubated) 
● Ventilatory ratio (product of minute ventilation and PaCO2) at 2, 3, 7, 14 days (if still intubated) 
● Incidence of ECMO at day 14 
● Use of vasoactive medications at day 14 
● CXR assessment of pulmonary edema by “radiographic assessment of lung edema” (RALE) score 
at 2, 3, 7, 14 days 
● Percentage of patients achieving pressure support ventilation equal to 5 cm H20 with PEEP equal 
to 5 cm H20 for 2 hours (measure of weaning) by day 28 and hospital discharge 
● ICU-free days by day 28 and hospital discharge 
● Hospital-free days by day 28 and hospital discharge 
● Incidence of tracheostomies by day 28 and hospital discharge 
● Incidence of LTAC facility by day 28 and hospital discharge 
● All-cause mortality by day 28 
● Hospital discharge by day 28 
● All-cause mortality by day 60 
● Change from baseline to day 3, 7 and 14 in plasma levels of Il-6, IL-8, PAI-1, Plasma TNFr-1, 
ICAM-1 RAGE 
Footnote: day 1 is the day when the IMP is first administered. Hour 1 of day 1 starts when the first 
dose of the IMP is administered. Subsequent days are measured in 24-hour intervals from hour 1. 
Therefore, day 2(±8h) signifies 24 hours ±8 hours from hour 1. 
 
7.2. 
SAFETY ENDPOINTS 
- 
Hematology (RBC, hematocrit, hemoglobin, WBC, neutrophils and lymphocytes absolute count, 
platelets count) and biochemistry (sodium, potassium, chloride, calcium, glucose, creatinine, eGFR 
albumin, AST, ALT, total and direct bilirubin). Change from screening to day 3±8h, 7±1, 14±2, 21±2 (if 
still receiving reparixin, or end of treatment), 28±2 and at hospital discharge 
- 
eGFR, absolute value and change from screening to day 3±8h, 7±1, 14±2, 21±2 (if still receiving 
reparixin, or end of treatment), 28±2 and hospital discharge 
- 
 ECG. Change from screening to day 3±8h, 7±1, 14±2, 21±2 (if still receiving reparixin, or end of 
treatment), 28±2 and at hospital discharge. 
- 
Incidence of secondary infections defined as new (occurring after the first IMP intake) infection in a 
previously known to be sterile site, including blood, body fluid or tissue, or new pathogen isolated from 
cultures of biological samples known to be previously infected by day 28±2 
- 
Incidence of TEAEs and TESAEs from the beginning of IMP administration up to the end of study 
participation

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 4 2  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
C CI
C
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 43 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
8. 
ADVERSE EVENTS 
8.1. 
DEFINITIONS 
Adverse event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not 
related to the medicinal product. 
 
Adverse Drug Reaction 
An Adverse Drug Reaction (ADR) is defined as an adverse event, which is reasonably likely to have been 
caused by the IMP. The definition also covers medication errors and use of the IMP outside what is foreseen 
in the protocol, including misuse and abuse of the product. For the purposes of IND safety reporting in the 
U.S., “reasonable possibility” means there are facts (evidence) or arguments to suggest a causal relationship 
between the drug and the adverse event. 
 
Serious Adverse Event/Reaction 
A Serious Adverse Event (SAE)/Reaction is defined as any untoward medical occurrence that at any dose: 
● results in death 
● is life-threatening (i.e., the patient is 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) 
● requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization means that the individual remained at the hospital or emergency ward 
for observation and/or treatment (usually involving an overnight stay) that would not have been appropriate 
in the physician's office or an 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, the event should be considered serious. 
● results in persistent or significant disability/incapacity 
NOTE: This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained 
ankle, back pain) which may interfere or prevent everyday life functions but does not constitute a substantial 
disruption. 
● is a congenital anomaly/birth defect 
● is a medically significant or important medical condition, i.e., an important medical event as determined 
by appropriate medical judgment, which may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
NOTE: An important medical condition is an event that may not result in death, be life-threatening, or 
require hospitalization but may be considered a SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in patient 
hospitalization, or the development of drug dependency or drug abuse. 
Pre-planned hospitalization or hospitalization for routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition, are not considered to be serious events. These events must be 
recorded in the AE section (except for hospitalization for study procedures) of the eCRF where a variable will 
be ticked to indicate that they are not SAEs.  
Death shall always be reported as SAE, and cause of death shall always be specified, when known. If unknown, 
“death NOS” (not otherwise specified) shall be reported as an event. 

REP0122  
Reparixin in ARDS  
Page 44 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
Unexpected Adverse Events 
An AE or ADR is considered unexpected if it is not listed in the Investigator Brochure (Reference Safety 
Information section). An event is unexpected also when it is not listed at the specificity or severity that has 
been observed and listed in the Investigator Brochure. Events that are mentioned in the Investigator Brochure 
as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug but are 
not specifically mentioned as occurring with the particular drug under investigation are considered 
unexpected. The determination of expectedness shall be made on the basis of the IB Reference Safety 
Information (RSI) section. 
According to the Investigator Brochure (Reference to Safety Information, section 6.4), for the purpose of 
this study and considering the current early clinical development status of the IMP for the indication 
investigated, each adverse event will be carefully evaluated and no Serious Adverse Reaction will be 
considered expected by the sponsor for the purpose of expedited reporting of SUSARs and the identification 
of SUSARs in the “Cumulative summary tabulation of serious adverse reactions” in the Development Safety 
Update Report on the IMP. 
 
Suspected serious unexpected adverse reaction 
A suspected serious unexpected adverse reaction (SUSAR) is defined as an adverse reaction that is both 
unexpected (not consistent with the applicable product information) and also meets the definition of a Serious 
Adverse Reaction. 
 
 
8.2. 
MONITORING FOR ADVERSE EVENTS 
Following study informed consent form signature, the Investigator or appropriate designee should 
inquire/monitor daily about the occurrence of an AEs. 
AEs should be reported for any clinically relevant untoward (unfavorable and unintended) change in a 
patient’s medical condition. Changes in any protocol-specific systemic parameter evaluated during the study 
are to be reviewed by the Investigator. Any untoward (unfavorable and unintended) change in a protocol-
specific parameter or questionnaire response that is clinically relevant is to be reported as an AE. These 
clinically relevant changes will be reported regardless of causality. 
 
 
8.3. 
RECORDING OF ADVERSE EVENTS 
All AEs (serious and non-serious) which occur from signature of the informed consent through patient 
participation in the study (last planned visit or early withdrawal date) will be collected and recorded in the 
eCRF. It is important that the AE dedicated section of the eCRF includes the duration of the AE 
(onset/resolution dates), the relationship to the drug, the severity, the outcome, the action(s) taken and 
relevant concomitant treatments dispensed. When possible, signs and symptoms indicating a common 
underlying pathology should be documented as one comprehensive event. 
All AEs should be followed-up to determine the outcome of the reaction. The Investigator should follow up 
the event until resolution or stabilization of the condition. It is the Investigator's responsibility to assure that 
the patients experiencing an AE receive definite treatment for any AE, if required. 
Medical conditions/diseases present before starting study treatment shall be documented in the medical 
history section of the eCRF; these conditions are considered AEs only if they increase either in frequency or 
severity once informed consent has been signed. 
8.3.1. Follow-up of patients with AEs 
The Investigator is responsible for adequate and safe medical care of patients during the trial and for 
ensuring that appropriate medical care and relevant follow-up procedures are maintained after the trial. All 
AEs should be followed-up to determine the outcome of the reaction. The Investigator should follow up the 
event until resolution or stabilization of the condition. It is the Investigator's responsibility to assure that the 
patients experiencing AEs receive definite treatment for any AE, if required. 
If a patient's conditions worsen due to a SAE, the Investigator will provide supporting documentation, as 
well as results of any relevant laboratory tests and redacted section of medical records may be provided to 

REP0122  
Reparixin in ARDS  
Page 45 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
the Sponsor and/or delegate, if relevant for the SAE. In case of death, a copy of the autopsy report, if 
performed, should also be provided. 
The Investigator shall inform the Sponsor with an appropriate written communication, whenever he 
becomes aware of new available information regarding the SAE, once the condition is resolved or stabilized 
and when no more information about the event is expected. Follow-up SAE information should be processed 
as initial SAE notification (see Sections 8.4, 8.5). 
For pharmacovigilance purposes, all SAEs should be followed-up in order to clarify as completely as 
possible their nature and/or causality and until all queries have been resolved. All SAEs will be followed up 
until the events resolve or the events or sequelae stabilize, or it is unlikely that any additional information 
can be obtained after demonstration of due diligence with follow-up efforts (i.e. patient or Investigator is 
unable to provide additional information, or the patient is lost to follow up), unless patient has withdrawn 
his/her consent. 
 
8.3.2. Relationship of AEs to the Investigational Medicinal Product 
The Investigator will assess the causal relationship between the AE and the IMP (either reparixin or placebo), 
according to the criteria in the Table below: 
Relationship of the AEs to the IMP 
 
None (Intercurrent 
Event) 
An event that is not and cannot be related to the Investigational Product, e.g. a 
surgical intervention for nevus removal performed during the study, but planned 
before patient enrolment into the study 
 
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test abnormality 
without temporal relationship to drug administration which makes a causal 
relationship improbable and in which other drugs, chemicals or underlying disease 
provide more plausible explanations 
Possible 
Relationship may exist, but could have been produced by the patient’s condition 
or treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of Investigational 
Product and cannot be due to the patient’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of Investigational 
Product and, if applicable, re-appears upon repeat exposure 
 
Any AE reported in the study having a possible, probable or highly probable relationship to the study drug 
will be considered as an ADR. On the other hand, AEs marked with relationship none or unlikely, will not 
be considered as ADR. 
 
8.3.3. Severity of adverse events 
The Investigator will grade the severity of any AE using the definitions in the Table below. For each 
episode, the highest severity grade attained should be reported. 
 
Severity of the Adverse Event 
 
Mild 
Grade 1 - Does not interfere with the patient's usual function (awareness of symptoms 
or signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with the patient's usual function (enough 
discomfort to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with the patient’s usual function (incapacity to work 
or to do usual activities [unacceptable]) 
 
 

REP0122  
Reparixin in ARDS  
Page 46 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
8.4. 
SERIOUS ADVERSE EVENT REPORTING 
8.4.1. Reporting Procedure to Dompé/CRO 
The Investigator must report all SAEs occurring during patient participation in the study, regardless of 
presumed causal relationship, to the appropriate Sponsor and CRO Pharmacovigilance contact within 24 
hours of learning of the event. Contact details for SAE reporting by the Investigator are provided in the 
section “Contact Information'' (See Page 2 of this Protocol). SAE form notification will be performed on a 
paper based or electronically using a validated e-system according to Sponsor indication and upon proper 
training on the e-system. Paper form can be used as back-up in case of unavailability of the eDC and after 
study termination. 
The Investigator should also report information on SAEs that continue after the patient has completed 
his/her participation in the study (whether study completion or withdrawal) unless the patient has withdrawn 
his/her consent. 
In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does not usually 
need to actively monitor patients for AEs once the trial has ended, if the Investigator becomes aware of a 
SAE occurring to a patient after that patient has ended his/her participation in the study (whether study 
completion of withdrawal), the SAE should be reported by the Investigator directly to the Dompé Global 
Pharmacovigilance Safety and Surveillance Department, even after the termination of the study. Such “post-
study cases” should be regarded for expedited reporting purposes as though they were study reports. 
Therefore, a causality assessment and determination of expectedness are needed for a decision on whether or 
not expedited reporting is required. 
Information on SAEs will be recorded on a specific SAE form. Both electronic and blank paper copies will 
be included in the Investigator’s Site File. Follow-up reports (as many as required) should be completed and 
emailed/faxed following the same procedure above. 
Whenever more than one SAE is observed, the Investigator should identify which is the primary adverse 
event, i.e., the most relevant one. If other events are listed in the same report, the Investigator should identify, 
along with their relatedness to the IMP, which adverse events are serious, and which are non-serious. In all 
cases, the Investigator is requested to record his/her opinion about the relatedness of the observed event(s) 
with the IMP. 
 
8.4.2. Conditions that should not be reported as serious adverse events 
Not applicable. 
 
8.4.3. Adverse events exemption 
Not applicable. There is no event to be considered routinely associated with any clinical study procedure, 
therefore requiring neither recording nor reporting. 
 
8.4.4. Reporting Procedure to IEC and to Regulatory Authorities in the European Union 
Reporting of Suspected Unexpected Serious Adverse Reaction 
The Investigator must report all SAEs to the Sponsor/CRO immediately, within 24 hours (see Section 8.4.1). 
Dompé Global Pharmacovigilance, Safety and Surveillance Department, with the support of the CRO as 
appropriate, shall report any SUSAR to the concerned IEC which approved the protocol and the Regulatory 
Authority (via the EudraVigilance Clinical Trial module) as soon as possible, and in no event later than:   
● seven calendar days after becoming aware of the information if the event is fatal or life threatening; 
to be followed by any relevant information within eight days. 
● fifteen calendar days after becoming aware of the information if the event is neither fatal nor life 
threatening. 
Treatment will be unblinded by Dompé Global Pharmacovigilance, Safety and Surveillance Department 
prior to regulatory submission of a SUSAR to Regulatory Authorities and IEC, and only cases referred to as 
active treatment will be considered expeditable for regulatory reporting, in line with law requirements. 

REP0122  
Reparixin in ARDS  
Page 47 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
If the results of an investigation show that an AE not initially determined to be reportable is reclassified as 
reportable, Dompé shall notify such SUSAR in a written safety report as soon as possible, but in no event 
later than 7/15 calendar days after the determination is made. 
Copies of all correspondence relating to reporting of any SAEs to the IEC should be maintained in the 
Investigator’s Files. 
Periodical Reporting to EU Regulatory Authorities and Investigators 
Dompé Global Pharmacovigilance, Safety and Surveillance Department will prepare and submit (via the 
CRO as applicable) to Investigators appropriate periodic safety updates as per applicable EU and local 
requirements and regulations. Dompé Global Pharmacovigilance, Safety and Surveillance Department shall 
also be responsible to prepare and submit annual safety reports (Development Safety Update Report – DSUR) 
to relevant Regulatory Authorities and to IECs. 
 
8.4.5. Reporting Procedures to IRB and to the FDA in the United States 
Reporting of Suspected Unexpected Serious Adverse Reaction 
The Investigator must report all SAEs to the Sponsor/CRO immediately, within 24 hours (see Section 8.4.1). 
In line with provisions set forth in 21CFR312, Dompé Global Pharmacovigilance, Safety and Surveillance 
Department, with the support of the CRO as appropriate, shall notify the Investigators and the FDA in an 
IND safety report of any SUSAR and of potential serious risks, from clinical trials or any other source, as 
soon as possible, but in no case later than: 
● seven calendar days after becoming aware of the information if the event is fatal or life threatening; 
to be followed by any relevant information within eight days. 
● fifteen calendar days after becoming aware of the information if the event is neither fatal nor life 
threatening. 
The Investigators in turn shall notify their IRB. Investigators are required to promptly report “to the IRB all 
unanticipated problems involving risk to human patients or others,” including adverse events that should be 
considered unanticipated problems (21 CFR 312.66). 
The blind should ordinarily be broken for IND safety reports submitted to FDA and all participating 
investigators. Treatment will be unblinded by Dompé Global Pharmacovigilance, Safety and Surveillance 
Department prior to regulatory submission of a SUSAR to FDA and IRB and only cases referred to as active 
treatment will be considered expedited for regulatory reporting, in line with law requirements. 
If the results of an investigation show that an AE not initially determined to be reportable is reclassified as 
reportable, Dompé Global Pharmacovigilance, Safety and Surveillance Department shall notify such SUSAR 
in a written safety report as soon as possible, but in no event later than 7/15 calendar days after the 
determination is made. 
Copies of all correspondence relating to reporting of any SAEs to the IRB should be maintained in the 
Investigator’s Files. 
Potential serious risks arising from clinical trials or any other source, to be reported to FDA and to the 
Investigators, include: 
- Any SUSAR. Dompé must report an adverse event as a suspected adverse reaction only if there is evidence 
to suggest to the Sponsor a causal relationship between the drug and the adverse event. 
- Findings from other studies that suggest a significant risk in humans exposed to the drug. Such a finding 
would result in a safety-related change in the overall conduct of the clinical investigation. 
- Findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug. 
- Increased rate of occurrence of serious suspected adverse reactions. 
 
Periodical Reporting to US Regulatory Authorities 
Based on the specific Investigator’s site requirements, Dompé Global Pharmacovigilance, Safety and 
Surveillance Department (via the CRO as applicable) will submit to IRBs and Investigators periodic safety 
updates, as per applicable local requirements and regulations. 

REP0122  
Reparixin in ARDS  
Page 48 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
Dompé Global Pharmacovigilance, Safety and Surveillance Department (via the CRO as applicable) shall 
also be responsible to prepare and submit annual safety reports (Development Safety Update Report – DSUR) 
to FDA and IRBs, as applicable. 
 
8.5. 
EXPOSURE TO IMP DURING PREGNANCY 
Women of childbearing potential are defined as all women physiologically capable of becoming pregnant. 
As the study will be conducted in hospitalized critically ill patients, we consider the possibility of pregnancy 
during the use of IMP to be highly unlikely. However, female patients of childbearing potential and their 
partners will be advised of the importance of avoiding pregnancy for at least 30 days after the end of IMP 
administration and of the potential risks associated with an unintentional pregnancy. The Investigator must 
report every pregnancy on a Pregnancy Report Form as soon as possible (within 24 hours of learning of the 
pregnancy) to the Pharmacovigilance Contacts specified in the section “Contact Information”, even if no AE 
has occurred, and follow it to term. If, however, the pregnancy is associated with an SAE (e g, if the mother 
is hospitalized for dehydration), in addition to the Pregnancy Report Form, a separate SAE report form must 
be filed as described in Section 8.6, with the appropriate serious criterion indicated on the SAE report form. 
Miscarriage, stillbirth and any malformation/disease must be reported as a SAE. 
Any pregnancy leads to the immediate withdrawal of the study patient from the trial. 
 
8.6. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded and reasoned in 
the eCRF, and the patient must be followed up until the resolution of the AE or as instructed by the medical 
expert. 
 
8.7. 
OVERDOSE 
Accidental or intentional overdose, which may or may not result in serious adverse reactions, is to be 
reported to CRO Pharmacovigilance, Dompé Global Pharmacovigilance, Safety and Surveillance Department 
and to Dompé Medical Expert, following the same procedure for SAE, within 24 hours from the 
Investigator’s knowledge of its occurrence. This includes reports related to drug intake through different 
routes (e.g. ingestion) or with suicidal intentions and consequent drug overdose. 
An overdose of reparixin is defined as the administration of 3 or more additional tablets on any given 
treatment day. 
The Investigator shall provide in the SAE form information about symptoms, corrective treatment, and 
outcome of overdose. The Medical Expert should be contacted to discuss corrective treatment, if necessary.

REP0122  
Reparixin in ARDS  
Page 49 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1. 
SAMPLE SIZE 
The sample size of the study is calculated based on results from literature32-35. Evaluation of the efficacy for 
this study is being accomplished through estimation of a 95% confidence interval. No hypotheses are 
specified for this study and no p-values are being calculated but for descriptive purposes, therefore no level 
of significance is specified. 
Considering a randomization ratio 1:1 (reparixin: placebo), a sample size of 60 evaluable subjects is 
considered adequate for assessing the difference between groups in primary endpoints, i.e., change from 
baseline in OI at day 7 and VFD at day 28. 
The given sample size will provide a reasonable precision in the estimation of group differences in primary 
endpoints to an expected margin of error for a 95% one-sided confidence interval of at most 46.5% the 
standard deviation, whatever it is: 
- 
Assuming a standard deviation of 11.5 points for OI, the 95% one-sided confidence interval for the 
difference between groups will have a width of 5.35 points; 
- 
Assuming a standard deviation of 8 days for VFD, the 95% one-sided confidence interval for the 
difference between groups will have a width of 3.75 days. 
If 10% of enrolled patients will not be evaluable for primary analysis, the total number of patients to be 
enrolled will be approximately 66. 
 
9.2. 
RANDOMIZATION 
Enrolled patients will be randomized in a 1:1 ratio to either reparixin or placebo according to the 
randomization list. Dropouts after randomization will not be replaced. 
The permuted block randomization list will be generated with a computer procedure by a CRO independent 
statistician not involved in the conduct of the study and will be provided to Dompé in a sealed envelope to 
prevent unblinding. The facility responsible for IMP packaging/labeling will also receive appropriate 
randomization codes for the purpose of IMP preparation. 
Randomization will be performed through the IRS. Each Patient Kit number will be randomly associated 
with a treatment group. Access to individual patient treatment codes will be allowed only in the event of a 
medical emergency where the knowledge of patient treatment is required to provide the patient with 
appropriate care. The investigator and Dompé Pharmacovigilance will have access to the randomization code 
for a specific patient in case of a medical emergency or for safety reasons. Unblinding events will be recorded 
and reported in the Clinical Study Report (CSR). The treatment assignment information will be kept 
confidential and will not be disclosed to any other. 
Once the study has been completed and the database has been locked, the treatment assignment information 
will be accessible to the study biostatistician(s) who will perform the statistical analyses and will generate 
reports. 
 
9.3. 
OVERVIEW OF PLANNED STATISTICAL ANALYSIS 
The study plans for the following statistical analyses: 
- Analyses for the Data Monitoring Committee: these analyses will be produced periodically according to 
the DMC Charter. 
- Final analysis: this analysis will be conducted when all enrolled subjects have completed the study and 
the study database has been locked and unblinded. 
 
 
9.4. 
ANALYSIS POPULATION 
The following populations will be defined:

REP0122  
Reparixin in ARDS  
Page 50 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
- The Safety (SAF) population will consist of all randomized patients who received at least one dose of the 
IMP. The SAF population will be analyzed according to the actual treatment received. The SAF 
population will be used to present results on safety data. 
- The Full Analysis Set (FAS) population will consist of all randomized patients who received at least one 
dose of the IMP. FAS population will be analyzed according to the intention-to-treat (ITT) principle, i.e. 
by treatment allocation. The FAS population will be used for the primary analysis of the study and to 
present results on efficacy data. 
 
 
9.5. 
STATISTICAL METHODOLOGY 
Statistical analysis will be performed by the CRO appointed by Dompé. 
Appropriate descriptive statistics will be produced by treatment arms according to the nature of the variable. 
For continuous data, the number of observations, mean, standard deviation, median and range (minimum and 
maximum) will be presented. For qualitative data, frequency distributions and percentages per category will 
be presented. Two-sided 95% confidence intervals around the mean or the proportions (Wilson method) will 
be presented. The number of subjects with missing data will be presented under the “Missing” category. 
Missing values will be included in the denominator count when computing percentages. When continuous 
data will be summarized, only the non-missing values will be evaluated for computing summary statistics. 
Any exception will be declared. 
For time-to-event variables, cumulative freedom from events will be evaluated using Kaplan-Meier (KM) 
method. The degree of uncertainty will be expressed with 95% confidence limits (calculated per the method 
proposed by Greenwood). Comparison of curves among arms will be performed with the log-rank test. KM 
graphs will be presented along with the number of patient-at-risk at exact time points. Subjects who are free 
from events at the time of DB lock will be censored at the DB lock date. Reasons for discontinuation will be 
incorporated into the analysis for determining censoring and failure status. Specifically, study discontinuation 
for Adverse Event, Death, Lost to follow-up or other negative outcomes will be considered as failure events. 
Subjects who have discontinued for other reasons without an event will be censored at the date of 
discontinuation. 
Unless otherwise specified, the significance level used for other statistical testing (for descriptive purposes) 
will be 0.05 and two-sided tests will be used. All patient data collected on the CRF will be listed by patient 
and center. 
The Statistical Analysis Plan (SAP) will be issued before database lock with more technical and detailed 
elaboration of the principal features of statistical analyses. Additional post-hoc analysis may be produced to 
further allow comparison between treatment and control, according to the results obtained. Any deviations 
from the original statistical plan (including unplanned analyses) will be documented in the Clinical Study 
Report. 
 
 
9.5.1. Analysis of efficacy variables 
9.5.1.1. Primary analyses 
Primary endpoints will be analyzed by means of regression models adjusting by pre-defined baseline factors 
(details will be provided in the SAP). Since patients who discontinue the IMP will not be withdrawn from 
the study but will be asked to complete safety and efficacy assessments as per the protocol, missing data due 
to intercurrent events will be addressed by using multiple imputation based on retrieved dropouts information. 
Retrieved dropout patients are defined as patients who discontinue study treatment and decide to remain in 
the study by following the schedule of assessments and continuing to adhere to protocol requirements. 
If not enough data was retrieved after study treatment discontinuation for assure the convergence of the MI- 
RD regression model (the final decision will be done at the time of the analysis and reported in the CSR), the 
same multiple imputation model will be fit using data from subjects of control group, washing-out the effect 
of treatment. This approach does not assume benefits for reparixin in case of discontinuation and limits a 
post-discontinuation clinical effect to that of placebo. 
The adjusted estimated treatment differences between reparixin and placebo will be displayed together with 

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 5 1  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
t he c orres p o n di n g 9 0 % c o nfi de nce i nter vals (t o reflect o ne-si de d 9 5 % c o nfi de nce i nter vals). Ass u m pti o n of 
N or mal distri b uti o n will be assesse d gra p hicall y. If re q uire d, a l o g tra nsf or mati o n mi g ht be a p plie d t o meet 
n or malit y ass u m pti o n.  
 
9. 5. 1. 2.  Sec o n dar y a nal yses  
Descri pti ve i n nat ure a nal yses will be perf or me d o n all sec o n dar y e n d p oi nts at eac h a vaila ble ti me p oi nt b y 
mea ns of descri pti ve statistics a n d b y a p pr o priate para metric tests de pe n di n g o n t he nat ure of t he varia ble 
a n d its distri b uti o n. Data tra nsf or mati o n mi g ht be use d i n or der t o satisf y t he ass u m pti o n of n or malit y 
re q ueste d b y para metric statistical tests. I n case s uc h ass u m pti o ns are n ot met, n o n-para metric c o u nter part 
tests will be use d. Details will be pr o vi de d i n t he S A P. C ha n ge fr o m baseli ne val ue (f or c o nti n u o us varia bles) 
a n d s hift ta bles vers us baseli ne (f or cate g orical varia bles) ma y als o be s u m m arize d f or all p ost -baseli ne visits.  
 
9. 5. 2.  A n al ysis of s afet y v ari a bles  
T E A Es a n d T E S A Es will be prese nte d b y treat me nt ar ms i n ter ms of n u m ber of T E A Es a n d T E S A Es a n d 
i nci de nce b y S yste m Or ga n Class a n d Preferre d Ter m usi n g Me d D R A. A nal yses will be pr o vi de d als o b y 
se verit y a n d relati o ns hi p t o t he st u d y dr u g. 
Vital si g ns, he mat ol o g y  a n d bi oc he mistr y  , e G F R a n d E C G para meters will be s u m marize d b y treat me nt at 
eac h a vaila ble ti me p oi nt b y mea ns of descri pti ve statistics.  
 
9. 5. 3.  S pecific ati o n of s u b gr o u ps f or a n al ysis  
I n t he prese nce of c o n gr u o us n u m bers, s u b gr o u p a nal yses of pri mar y a n d ke y sec o n dar y e n d p oi nts will be 
perf or me d o n t he f oll o wi n g s u b gr o u ps defi ne d b y baseli ne c haracteristics:  
- A ge class,  
- Ge n der,  
- Race,  
- Et h nicit y.  
Statistical details a n d p ote ntial ne w s u b gr o u ps defi niti o ns will be re p orte d i n t he S A P.  
 
9. 5. 4.  I nter me di ate a n al yses f or t he D M C 
D M C meeti n gs will be perf or me d d uri n g t he trial t o m o nit or t he safet y of patie nts a n d t o pr otect st u d y 
s u bjects fr o m u n d ue har m. I nf or mati o n o n accr ual, eli gi bilit y, c o nc o mita nt me dicati o ns, me dical hist or y, 
c o nc o mita nt diseases, disc o nti n uati o n, a d verse e ve nt s a n d ot her safet y assess me nts will be a nal yze d at eac h 
D M C meeti n g. Access t o u n bli n de d i nf or mati o n o n t he efficac y a nal yses is all o we d o n D M C re q uest t o 
bala nce patie nt safet y ris k a gai nst a p ossi ble gai n i n efficac y.  
F urt her details will be pr o vi de d i n  Secti o n 1 2. 6 a n d i n t he D M C C harter, w here all r oles a n d res p o nsi bilities 
will be defi ne d.  
T he D M C will c o nsi der t he a p pr o priate ness of trial c o nti n uati o n if t here is e mer gi n g e vi de nce t hat re pari xi n 
is har mf ul. Si nce t he D M C d oes n ot m o nit or pri mar y e n d p oi nts f or earl y efficac y ter mi nati o n, n o T y pe I err or 
a dj ust me nt is necessar y.  
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

REP0122  
Reparixin in ARDS  
Page 52 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
9.6. 
Missing data 
All reasonable efforts will be made to reduce the rate of missing data. Investigators will be trained about 
the importance of patient retention and full data capture. Also, any reasonable attempts should be made by 
the Investigators to emphasize continued patient’s participation for the full duration of the trial. 
Details on how missing data will be handled in the primary analysis are reported in section 9.5.1.1.

REP0122  
Reparixin in ARDS  
Page 53 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
10. 
ETHICAL CONSIDERATIONS 
10.1. 
INDEPENDENT ETHICS COMMITTEE (IEC) / INSTITUTIONAL REVIEW BOARD 
(IRB) 
It is the responsibility of the CRO appointed by Dompé or of the Study PI to obtain approval of the trial 
protocol/amendments from the appropriate IEC/IRB. 
Prior to the initiation of the study, the followings will be submitted to the IEC/IRB for approval: 
- 
the study protocol, 
- 
the Informed Consent Form (ICF), 
- 
the current version of the Investigator’s Brochure, 
- 
Investigator’s current curriculum vitae (CV) as well as the current CVs of all key study personnel, 
- 
Insurance certificate, 
- 
any other IEC/IRB requested document(s). 
A copy of the IRB approval will be sent to Dompé along with relevant correspondence with the IEC/IRB, 
a roster of IEC/IRB members or the US Department of Health and Human Services (DHHS) general 
assurance number. 
The study will not be started until full written approval has been obtained from the appropriate IEC/IRB. 
The letter of approval should be dated, and should specify the type (e.g. protocol number) and the date of the 
documents which were reviewed and approved. 
The CRO appointed by Dompé or the PI will submit any future amendment to the protocol to the IEC/IRB 
which granted the original approval. Any amendment will be implemented only when full approval has been 
obtained from the appropriate IEC/IRB, except for those amendments which involve only logistical or 
administrative aspects of the study. 
The CRO appointed by Dompé or the PI will send to the IEC/IRB any updated Investigator’s Brochure. 
The CRO appointed by Dompé or the PI will also submit to the IEC/IRB which approved the protocol, at 
least annually, any required progress reports and study update, and will inform the IEC/ IRB of the 
termination of the study. 
The CRO appointed by Dompé or the PI will report to the IEC/IRB any serious ADRs, life-threatening 
problems or deaths occurred at other sites participating in this clinical trial and/or in other clinical studies 
conducted with reparixin. 
 
 
10.2. 
ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in compliance with the protocol and current GCP, adopting the principles of 
the Declaration of Helsinki, and all applicable regulatory requirements (ICH E6, 45CFR46, and FDA 21 CFR 
sections 11, 50, 56, 312). 
Prior to study initiation, the protocol and the informed consent documents will be reviewed and approved 
by the IEC/IRB. Any amendments to the protocol or consent materials must also be approved before they are 
implemented. 
 
10.3. 
SUBJECT INFORMATION AND CONSENT 
No study-related procedures (including non-invasive and diagnostic procedures) will be undertaken prior to 
completion of the consenting process. 
When an eligible subject is identified, informed consent will be pursued. Consent will be sought from the 
subjects themselves, if this is possible. However, it is recognized that the vast majority of subjects will be 
unable to give written informed consent themselves due to alteration in their level of consciousness caused 
by therapeutic sedation. Hence, legally authorized representative consent will be required for most subjects.

REP0122  
Reparixin in ARDS  
Page 54 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
The Investigator or delegate personnel, according to site procedures, will explain the study fully to subjects 
and/or their legally authorized representatives sing the ICF. The Investigator is responsible for ensuring that 
subjects and/or their legally authorized representatives understands the risks and benefits of participating in 
the study and answering any questions they may have throughout the study and sharing any new information 
in a timely manner that may be relevant to subjects’ and/or their legally authorized representatives’ 
willingness to continue with study participation. Although subjects and/or their legally authorized 
representatives will be informed that the consent could be withdrawn at any time, the Investigator will also 
emphasize that missing data diminish the scientific value of all subjects’ contributions. Similarly, subjects 
and/or their legally authorized representatives will be informed that safety data might have to be collected 
after their participation in the study has been completed. If subjects and/or their legally authorized 
representatives are willing to participate in the study, they will be requested to give written informed consent 
after being given sufficient time to consider their participation and the opportunity to ask for further details. 
The ICF will be signed and personally dated by both the subjects and/or their legally authorized 
representatives as well as the Investigator or delegate personnel according to site procedures. A copy of the 
signed form will be provided to subjects and/or their legally authorized representatives, and the original 
signed ICF will be retained and filed in the Investigator Site File. Subject consent will be documented in the 
hospital records. 
Individual (i.e. site specific; local language) ICFs will be provided to the site once approved by the IEC/IRB. 
Any changes requested by the IEC/IRB must be approved by Dompé prior to the documents being used. 
 
10.3.1. IDENTIFICATION OF LEGALLY AUTHORIZED REPRESENTATIVES 
As stated before, due to their critical illness, most subjects will not be able to provide informed consent. 
Accordingly, written informed consent will be sought from a legally authorized representative. As this is an 
international study, the appropriate local country guidance and laws will be followed for each country. A 
legally authorized representative may be a Personal Legal Representative or Professional Legal 
Representative. 
The Personal Legal Representative may be a relative, partner or close friend. Any country specific guidance 
on who may act as a Personal Legal Representative will be followed. Once the Personal Legal Representative 
has been informed about the study, he/she will be given a copy of the ICF and will be asked to give an opinion 
as to whether the subject would object to taking part in the study. After being given an adequate amount of 
time to consider the information, if the Personal Legal Representative decides that the subject would have no 
objection to participating in the study then he/she will be asked to sign two copies of the ICF. 
If no Personal Legal Representative is available, then a doctor at the investigational site who is not connected 
with the conduct of the study may act as a Professional Legal Representative. Any country-specific guidance 
on who may act as a Professional Legal Representative will be followed. After being informed about the 
study, the Professional Legal Representative will be given a copy of the ICF. If the Professional Legal 
Representative decides that the subject is suitable for entry into the study, then he/she will be asked to sign 
two copies of the ICF. 
 
10.3.2 RETROSPECTIVE SUBJECT INFORMED CONSENT 
Subjects for whom consent was given by a legally authorized representative will be informed of their 
participation in the study by the Investigator. This process will take place once the subject has regained the 
capacity to understand the details of the study. The timing of this process will thus vary between subjects. 
However, every attempt to obtain retrospective consent must be made when the subject’s condition is 
appropriate. Once informed, subjects will be given an adequate amount of time to consider their decision to 
consent to continued participation in the study and to sign an ICF. 
If the consent has been given by the legally authorized representative, the subject should be informed about 
their participation in the study and should have the opportunity to confirm or revoke their consent. If the 
subject does not give retrospective consent, then the subject will be asked if the data collected to that time 
point can be analyzed. If the subject does not allow any of their data to be used, then the data collected from 
the subject until that time point will not be entered into the analyses and no further data will be collected; the

REP0122  
Reparixin in ARDS  
Page 55 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
subject will be considered as withdrawn and the reason for withdrawal will be “retrospective consent not 
given”. 
 
10.4. 
CONFIDENTIALITY 
All information obtained during the conduct of the study will be regarded as confidential. An agreement of 
disclosure will be obtained in writing by the patient and will be included in the ICF. Patient’s data collected 
during (or after completion of) the study will be handled in accordance with applicable USA data protection 
laws, HIPAA regulations, and European data protection Regulation (EU) No. 679/2016 of the European 
Parliament and of the European Council regarding the protection of natural person’s personal data and the 
free circulation of said data (hereinafter GDPR EU No. 679/2016) and according the standards of Good 
Clinical Practice. 
On the eCRF patients will be identified ONLY by the assigned patient number. If patient names are included 
on copies of documents submitted to Dompé or the CRO appointed by Dompé, the names will be obliterated 
or masked and the assigned patient number added to the document. 
The Investigator should keep a separate identification log for patients screened in the trial. 
 
 
10.5. 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 
Before the trial formally starts, Dompé will take out a study-specific insurance covering the amount 
requested by the respective national laws for patients/Investigators/Institutions participating in the clinical 
trial. 
In case of questions about medical care, cost for medical care or insurance, patients can talk to their 
Investigator. Contact details will be given in the ICF. 
Insurance and any updates will be provided to the Investigator before trial commencement for filing into the 
Investigator Site File.

REP0122  
Reparixin in ARDS  
Page 56 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
11. 
DATA HANDLING AND RECORD-KEEPING 
11.1. 
CASE REPORT FORM (CRF) 
All data relating to the study will be recorded on the eCRF to be provided by the CRO, through an electronic 
data capture system. eCRF should not be made available in any form to third parties, except for authorized 
Dompé designees or representatives of appropriate Health/Regulatory Authorities, without written 
permission from Dompé. 
An eCRF is required and should be completed for each consented patient, regardless of actual enrollment. 
All entries must be written in English. Source documents should be available to support all the data recorded 
in the eCRF; location of source documents will be specified and listed at the center Initiation Visit. 
The eCRF must be available for review by designated Dompé representatives at each scheduled 
monitoring/audit visit. The PI is responsible for verifying that all data entries in the eCRFs are accurate and 
correct. The PI must sign the completed eCRF before database lock and its submission to the Sponsor. 
 
 
11.2. 
DATA MANAGEMENT 
Data management will be performed by the CRO appointed by Dompé. Main Data Management activities 
and procedures will be accurately described in the DMP, created by the CRO and approved by Dompé. 
Data collection will involve the use of an EDC system, to which only authorized personnel will have access. 
In addition to periodic monitoring occurring within the system by Sponsor/CRO Monitors, programmatic 
edit checks will be used to review the data for completeness, logic, and adherence to study protocol (following 
the Data Validation Plan). As a result of this monitoring and these checks, queries may be electronically 
issued to the study centers and electronically closed by those study centers. The identifying information 
(assigned username, date, and time) for both the originator of the query (if created during the monitoring 
process) and the originator of the data change (if applicable), as well as the PI’s approval of all changes 
performed on his or her patients’ data, will be collected. Reconciliation of study data and SAEs between 
Clinical and Drug Safety databases will be performed on an ongoing basis and before database lock. 
Procedure will be detailed in the DMP. 
Encoding of specific data will be carried out. For this trial, Medical History, Adverse Events and 
Concomitant Medication will be coded; Medical Dictionary for Regulatory Activities (MedDRA) and World 
Health Organisation (WHO)-DRUG Enhanced dictionaries will be used, and version number of each 
dictionary will be documented in the DMP. Dictionary version numbers will not be changed during the study. 
All data collected in the context of this study will be stored and evaluated per regulatory requirements and 
applicable guidelines for electronic records. Also, data will be stored and evaluated in such a way as to 
guarantee patient confidentiality and in accordance with relevant legal stipulations. Study records (e.g., 
copies of eCRFs, regulatory documents) will be retained at the study center, along with adequate source 
documentation, according to Competent Authority and ICH requirements. All study records must be available 
for audit by Dompé, its authorized representatives, or Regulatory Authorities. 
The investigator/institution should maintain adequate and accurate source documents and trial records that 
include all pertinent observations on each of the site’s trial subjects. Source data should be attributable, 
legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, 
should not obscure the original entry, and should be explained, if necessary, via an audit trail. 
 
 
 
11.3. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF, AND DURING THE 
STUDY 
The following documents will be required from the Investigator prior to the initiation visit (and during the 
course of the study in case of any update): 
- 
Current, signed and dated Curriculum Vitae of the PI any Sub-Investigators/co-workers. Updates 
should be provided at least every two years. 
- 
Confidential disclosure agreement Form in accordance also with European data protection 

REP0122  
Reparixin in ARDS  
Page 57 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
Regulation (EU) No. 679/2016 (GDPR). 
- 
Normal ranges of all laboratory tests to be performed at the study site and a recent certification or 
accreditation of established quality control (or other documentation of established quality control or 
external quality assessment or other validation). Updates should be provided as soon as any reference 
value has changed. 
- 
A signed page of the final clinical protocol and any amendments. 
- 
IEC/IRB approval documentation, IEC/IRB-approved ICFs and study materials. Documentation of 
continuing IEC/IRB review and annual renewals. 
- 
A signed copy of the study Financial Agreement/Clinical Study Agreement with Dompé (or CRO 
appointed by Dompé), including all study specific costs. 
- 
List and any updates of delegated responsibility (Study Team Signature List / Delegation of 
Responsibilities form). 
- 
FDA Form 1572 and financial disclosure form 3455 from all the persons listed on the 1572. If 
applicable, the PI will provide an updated financial disclosure agreement to the Sponsor 1 year after 
the completion of the study. 
 
 
11.4 
ESSENTIAL DOCUMENT RETENTION 
The Investigator will retain copies of all the essential documents (as defined by ICH-GCP) until at least 2 
years after the last approval of a marketing application in an ICH region, and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the Investigational Product. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirements. The Investigator should 
take measures to prevent accidental or premature destruction of these documents. 
The essential documents include, but are not limited to: the signed protocol, copies of the completed eCRF, 
and Diary, signed Patient Informed Consent Forms from all patients who consented, hospital records and 
other source documents, and all other documentation included in the Investigator Site File and 
Pharmacy/Dispensing File. 
The Investigator will inform Dompé (or designee) of the storage location of these essential documents and 
must contact Dompé before disposing of any. If the Investigator wishes to assign the files to someone else or 
to remove them to another location, he/she should consult with Dompé about this change. 
Dompé will inform the Investigator in writing when these documents no longer need to be retained.

REP0122  
Reparixin in ARDS  
Page 58 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
12 
STUDY MANAGEMENT 
The study will be performed in accordance with the protocol, the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, October 2013) and ICH Harmonised Tripartite Guideline for Good Clinical 
Practice (ICH-GCP) and any local regulations. 
 
12.1 
REGULATORY BODY OF APPROVAL 
The CRO appointed by Dompé will obtain the necessary approval from the Competent Authorities, as 
needed, prior to initiation of the study. In the US, Dompé or other consultant appointed by Dompé will submit 
to the FDA this protocol under a new ARDS-specific IND, according to 21 CFR Part 312.30. 
The study will not be started until written approval from the relevant Competent Authorities (or no objection 
within the timeframe set by the local regulation, as applicable) has been received by Dompé. 
 
12.2. 
SERIOUS BREACHES MANAGEMENT 
Process (as defined under art. 52 of European Regulation 536/2014): 
Institutions, CRO, and investigators involved in the clinical trial management must notify the Sponsor about 
any Serious Breaches and suspected Serious Breach within 24 hours from the identification of such Serious 
Breach.  
If not otherwise specified in relevant study plans and agreements with the contracted CRO, the Sponsor will 
manage the event according to the internal process for the management and notification to the relevant 
competent authority. 
Definitions: 
Serious Breach: a breach likely to affect to a significant degree the safety and rights of a subject, or the 
reliability 
and 
robustness 
of 
the 
data 
generated 
in 
the 
clinical 
trial. 
Suspected Serious Breach: an incident, which at the time of communication from the investigators or from 
the service providers to the Sponsor, has not yet been assessed by the Sponsor to be a Serious Breach. 
 
12.3 
MONITORING 
Monitoring will be carried out by the monitor of the designated CRO. 
The purpose of the monitoring is to verify that the rights and the wellbeing of the patient are protected, that 
the reported data are accurate, complete, and verifiable from source documents and that the conduct of the 
trial complies with the currently approved protocol and any amendments, with ICH GCP, and with regulatory 
requirements. 
Prior to study start, the Investigator will be informed of the anticipated frequency of the monitoring visits. 
(S)He will also receive a notification prior to each monitoring visit during the study. It is expected that the 
PI and/or his/her Sub-Investigator(s) and other appropriate staff will be available on the day of the visit to 
discuss study conduct and to cooperate with the sponsor representative to ensure that any problems detected 
during these monitoring visits are resolved. 
 
12.4 
ACCESS TO RECORD 
The Investigator will allow designated Dompé representatives, including staff from the appointed CRO, and 
Regulatory/Ethics Bodies, to have direct access to the source documents to verify the data reported in the 
eCRF. Source documents are the originals of any documents used by the Investigator or hospital/institution 
that allow verification of the existence of the patient and substantiate the integrity of the data collected during 
the trial. The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial patients. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained, if necessary, via an audit trail. 
All study records must be available for audit by Dompé, its authorized representatives, and Regulatory 

REP0122  
Reparixin in ARDS  
Page 59 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
Inspection by Regulatory Authority. 
 
 
12.5 AUDIT AND INSPECTION 
In addition to the institutional IEC/IRB(s), audit activities will be performed by the Dompé Quality 
Assurance Unit or any other third party delegated by Dompé, as appropriate. 
 
12.6 
PROTOCOL AMENDMENTS 
Changes to the Study Protocol will be implemented only when written amendments have been signed by all 
individuals who signed the Protocol. 
Any amendment will be sent to the IEC/IRB and Competent Authority / FDA, as appropriate. No deviations 
from or changes to the protocol will be implemented without documented approval of an amendment from 
the IEC/IRB which granted the original approval, except where necessary to eliminate an immediate hazard(s) 
to trial patients, or when the change(s) involves only logistical or administrative aspects of the trial. The 
deviations from or changes to the protocol implemented to eliminate an immediate hazard to the trial patient 
and the proposed amendment, if appropriate, should be submitted to the IEC/IRB for review and approval as 
soon as possible. 
Any other deviation from the protocol that has not been approved by Dompé and the IEC/IRB could result in 
a discontinuation from the study at the center involved. 
Any written amendment will be sent to all recipients of the protocol. 
 
12.7 
DATA MONITORING COMMITTEE 
An independent DMC will be appointed with the responsibility of safeguarding the interests of trial 
participants, assessing the safety and efficacy of the interventions during the trial, and monitoring the overall 
conduct of the clinical trial. These tasks will be accomplished on an ongoing basis throughout the trial. The 
DMC will provide recommendations about stopping or continuing the trial. In order to contribute to 
enhancing the integrity of the trial, the DMC can also formulate recommendations relating to the 
selection/recruitment/retention of participants, their management, improving adherence to protocol-specified 
regimens and retention of participants, and the procedures for data management and quality control. 
The DMC will be advisory to the clinical trial leadership group (the Scientific Committee of the study). The 
Scientific Committee comprised the sponsor’s study team and lead study investigators, who jointly have 
responsibility for the design, conduct and analysis of the clinical trial. The Scientific Committee is responsible 
for promptly reviewing the DMC recommendations, to decide whether to continue or terminate the trial, and 
to determine whether amendments to the protocol or changes in the study conduct are required. 
 
12.8. DISCONTINUATION OF THE STUDY 
Dompé reserves the right to stop the study at any time on the basis of new information regarding safety or 
efficacy, or if study progress is unsatisfactory, or for other valid administrative reasons. 
After such a decision is made, the Investigator must inform all relevant persons e.g. study staff, patients etc. 
within 2 weeks. All delivered study materials must be collected and all eCRF completed to the extent possible. 
Study discontinuation will be notified to the IEC and Competent Authority/FDA within 15 days from 
decision. The Investigator will inform his/her IRB within the same timeframe. 
 
12.9. 
PUBLICATIONS 
As this study is part of a multicenter trial, publications derived from this study will be planned and agreed 
with the participating Study Investigators. Publications will include input from the Investigators, his/her 
colleagues, other investigators in this trial and Dompé personnel. Such input will be reflected in publication 
authorship. All PIs contributing patients to the study are eligible for inclusion in publications derived from 
this study. The first authorship will be offered (upon agreement of all involved) to the PI with the greatest 
number of enrolled patients whereas the senior authorship will be offered to the lead PI (s). Authorship order 

REP0122  
Reparixin in ARDS  
Page 60 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
can be adjusted as deemed necessary and with the agreement of all PIs and Dompé personnel. 
Any manuscript, abstract or other publication or presentation of results or information arising in connection 
with the study must be prepared in conjunction with Dompé and must be submitted to Dompé for review and 
comment at least 45 days prior to submission for publication or presentation. The Sponsor reviews proposed 
manuscripts prior to submission within a reasonable period (30-90 business days in relation with the 
complexity of the work). If such draft contains confidential patentable information, the Investigator will 
refrain from publishing any such information for a period not exceeding 180 days, to enable Dompé to file 
for the protection of any intellectual or proprietary property interest. 
The Sponsor agrees that the study results (including negative and inconclusive as well as positive results) 
can be made publicly available by the Investigator in the form of: publications in peer reviewed journals; 
presentation of the results at scientific meetings; and posts of the results on internet-based public registers 
and databases. 
Regardless, study results will be communicated in full to the Competent/authority/FDA by the submission 
of a complete CSR. 
The Investigator(s) will also be provided by the Sponsor with the CSR and the results of any additional 
analysis, tables, figures, etc. undertaken for the purposes of the article, in order to take responsibility for the 
content of the publication(s). 
On an exceptional basis, the Sponsor may temporarily delay registration of certain data elements (e.g. 
compound, name, outcome, measures etc.) to seek necessary intellectual property protection. This is because 
early disclosure of such data could, in some circumstances, prevent or negatively impact patentability.

REP0122  
Reparixin in ARDS  
Page 61 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
13. 
REFERENCES 
1. Allegretti M, Cesta MC, Bizzarri C, et al. 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) 
ligands as novel noncompetitive CXCL8 inhibitors. J Med Chem. 2005 Jun 30;48(13):4312-31; 
2. Bertini R, Allegretti M, Bizzarri C, et al. A new class of non-competitive allosteric inhibitors of the 
inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. PNAS 
2004; 101: 11791-6 
3. Zarbock A, Allegretti M, Ley K. Therapeutic inhibition of CXCR2 by Reparixin attenuates acute 
lung injury in mice. Br J Pharmacology 2008; 155: 357–364 
4. Hosoki K, Rajarathnam K, Sur S. Attenuation of murine allergic airway inflammation with a 
CXCR1/CXCR2 chemokine receptor inhibitor. Clin Exp Allergy 2019; 49:130-132 
5. Cheng IY, Liu CC, Lin JH, et al. Particulate Matter Increases the Severity of Bleomycin-Induced 
Pulmonary Fibrosis through KC-Mediated Neutrophil Chemotaxis. Int J Mol Sci 2020; 21:227 
6. Tavares LP, Garcia CC, Machado MG, et al. CXCR1/2 Antagonism Is Protective during Influenza 
and Post-Influenza Pneumococcal Infection. Front Immunol 2017; 8:1799; 
7. Kaiser R, Leunig A, Pekayvaz K et al. Self-sustaining interleukin-8 loops drive a prothrombotic 
neutrophil phenotype in severe COVID-19. JCI Insight 2021; 6:e150862 
8. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 May 
4;342(18):1334-49 
9. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin 
definition. JAMA 2012; 307: 2526–33 
10. Meyer NJ, Gattinoni L, Calfee CS. Acute respiratory distress syndrome. Lancet 2021; 398:622-637 
11. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 
2010;10:826-837. 
12. Vénéreau E, Ceriotti C, Bianchi ME. DAMPs from cell death to new life. Front Immunol 
2015;6:422. 
13. Frevert CW, Huang S, Danaee H, et al. Functional characterization of the rat chemokine KC and its 
importance in neutrophil recruitment in a rat model of pulmonary inflammation. J Immunol. 1995; 
154:335–44 
14. Goodman RB, Strieter RM, Martin DP, et al. Inflammatory cytokines in patients with persistence 
of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996; 154(Pt 1):602–11. 
15. Steinberg KP, Milberg JA, Martin TR, et al. Evolution of bronchoalveolar cell populations in the 
adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994; 150:113–22 
16. Zemans RL, Matthay MA. What drives neutrophils to the alveoli in ARDS? Thorax 2017;72:1-3 
17. Donnelly SC, Strieter RM, Kunkel SL, et al. Interleukin-8 and development of adult respiratory 
distress syndrome in at-risk patient groups. Lancet. 1993; 341:643–7 
18. Groeneveld AB, Raijmakers PG, Hack CE, et al. Interleukin 8-related neutrophil elastase and the 
severity of the adult respiratory distress syndrome. Cytokine. 1995; 7:746–52 
19. Miller EJ, Cohen AB, Nagao S, et al. Elevated levels of NAP-1/interleukin-8 are present in the 
airspaces of patients with the adult respiratory distress syndrome and are associated with 
increased mortality. Am Rev Respir Dis. 1992; 146:427–32 
20. Bikfalvi A, Billottet C. The CC and CXC chemokines: major regulators of tumor progression 
and the tumor microenvironment. Am J Physiol Cell Physiol. 2020;318:C542-C554 
21. Stillie R, Farooq SM, Gordon JR, et al. The functional significance behind expressing two IL-8 
receptor types on PMN. J Leukoc Biol 2009; 86:529-543 
22. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 
2004; 303:1532–5. 
23. Camicia G, Pozner R, de Larrañaga G. Neutrophil Extracellular Traps in Sepsis. Shock. 2014; 
42:286–94 
24. Caudrillier A, Kessenbrock K, Gilliss BM, et al. Platelets induce neutrophil extracellular traps in 
transfusion related acute lung injury. J Clin Invest. 2012; 122:2661–71. 
25. Liu S, Su X, Pan P, et al. Neutrophil extracellular traps are indirectly triggered by 
lipopolysaccharide and contribute to acute lung injury. Sci Rep. 2016; 6:37252. 
26. Li H, Zhou X, Tan H, et al. Neutrophil extracellular traps contribute to the pathogenesis of acid- 
aspiration-induced ALI/ARDS. Oncotarget 2018;9:1772-1784. 
27. Bao Z, Ye Q, Gong W et al. Humanized monoclonal antibody against the chemokine CXCL-8 (IL- 
8) effectively prevents acute lung injury. Int Immunopharmacol 2010;10:259-63.

REP0122  
Reparixin in ARDS  
Page 62 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
28. Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with 
acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016; 315: 788– 
800. 
29. Calfee CS, Delucchi K, Parsons PE; NHLBI ARDS Network. 
Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from 
two randomized controlled trials. Lancet Respir Med. 2014 Aug;2(8):611-20 
30. Delucchi K, Famous KR , Ware LW. Stability of ARDS subphenotypes over time in two 
randomized controlled trials. Thorax 2018 May;73(5):439-445. 
31. Famous KR, Delucchi K, Ware LB. Acute respiratory distress syndrome subphenotypes respond 
differently to randomized fluid management strategy. Am J Respir Crit Care Med 
2017;195(3):331-338 
32. Go L, Budinger GR, Kwasny MJ, Peng J, Forel JM, Papazian L, Jain M. Failure to Improve the 
Oxygenation Index Is a Useful Predictor of Therapy Failure in Acute Respiratory Distress 
Syndrome Clinical Trials. Crit Care Med. 2016 Jan;44(1):e40-4. 
33. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with 
lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the 
acute respiratory distress syndrome. N Engl J Med. 2000; 342:1301–8. 
34. Brower RG, Lanken PN, MacIntyre N, MAtthay MA, et al. Higher versus lower positive 
end-expiratory pressures in patients with the acute respiratory syndrome. N Engl J Med 
2004;351:327-36 
35. Papazian L, Forel J, Gacouin A et al. Neuromuscular blockers in early acute respiratory 
distress syndrome. N Engl J Med 2010;363: 1107-1116 
36. Yehya N, et al. Reappraisal of Ventilator-Free Days in Critical Care Research. Am J Respir Crit 
Care Med. 2019 Oct 1;200(7):828-836

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 6 3  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
1 4.  
A P P E N DI C E S  
 
1 4. 1.  
A P P E N DI X 1 - S P O N S O R A P P R O V A L P A G E  
 
 
 
 
S p o ns or Me dical E x pert: _
 
 
 
 
 
 
 
S p o ns or Cli nical Trial Ma na ger
 
 
 
 
 
 
 
S p o ns or De vel o p me nt Direct o
 
 
 
 
 
P P D
P P D
P P D

REP0122  
Reparixin in ARDS  
Page 64 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
14.2. 
APPENDIX 2 - INVESTIGATOR’S SIGNATURE PAGE 
 
Investigator’s Statement 
 
 
I have read study protocol REP0122 (Phase II, proof-of-concept, randomized, double-blinded, placebo- 
controlled, multicenter study to assess efficacy and safety of reparixin as add-on therapy to standard of care 
in adult patients with Acute Respiratory Distress Syndrome) and agree to conduct the study as outlined in the 
protocol, and in accordance with the Declaration of Helsinki, ICH-GCP and any local regulations, being 
responsible for personally supervise the study conduct and ensure study staff complies with protocol 
requirement. 
 
Principal Investigator:  Name (block letters)  
 
 
 
 
Signature:  
 
Date:  
/ 
/ 

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 6 5  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
1 4. 3.  
A P P E N DI X 3 - P A C K A GI N G A N D L A B E LI N G D E T AI L S  
A Patie nt Kit will be pre pare d f or eac h patie nt f or a 
 
. 
Sa m ple la bel c o nte nt is s u m marize d bel o w a n d will be a dj uste d t o meet l ocal re g ulat or y re q uire me nts.  
N O T E : 
Kit N o. X X Y Y  
 
acc or di n g t o t he ra n d o mizati o n list (a n d I R S s yste m dr u g dis pe nsati o n n u m ber) 
Patie nt N o.  
 
t o be fille d b y I n vesti gat or acc or di n g t o Patie nt Ra n d o mizati o n N u m ber 
I n vesti gat or:  
  t o be fille d b y I n vesti gat or acc or di n g t o PI na me 
 
T he f oll o wi n g re prese nts a te m plate of t he mi ni mal details t o be prese nte d i n la bels.  
C o nte nt of t he L a bel f or e ac h P atie nt Kit  
 
 
* T h e n u m ber of KI T will be re p orte d acc or di n g t o t he ra n d o mizati o n list t h at will be ge nerate d    
* * F or U S la bels o nl y  
C o nte nt of t he L a bel f or t he 
 
 
* T h e n u m ber of KI T will be re p orte d acc or di n g t o t he ra n d o mizati o n list t h at will be ge nerate d    
* * F or U S la bels o nl y  
 
S T U D Y  R E P 0 1 2 2
S p o n s or  D o m p e f ar m a c e uti ci s. p. a.; Vi a S a nt a L u ci a 6, Mil a n - It al y
I N V E S TI G A T O R: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
KI T N o. X X Y Y *
P A TI E N T  N o. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I N V E S TI G A TI O N A L P R O D U C T:  r e p ari xi n ( 6 0 0 m g) or pl a c e b o  or al t a bl et s
C O N T AI N S: 
c o d e d B A T C H  N o.
c o d e d  E X PI R Y  D A T E  m m/ y y y y 
D O  N O T S T O R E  A T  > 3 0 ° C
D O N O T  F R E E Z E
DI R E C TI O N S: 
.
A d mi ni str ati o n of t h e dr u g m u st b e t hr o u g h a n a s o- g a stri c t u b e a n d/ or or al u s e aft er
e xt u b ati o n. R ef er t o t h e pr ot o c ol  f or t h e t a bl et di si nt e gr ati o n pr o c e d ur e a n d u s e aft er
e xt u b ati o n.
F or cli ni c al tri al u s e o nl y.  C a uti o n:  N e w Dr u g- Li mit e d  b y F e d er al  ( or U nit e d St at e s)  l a w t o
i n v e sti g ati o n al u s e * *
S T U D Y R E P 0 1 2 2 
S p o n s or D o m p e f ar m a c e uti ci s. p. a.
I N V E S TI G A T O R:
KI T N o. X X Y Y* 
P A TI E N T  N o.
I N V E S TI G A TI O N A L P R O D U C T:  r e p ari xi n ( 6 0 0 m g) or pl a c e b o  or al  t a bl et s
C O N T AI N S: 
c o d e d B A T C H  N o. 
c o d e d  E X PI R Y  D A T E  m m/ y y y y 
D O N O T S T O R E A T > 3 0 ° C
D O N O T F R E E Z E
DI R E C TI O N S: A d mi ni str ati o n  of t h e dr u g m u st b e t hr o u g h a n a s o- g a stri c t u b e
t hr e e ti m e s a  d a y ( 2 t a bl et s a d mi ni st er e d a p pr o xi m at el y e v er y 8 h o ur s) a n d/ or or al
u s e aft er e xt u b ati o n. R ef er t o t h e pr ot o c ol f or t h e t a bl et di si nt e gr ati o n  pr o c e d ur e
a n d u s e aft er e xt u b ati o n.
F or  cli ni c al  tri al u s e  o nl y.  C a uti o n:  N e w Dr u g- Li mit e d  b y  F e d er al  ( or U nit e d St at e s) l a w t o
i n v e sti g ati o n al u s e**
C CI
C CI
C CI
C CI
P P D
P P D

REP0122  
Reparixin in ARDS  
Page 66 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
14.4. 
APPENDIX 4 - METHODOLOGICAL DETAILS 
14.4.1. Calculation of Oxygenation Index 
 
 
 
OI: oxygenation index 
FIO2: fractional inspired oxygen 
Paw: mean airway resistance 
PaO2: arterial partial oxygen pressure 
The Paw is calculated from the following formula: 
 
 
PIP: peak inspiratory pressure 
PEEP: plateau end-expiratory pressure 
From: Durand M et al. Oxygenation index in patients with meconium aspiration: conventional and extracorporeal 
membrane oxygenation therapy. Critical Care Med. 18(4):373-7, 1990 
 
The investigators are encouraged to record the Paw as depicted on the ventilator display screen. If this 
information is not available the PI can use the formula presented above to calculate the Paw. 
 
14.4.2. SOFA score 
 
 
SOFA 
0 
1 
2 
3 
4 
Respiration 
PaO2/FiO2 
 
 
 
 
 
(mmHg) 
≥400 
<400 
<300 
<200 
<100 
Coagulation 
Platelets x 103 
mm3 
 
 
≥150 
 
 
<150 
 
 
<100 
 
 
<50 
 
 
<20 
Liver 
 
 
 
 
 
Bilirubin 
(mg/dL) 
<1.2 
1.2-1.9 
2.0-5.9 
6.0-11.9 
>12.0 
Cardiovascular 
 
 
 
dopamine <5 or 
 
 
 
MAP ≥ 
70 
MAP < 
70 
dobutamine (any 
dopamine 5.1-15 or 
dopamine >15 or 
Hypotension 
mmHg 
mmHg 
      dose) 
epinephrine ≤0.1 
epinephrine >0.1 
 
 
 
 
 
or 
norepinephrine 
 
 
 
 
or norepinephrine 
≤0.1 
>0.1 
CNS 
Glascow Coma 
 
 
 
 
 
Score 
15 
13-14 
10-12 
6-9 
<6 
Renal 
Creatinine 
 
 
 
 
 
(mg/dL) 
<1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 
>5.0 
or Urine output 
 
 
 
 
 
(mL/d) 
 
 
 
<500 
<200 
01 = Fi02 x Paw
Pa02
Formula:
Paw = ((Inspiratory Time x Frequency) / 60) x (PIP - PEEP) +PEEP

REP0122  
Reparixin in ARDS  
Page 67 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
SOFA score is calculated every 24 hours using (for each organ system) the worst variable recorded within 
the same 24 hours. The best possible score corresponds to 0 whereas the worst score corresponds to 24. 
MAP, mean arterial pressure; CNS, central nervous system; SaO2, peripheral arterial oxygen saturation. 
PaO2/FIO2 ratio was used preferentially. If not available, the SaO2/FIO2 ratio is used 
vasoactive medications administered for at least 1 hr (dopamine and norepinephrine μmg/kg/min). 
 
Adapted from: Jones AE, Trzeciak S, Kline JA. The Sequential Organ Failure Assessment Score for predicting 
outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department 
presentation. Crit Care Med 2009; 37: 1649-1654 
 
 
14.4.3. RALE score 
 
 
 
From: Zimatore et al. Accuracy of the radiographic assessment of lung edema score for the diagnosis of ARDS. Front 
Physiol 2021, http://dx.doi.org/10.3389/fphys.2021.672823 
 
 
14.4.4. Ventilatory ratio (VR) 
 
VR=[minute ventilation (ml/min) × PaCO2 (mm Hg)]/[predicted body weight × 100 (ml/min) × 37.5 
(mm Hg)] 
From: Sinha P et al. Physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress 
syndrome. Am J Respir Crit Care Med 2019; 199: 333-341
Consohdalion'
Calculation of the RALE score for radiograph
Consolidation Score
Extent of alveolar
opacities
0
None
1
<25%
2
25-50%
3
50 - 75 %
4
>75%
Density*1
Density Score
Density of alveolar
opacities
1
Mary
2
Moderate
3
Dense
Final RALE Scored
Right Lung
Left Quadrant
Upper Quadrant
Upper Quadrant
Cons x Den = O1 Score
Cons x Den = Q3 Score
Lower Quadrant
Lower Quadrant
Cons x Den = Q2 Score
Cons x Den - Q4 Score
ToW RALE - QI + Q2 + Q3 + Q4
Score
QI
02
03
Q4
Total
Consolidation
2
1
3
4
Density
3
3
3
3
Quadrant Score
2x3
= e
1 x3
= 3
3x3
= 8
4x3
= 12
30
a Consolidation Is scored for each quadrant
s Density is scored for each quadran1 having a
consolidation > 0
I' Quadrant consolidation Score is Q than Quadrant
score il 0

REP0122  
Reparixin in ARDS  
Page 68 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
14.4.5. Acute lung Injury Score 
 
 
 
From: Murray JF et al. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir 
Dis 1988;138:720-3 
 
The final score is obtained by dividing the collective score by the number of components that were used. 
 
14.4.6. Norepinephrine equivalents 
 
All doses in mcg/kg/min except vasopressin, which is U/min. NEE norepinephrine equivalents 
 
From: Vallabhajosyula S. Development and performance of a novel vasopressor-driven mortality prediction model in 
septic shock. Ann. Intensive Care 2018;8:112 
 
 
14.4.7. Suggested ventilation protocol 
● Ventilator mode: volume assist–control 
● Initial tidal volume: 6–8 ml/kg of predicted body weight 
● Plateau pressure: ≤32 cm of water 
● Oxygenation goal: PaO2 of 55–80 mm Hg or SpO2 of 88–95% 
●  Permitted combinations of FiO2 and PEEP, respectively (cm of water): 0.3 
and 5, 0.4 and 5, 0.4 and 8, 0.5 and 8, 0.5 and 10, 0.6 and 10, 0.7 and 10, 
0.7 and 12, 0.7 and 14, 0.8 and 14, 0.9 and 14, 0.9 and 16, 0.9 and 18, 1.0 
and 18, 1.0 and 20, 1.0 and 22, and 1.0 and 24 
● pH goal: 7.20–7.45 
●  Procedure when oxygenation goal not achieved despite adjustments to FiO2 
and PEEP: use inhaled nitric oxide, almitrine mesylate, prone positioning, 
or any combination thereof 
●  Procedure when plateau pressure is >32 cm of water for at least 10 min (in 
the following order, as needed): increase sedation, reduce tidal volume to 
4 ml/kg, decrease PEEP by decrements of 2 cm of water, and perform injection 
of cisatracurium in a bolus of 20 mg (not to be given again if plateau 
pressure decreased by <2 cm of water because further doses would
Component
0
1
2
3
4
Chest X-riy
{Alvrolar infiltrate*)
No
1 quadrant
2 quadrant*
3 quadrants
4 quadrants
Hypoxaemia
(PeO/FiOj, mmHg)
23Q0
225-299
175-224
100-174
S1W
PEEP
(PEEP-jetting, cmH.O
SS
6-8
9-11
12-14
515
Compliance
{Static mUcmH.O)
280
60-79
40-59
30-39
£29
Vasoactive Agent 
Dose 
NEE
Epinephrine
0.1
0 1
Norepinephrine
0.1
0.1
Dopamine
15
0 1
Phenylephrine
1
0.1
Vasopressin
0.04
0.1

R E P 0 1 2 2  
Re p arixi n i n A R D S  
Pa ge 6 9  of 7 9  
 Pr ot oc ol Versi o n/ Date: Versi o n 3. 0 –  Fe br uar y 8, 2 0 2 4  
 
 
 
 
 
 
pr o ba bl y be f utile, b ut per mitte d if t he dr u g ha d its i nte n de d effect)  
● Pr oce d ure t o c orrect h y perca p nia w he n p H is < 7. 2 0 (i n t he f oll o wi n g or der,  
as nee de d): c o n nect Y-piece directl y t o e n d otrac heal t u be, i ncrease res pirat or y 
rate t o a ma xi m u m of 3 5 c ycles per mi n, a n d i ncrease ti dal v ol u me 
t o a ma xi m u m of 8 ml/ k g 
● Wea ni n g atte m pt: starti n g o n da y 3, if Fi O 2 ≤0. 6  
●  G oals d uri n g wea ni n g pr oce d ure: S p O 2 ≥8 8 % a n d res pirat or y rate 2 6 – 3 5 c ycles 
per mi n  
● Wea ni n g pr oce d ure: decrease P E E P o ver 2 0 – 3 0 mi n t o 5 c m of water 
Press ure -s u p p ort ve ntilati o n le vels use d d uri n g wea ni n g pr oce d ure: 2 0, 
1 5, 1 0, a n d 5 c m of water  
●  If wea ni n g pr oce d ure fails at a press ure -s u p p ort ve ntilati o n le vel of 2 0 c m 
of water, s witc h t o v ol u me assist – c o ntr ol m o de of ve ntilati o n  
●  After at least 2 hr of s uccessf ul press ure -s u p p ort ve ntilati o n at a le vel of 5 c m 
of water, disc o n nect patie nt fr o m t he ve ntilat or  
 
A d o pte d fr o m: Pa pazia n L. et al. Ne ur o m usc ular bl oc kers i n earl y Ac ute Res pirat or y Distress S y n dr o me. N. E n g. 
J. Me d 2 0 1 0; 3 6 3: 1 1 0 7-1 1 1 6  
 
1 4. 4. 8.  F or m ul a f or c alc ul ati o n of pre dicte d b o d y wei g ht:  
pre dicte d b o d y wei g ht ( P B W):  
Males = 5 0 + 2. 3 [ hei g ht (i nc hes) –  6 0]  
Fe males = 4 5. 5 + 2. 3 [ hei g ht (i nc hes) –  6 0]  
 
1 4. 4. 9.  F or m ul a f or c alc ul ati o n of e G F R:  
Re nal f u ncti o n will be e val uate d b y esti mate d Gl o mer ular Filtrati o n Rate (e G F R), calc ulate d usi n g t he 2 0 2 1 
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n ( 2 0 2 1 C K D -E PI) as per t he f oll o wi n g f or m ula:  
e G F R cr = 1 4 2 x mi n( S cr/ κ, 1)α x ma x( S cr/ κ, 1)-1. 2 0 0 x 0. 9 9 3 8 A ge  x 1. 0 1 2 [if fe male]  
w here:  
S cr = sta n dar dize d ser u m creati ni ne i n m g/ d L  
κ = 0. 7 (fe males) or 0. 9 ( males)  
α = -0. 2 4 1 (fe male) or -0. 3 0 2 ( male)  
mi n( S cr/ κ, 1) is t he mi ni m u m of Scr/ κ or 1. 0 
ma x( S cr/ κ, 1) is t he ma xi m u m of Scr/ κ or 1. 0 
A ge ( years)  
 
Fr o m:  C K D -E PI Creati ni ne E q uati o n ( 2 0 2 1) | Nati o nal Ki d ne y F o u n dati o n  
 
 
1 4. 4. 1 0.  H a n dli n g of s a m ples f or ass a ys  
L ocal la b orat ories will perf or m he mat ol o g y/ bi oc he mistr y tests ( Safet y La b orat or y Tests).  
 meas ure me nt of i nfla m mat or y mar kers (Il-6, I L -8, P AI -1, T N Fr 1, I C A M -1, R A G E) will 
be perf or me d b y a ce ntral  la b orat or y selecte d b y D o m pé. 
All ste ps will be trac ke d t o e ns ure c orrect data re p orti n g.  
All sa m ples s u b mitte d t o t hese la bs will be destr o ye d after t he C S R has bee n iss ue d or after t he patie nt has 
wit h dra w n his/ her c o nse nt.  
 
C CI

REP0122  
Reparixin in ARDS  
Page 70 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
14.4.11 Ventilator-free days (VFDs) 
 
VFDs is a well-known endpoint, often used in adult and pediatric ARDS trials; 28-day is the most common 
time frame for VFDs in ARDS. 
VFDs at 28 days is defined as follows36: 
● VFDs = 0 if the patients die within 28 days 
● VFDs = 28 − x if successfully liberated from ventilation x days after initiation 
● VFDs = 0 if the patients are mechanically ventilated for >28 days 
 
 

REP0122  
Reparixin in ARDS  
Page 71 of 79 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 
 
 
14.5. 
  APPENDIX 14.5 - CLINICAL TRIALS SUBJECT TO TRANSITION FROM EUROPEAN 
DIRECTIVE 2001/20/EC TO CLINICAL TRIAL REGULATION EU NO 536/2014 
 
REP0122 (EudraCT 2022-001612-25) constitutes a Consolidated Protocol and the minor differences 
between the nationally authorized trials is summarized in the following table: 
 
EU Member State 
Minor Difference of trial conduct 
Germany 
Chest imaging has to be performed as per local clinical 
practice/needs. 
 
 
 

REP0122  
Reparixin in ARDS  
Page 72 of 79 
 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 CONFIDENTIAL 
 
14.6. 
SUMMARY OF CHANGES 
   Miscellaneous: Typos/editing have been corrected throughout the entire document. 
REASON:   
. 
  
1.  
SYNOPSIS 
   
 Randomization and Baseline assessments, changed from: 
Patients successfully completing the screening process and confirmed eligible for the study will be randomized 
to either reparixin or placebo at the latest within 48 hours from screening assessment. 
  
To: 
  
Randomization and Baseline assessments: Patients successfully completing the screening process and 
confirmed eligible for the study will be randomized to either reparixin or placebo within 24 hours and as soon 
as possible from screening assessment. 
  
REASON: 
 
  
Inclusion criteria 
 
Inclusion Criterion No. 6 changed from: 
 
To: 
patient is transferred from a non-participating hospital to a 
participating site a 12-hour period beyond the 48 hours is allowed) 
 REASON: 
 
   
 
was removed 
 REASON:
 
  
 
Inclusion Criterion No. 8 (currently No. 7) changed from: 
Females of child-bearing potential who are sexually active must be willing not to get pregnant within 30 days 
after the last Investigational Medicinal Product (IMP) dose and must agree to at least one of the following 
reliable methods of contraception: 
a.      Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives from at 
least 2 months before the screening visit until 30 days after the last IMP dose; 
b.     A sterile sexual partner; 
CCI
CCI
CCI
CCI

REP0122  
Reparixin in ARDS  
Page 73 of 79 
 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 CONFIDENTIAL 
c.      Abstinence. 
Female participants of non-child-bearing potential or in post- menopausal status for at least 1 year will be 
admitted. For all female subjects with child-bearing potential, pregnancy test result must be negative before 
first drug intake. 
  
To: 
Females of child-bearing potential who are sexually active must be willing not to get pregnant within 30 days 
after the last Investigational Medicinal Product (IMP) dose and must agree to at least one of the following 
reliable methods of contraception: 
a.   
Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives from 
at least 2 months before the screening visit until 30 days after the last IMP dose; 
b.     A sterile sexual partner; 
c.      Abstinence. 
In patients non able to personally consent to above due to complications of acute illness and/or its treatment 
assurances for the above must be given by LR and reiterated by patient when/if she is able to do so. 
Female participants of non-child-bearing potential or in post- menopausal status for at least 1 year will be 
admitted. For all female subjects with child-bearing potential, pregnancy test result must be negative before first 
drug intake. 
 REASON: 
 
 
  
Exclusion criteria 
 
Exclusion Criterion No. 1 changed from: 
 Moderate-Severe chronic hepatic disease (as verified by relevant history, imaging, if pre-existent, and Child-
Pugh Score B and C) 
 To: 
 Moderate-Severe chronic hepatic disease (as verified by a previously known Child-
Child-Pugh score is not known it should not be calculated while the patient is acutely ill. In that case the patient 
is 
  
 REASON: 
 
 
  
 
Exclusion Criterion No. 2 changed from: 
 Severe chronic renal dysfunction: eGFR (MDRD) < 30 mL/min/1.73m2 
 To: 
 Severe chronic renal dysfunction: eGFR (2021 CKD-EPI) < 30 mL/min/1.73m2. If baseline (chronic) renal 
function is not known the patient is only excluded if in need of acute renal replacement therapy (currently on 
RRT or to be imminently placed on RRT) 
REASON:
 
CCI
CCI
CCI

REP0122  
Reparixin in ARDS  
Page 74 of 79 
 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 CONFIDENTIAL 
 
 
 
 
 
Exclusion Criterion No. 5 was removed 
 REASON: 
 
   
 
Exclusion Criterion No. 7 (currently No. 6) changed from: 
Anticipated extubation within 24 hours of enrollment. 
 To: 
 Anticipated extubation within 24 hours of screening. (In such cases re-screening is allowed if the patient is 
within the enrollment window). 
REASON: 
 
 
 
 
 Exclusion Criterion No. 8 was removed 
 REASON: 
 
   
 
Exclusion Criterion No. 9 was removed 
 REASON: 
 
   
 
Exclusion Criterion No. 10 (currently No. 7) changed from: 
Evidence of GI dysmotility e.g. due to acute pancreatitis or immediate post op state, as demonstrated by persistent 
gastric distention, enteral feeding intolerability and/or persistent gastric residuals >500 ml). 
 To: 
 Evidence of GI dysmotility as demonstrated by presence of all the following: persistent gastric distention and 
enteral feeding intolerability and persistent gastric residuals >500 ml). 
 REASON: 
 
  
  
  
 
Exclusion Criterion No. 11 (currently No. 8) changed from: 
  
Anticipated discharge from the hospital or transfer to another hospital within 72 hours of screening. 
  
To: 
  
CCI
CCI
CCI
CCI
CCI
CCI

REP0122  
Reparixin in ARDS  
Page 75 of 79 
 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 CONFIDENTIAL 
Anticipated transfer to a hospital not participating in the trial within 72 hours of screening. 
  
REASON: 
 
  
  
  
 
Exclusion criterion No. 13 (currently No. 10) changed from: 
 History of: 
a)   Documented allergy/hypersensitivity to more than one medication belonging to the class of sulfonamides 
such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib (hypersensitivity to 
sulphanilamide antibioitcs alone , e.g. sulfamethoxazole does not qualify for exclusion) and to the study 
product and/or its excipients 
b)   Lactase deficiency, galactosemia or glucose-galactose malabsorption. 
c)   History of GI bleeding or perforation due to previous NSAID therapy or recurrent peptic 
ulcer/haemorrhage 
d)   Hypersensitivity to ibuprofen 
 To: 
History of: 
a)   Documented allergy/hypersensitivity to sulfonamides, ibuprofen and other COX-1 and 2 inhibitors, and to 
the study product and/or its excipients. 
b)   Lactase deficiency, galactosemia or glucose-galactose malabsorption. 
c)   History of peptic ulcer, GI bleeding or perforation due to previous NSAID therapy. 
REASON: 
 
 
   
 
Exclusion Criterion No. 14 (currently No. 11) changed from: 
 Active bleeding (excluding menses) or bleeding diathesis including patients on chronically high doses of 
NSAIDs 
 To: 
 Active bleeding (excluding menses) from uncontrolled site that cannot be definitively resolved prior to 
enrollment. 
 REASON: 
 
   
 
Exclusion Criterion No. 16 (currently No. 13) changed from: 
 Women of childbearing potential and fertile men who do not agree to use at least one primary form of 
contraception during the study and up to 30 days after the last IMP dose 
 To: 
Women of childbearing potential and fertile men who do not agree to use at least one primary form of 
contraception during the study and up to 30 days after the last IMP dose. For patients non able to personally 
consent to above due to complications of acute illness and/or its treatment assurances for the above must be given 
by LR and reiterated by patient when/if he/she is able to do so. 
CCI
CCI
CCI

REP0122  
Reparixin in ARDS  
Page 76 of 79 
 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 CONFIDENTIAL 
 REASON: 
 
 
  
  
Test Product, Dosage and Mode of Administration changed from 
Reparixin 600 mg tablets, administered crushed through nasogastric tube at the dose of 1200 mg TID (2 tablets 
TID) as add-on to the standard of care 
 To: 
Reparixin 600 mg tablets, administered crushed through nasogastric tube at the dose of 1200 mg TID (2 tablets 
TID) as add-on to the standard of care. After extubation and if the patient can swallow, reparixin may be 
administered orally 
REASON: 
 
    
Reference product, Dosage and Mode of Administration changed from 
Placebo tablets. Administered crushed through nasogastric tube with the same schedule as reparixin as add-on 
to the standard of care 
 To: 
 Placebo tablets. Administered crushed through nasogastric tube with the same schedule as reparixin as add-on 
to the standard of care. After extubation and if the patient can swallow placebo may be administered orally 
 REASON: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
  2.5. SUMMARY OF CLINICAL DATA 
  Updated 
 
CCI
CCI
CCI
CCI
CCI

REP0122  
Reparixin in ARDS  
Page 77 of 79 
 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 CONFIDENTIAL 
 2.5.2. Safety 
 ADRs from IV formulation and oral formulation in the oncologic studies as well as the respiratory studies 
updated 
 
   
2.6. DISEASE REVIEW AND STUDY RATIONALE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  3. OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN 
 3.3. OVERALL STUDY DESIGN 
 The following sentence was added: The IMP may be administered orally after extubation and between 
extubation and day 14 should the patient be able to swallow. In such cases the IMP may be administered either 
intact or crushed and mixed with a vehicle as per speech swallow evaluation. 
 3.4. STUDY TIME TABLE  was updated 
 4. SELECTION OF STUDY POPULATION 
 4.1. INCLUSION CRITERIA were updated 
 
 4.2. EXCLUSION CRITERIA were updated 
 
  5.  
STUDY MEDICATION 
 5.1.1.   
Presentation of the Investigational Medicinal Product changed from 
In this study the IMP will be either reparixin or matched placebo, which will be provided in the form of 
tablets to be disintegrated for naso-gastric tube administration 
  
To: 
  
In this study the IMP will be either reparixin or matched placebo, which will be provided in the form of 
tablets to be disintegrated for naso-gastric tube administration or administered orally after extubation. 
CCI
CCI
CCI
CCI

REP0122  
Reparixin in ARDS  
Page 78 of 79 
 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 CONFIDENTIAL 
  
REASON: 
 
  
   
5.2.  DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION the following sentences were 
added: “ If the patient becomes extubated prior to the end of treatment on day 14 and if swallowing 
ability has been restored as per clinical judgment, the IMP can be administered orally. In such cases 
the IMP may be administered either intact or crushed and mixed with vehicle as per speech swallow 
recommendation.” 
  REASON:
 
       
5.3.  CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION 
OR DISCONTINUATION OF THE IMP 
     
5.3.2. Criteria for discontinuation of the IMP changed from: 
  The IMP must be discontinued in the case: 
 
 
 
 The patient is discharged home; 
 Any medical condition that may threaten the safety of the patient if they continue to receive study 
treatment (as per investigator or Sponsor evaluation); 
 Withdrawal of informed consent by the patient or his/her legal representative (in this case, the 
patient / representative will be asked whether they consent to usage of the data already collected 
in the study; if not, the data will be deleted); 
 Pregnancy occurs. 
 To: 
 The IMP must be discontinued in the case: 
 Upon initiation of renal replacement therapy; 
 Upon increase of ALT and/or 
 
 The patient is discharged home; 
 Withdrawal of informed consent by the patient or his/her legal representative (in this case, the 
patient / representative will be asked whether they consent to usage of the data already collected 
in the study; if not, the data will be deleted); 
 Pregnancy occurs; 
  Development of Serious AE probably or possibly related to IMP, as per PI’s judgment; 
  Inadvertent missing of 3 or more consecutive doses of the IMP; 
  Inability to resolve within 24 hours any medical condition/event that led to temporary 
withholding of the IMP (see also 5.3.3.); 
 Recurrence of AE probably or possibly related to IMP upon re-introduction of the IMP. 
   
CCI
CCI

REP0122  
Reparixin in ARDS  
Page 79 of 79 
 
 Protocol Version/Date: Version 3.0 – February 8, 2024 
 
 
 
 
 CONFIDENTIAL 
Added: 5.3.3 
Criteria for temporary withholding of the IMP 
 The IMP can be temporarily withheld upon: 
  Development of AE (excluding Serious AE) probably or possibly related to IMP, as per PI’s 
judgment 
  Any AE (including Serious AE) not thought to be related to IMP as per PI's judgment. 
  Any medical condition that may threaten the safety of the patient if they continue to receive study 
treatment (as per investigator or Sponsor evaluation) 
 REASON:  
 
 
 
    
5.5.2. Medications to be used with caution: language was updated
 
 
 
 Added: 12.2 
SERIOUS BREACHES MANAGEMENT 
 
APPENDIX 14.3 - PACKAGING AND LABELING DETAILS 
Kits and Blister labels have been updated as follows: 
 
SPONSOR Fax number has been removed 
 
DIRECTIONS has been changed from: 
Administration of the drug must be through a naso-gastric tube three times per day (2 tablets for each 
administration at a time about every 8 hours). Refer to the protocol for the tablet disintegration procedure  
To: 
Administration of the drug must be through a naso-gastric tube three times a day (2 tablets administered 
approximately for each administration at a time about every 8 hours) and/or oral use after extubation. Refer 
to the protocol for the tablet disintegration procedure and use after extubation. 
REASON:  
. 
 
APPENDIX 14.5-CLINICAL TRIALS SUBJECT TO TRANSITION FROM EUROPEAN DIRECTIVE 
2001/20/EC TO CLINICAL TRIAL REGULATION EU NO 536/2014 was added. 
CCI
CCI
CCI