Reparixin 1200 mg TID as add-on to SoC to Limit Disease Progression in Hospitalised Patients With COVID-19 and Other Community-Acquired Pneumonia. A Multicentre, Randomized, Double-blinded, Placebo-controlled, Phase III Trial (REPAVID-22)
Phase: PHASE3
Conditions: Infectious Pneumonia, Severe COVID-19
Sponsor: Dompé Farmaceutici S.p.A

Study REP0321 
Reparixin in COVID-19 and other CAP (REPAVID-22) 
Page 1 of 67 
 
 
 
Protocol Version/Date: v2.0 – Final  20Jun2022  
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
Title:  Reparixin 1200 mg three times a day as add-on therapy to standard of care to limit disease 
progression in hospitalised adult patients with COVID-19 and other community-acquired pneumonia. A 
multinational, multicentre, randomised, double-blinded, placebo-controlled, parallel-group phase III trial. 
(REPAVID-22) 
Study Number: 
 REP0321 
 
 
IND/EudraCT number: 
150182/ 2021-006951-32             
 
 
Investigational Product: 
Reparixin 
 
 
Phase of the study: 
Phase III 
 
 
 
Protocol Version - Date: 
Version No. 2 – Final -  June 20, 2022  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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  
 –  Cli nical De vel o p me nt Ass ociate Direct or  
 
 
 
 
Cli nic al O per ati o n M a n a ger  
 Cli nical O perati o n Se ni or Ma na ger  
     
 
 
De vel o p me nt  Direct or  
 Hea d of Cli nical D e 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  
 
 
 
 
 
 
D at a m a n a ge me nt  &  st atistics: 
 
    
 
 
 
 
 
 
 
 
 
P H A R M A C O VI GI L A N C E : D o m pé Gl o bal P har mac o vi gila nce,  Safet y a n d S ur veilla nce de part me nt: 
 
 
 
 
 
C O O R DI N A TI N G  I N V E S TI G A T O R:  
                     
Os pe dale Sa n Raffaele. Mila n, Ital y.   
 
 
 
      
 
 
 
 
 
 
 
 
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
P P D
P P D

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Table of Contents 
1. 
STUDY SYNOPSIS .......................................................................................................... 8 
2. 
SCHEDULE OF EVALUATION .................................................................................. 15 
2.1. 
BACKGROUND INFORMATION ................................................................................. 17 
2.2 
RELEVANT NON-CLINICAL PHARMACOLOGY ..................................................... 17 
2.3. 
A SUMMARY OF TOXICOLOGY DATA ..................................................................... 18 
2.4. 
PHARMACOKINETICS AND PRODUCT METABOLISM ......................................... 19 
2.5. 
A SUMMARY OF CLINICAL DATA ............................................................................ 19 
2.5.1. 
Efficacy in patients with Covid-19 ................................................................................... 20 
2.5.2. 
Safety ................................................................................................................................ 21 
2.6. 
DISEASE REVIEW AND STUDY RATIONALE .......................................................... 22 
2.6.1. 
Alternative treatments ....................................................................................................... 24 
2.6.2. 
Risk – benefit evaluation .................................................................................................. 24 
2.6.3. 
Description of the Investigational Products ...................................................................... 25 
3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN ........................... 26 
3.1. 
STUDY OBJECTIVES ..................................................................................................... 26 
3.2. 
STUDY ADMINISTRATIVE STRUCTURES, STAFF AND RESPONSIBILITY ....... 26 
3.3. 
OVERALL STUDY DESIGN .......................................................................................... 26 
3.3.1. 
Rationale for Selection of dose, control group and treatment schedule in the study ........ 26 
4. 
SELECTION OF STUDY POPULATION................................................................... 28 
4.1. 
INCLUSION CRITERIA.................................................................................................. 28 
4.2. 
EXCLUSION CRITERIA ................................................................................................ 28 
4.3. 
ASSIGNMENT OF PATIENT NUMBER ....................................................................... 29 
5. 
STUDY MEDICATION ................................................................................................. 30 
5.1. 
PRESENTATION, PACKAGING AND LABELING, SUPPLY, AND STORAGE OF 
THE INVESTIGATIONAL MEDICINAL PRODUCT ................................................... 30 
5.1.1. 
Presentation of the Investigational Medicinal Product ..................................................... 30 
5.1.2. 
Manufacturing, Packaging and Labelling of IMP ............................................................. 30 
5.1.3. 
Supply, Storage and Handling of IMP .............................................................................. 30 
5.1.4. 
Binding .............................................................................................................................. 31 
5.2. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION................................ 31 
5.3. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION OR 
DISCONTINUATION OF THE IMP ............................................................................... 31 
5.3.1. 
Criteria for schedule adjustment/dose-modification ......................................................... 31 
5.3.2. 
Criteria for discontinuation of the IMP ............................................................................. 32 
5.4. 
ACCOUNTABILITY OF THE IMP ................................................................................ 32 
5.4.1. 
Assessment of compliance ................................................................................................ 33 
5.5. 
PRIOR AND CONCOMITANT MEDICATION ............................................................ 33 
5.5.1. 
Reporting of prior and concomitant medication ............................................................... 33 
5.5.2 
Prohibited medications...................................................................................................... 33 
6. 
STUDY PROCEDURE AND ASSESSMENT .............................................................. 34 
6.1. 
STUDY VISITS AND STUDY EVENTS/PROCEDURES DETAILS ........................... 34 
6.2. 
EARLY PATIENT WITHDRAWAL ............................................................................... 36 
6.2.1. 
Withdrawal criteria ........................................................................................................... 36 
6.2.2. 
Replacement procedures ................................................................................................... 36 
6.3. 
END OF STUDY .............................................................................................................. 36 
6.4. 
PATIENT MANAGEMENT AFTER STUDY COMPLETION OR TERMINATION .. 36 

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7.  
S T U D Y E N D P OI N T S  ..................................................................................................... 4 0  
7. 1.  
E F FI C A C Y E N D P OI N T S  ................................................................................................ 4 0  
 
 
7. 3.  
S A F E T Y E N D P OI N T S  .................................................................................................... 4 1  
7. 4  
P H A R M A C O KI N E TI C E N D P OI N T  ............................................................................... 4 1  
8.  
A D V E R S E E V E N T S  ...................................................................................................... 4 2  
8. 1.  
D E FI NI TI O N S  .................................................................................................................. 4 2  
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 3  
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 3  
8. 3. 1.  
F oll o w -u p of patie nts wit h A Es  ........................................................................................ 4 3  
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 4  
8. 3. 3.  
Se verit y of a d verse e ve nts  ................................................................................................ 4 4  
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 5  
8. 4. 1.  
Re p orti n g Pr oce d ure f or t he I n vesti gat or t o D o m pé/ C R O  ................................................ 4 5  
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 5  
8. 4. 3.  
A d verse e ve nts e xe m pti o n  ................................................................................................ 4 5  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................... 4 8  
9. 1.  
S A M P L E SI Z E  ................................................................................................................. 4 8  
9. 2.  
R A N D O MI Z A TI O N ......................................................................................................... 4 8  
9. 3.  
O V E R V I 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 8  
9. 4.  
I N T E RI M A N A L Y SI S ..................................................................................................... 4 8  
9. 5.  
A N A L Y SI S P O P U L A TI O N  ............................................................................................. 4 9  
9. 6.  
E S TI M A N D S  .................................................................................................................... 4 9  
9. 7.  
S T A TI S TI C A L M E T H O D O L O G Y  ................................................................................. 5 1  
1 0.  
E T HI C A L C O N SI D E R A TI O N S  ................................................................................... 5 4  
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 4  
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 4  
1 0. 3.  
P A TI E N T I N F O R M A TI O N A N D C O N S E N T  ................................................................ 5 4  
1 0. 4.  
C O N FI D E N TI A LI T Y ....................................................................................................... 5 5  
1 0. 5.  
C O M P E N S A TI O N F O R M E DI CI N E -I N D U C E D I NJ U R Y A N D I N D E M NI FI C A TI O N5 5  
1 1.  
D A T A H A N D LI N G A N D R E C O R D -K E E PI N G  ......................................................... 5 6  
1 1. 1.  
C A S E R E P O R T F O R M ( C R F)  ........................................................................................ 5 6  
1 1. 2.  
D A T A M A N A G E M E N T .................................................................................................. 5 6  
1 1. 3.  
D O C U M E N T A TI O N R E Q UI R E D P RI O R T O I NI TI A TI O N O F, A N D D U RI N G T H E 
S T U D Y  ............................................................................................................................. 5 6  
1 1. 4  
E S S E N TI A L D O C U M E N T R E T E N TI O N  ...................................................................... 5 7  
1 2  
S T U D Y M A N A G E M E N T  .............................................................................................. 5 8  
1 2. 1  
R E G U L A T O R Y B O D Y O F A P P R O V A L  ....................................................................... 5 8  
1 2. 2  
M O NI T O RI N G  ................................................................................................................. 5 8  
1 2. 3  
A C C E S S T O R E C O R D  .................................................................................................... 5 8  
1 2. 4 A U DI T A N D I N S P E C TI O N  ......................................................................................................... 5 8  
1 2. 5  
D A T A M O NI T O RI N G C O M MI T T E E  ............................................................................ 5 8  
1 2. 6   
P R O T O C O L A M E N D M E N T S  ........................................................................................ 5 9  
1 2. 7.  
DI S C O N TI N U A TI O N O F T H E S T U D Y ......................................................................... 5 9  
1 3.  
R E F E R E N C E S  ................................................................................................................ 6 1  
1 4.  
A P P E N DI C E S  ................................................................................................................. 6 2  
C CI

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14.1. 
APPENDIX 1 - SPONSOR APPROVAL PAGE ............................................................. 62 
14.2. 
APPENDIX 2 - INVESTIGATOR’S SIGNATURE PAGE ............................................. 63 
14.3. 
APPENDIX 3 - PACKAGING AND LABELING DETAILS ......................................... 64 
14.4. 
METHODOLOGICAL DETAILS ................................................................................... 65 
14.4.1. 
National Institute of Allergy and Infectious Disease - Ordinal Scale (NIAID-OS) .......... 65 
14.4.2. 
Calculation of eGFR ......................................................................................................... 65 
14.4.3. 
Handling of samples for assays ......................................................................................... 65 
14.4.4 
National Early Warning Score (NEWS) ........................................................................... 66 
14.4.5. 
Pneumonia Severity Index (PSI) ....................................................................................... 66 
14.4.6          SpO2/FiO2 - PaO2/FiO2, and SpO2 - PaO2 conversion tables……………………….….67 
 
 

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List of A b bre vi ati o ns a n d D efi niti o ns of Ter ms  
 
A B G  
Arterial Bl o o d Gas  
A D R  
A d verse Dr u g Reacti o n  
A E  
A d verse E ve nt  
AI D S  
Ac q uire d I m m u n o Deficie n c y S y n dr o me 
A LI  
Ac ute L u n g I nj ur y  
A L T  
Ala ni ne A mi n otra nsferase  
A N C  
A bs ol ute Ne utr o p hil C o u nt  
A R D S  
Ac ute Res pirat or y Distress S y n dr o me  
A S T  
As partate A mi n otra nsferase  
A U C  
Area U n der t he C ur ve  
B A L  
Br o nc h o -Al ve olar La v a ge  
B P  
Bl o o d Press ure  
B U N  
Bl o o d Urea Nitr o ge n  
C A P  
C o m m u nit y -Ac q uire d P ne u m o nia  
C B C  
C o m plete Bl o o d C o u nt  
C D E  
Cat Da n der E xtract  
C ma x  
Ma xi m u m c o nce ntrati o n  
C R A  
Cli nical Researc h Ass ociate  
C R O  
C o ntract Researc h Or ga nizati o n  
C R P  
C -Reacti ve Pr otei n  
C O VI D  
C or o na Vir us Disease  
C S R  
Cli nical St u d y Re p ort  
Css  
C o nce ntrati o n, stea d y state  
 
 
C V  
C urric ul u m Vitae  
C Y P  
C yt oc hr o me P 4 5 0   
D M C  
Data M o nit ori n g C o m mittee  
D M P  
Data Ma na g e me nt Pla n  
E C G  
Electr ocar di o gra m  
E C M O  
E xtrac or p oreal Me m bra n e O x y ge nati o n  
e C R F  
electr o nic Case Rec or d F or m  
E D C  
Electr o nic Data Ca pt ure  
E Q -5 D -5 L  
E Q -5 D -5 L q uesti o n naire  
e G F R  
Esti mate d Gl o mer ular Filtrati o n Rate  
F A S  
F ull A n al ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
Fi O 2 
Fracti o n of i ns pirati o n o x y ge n  
G C P  
G o o d Cli nical Practice  
H R  
Heart Rate  
I C F 
I nf or me d C o nse nt F or m 
I C U 
I nte nsi ve Care U nit  
I D S A/ A T S 
I nfecti o us Diseases S ociet y of A merica/ A merica n T h oracic S ociet y 
I E C 
I n de p e n de nt Et hics C o m mittee 
I L 
I nterle u ki n 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct 
I M V 
I n vasi ve Mec h a nical Ve ntilati o n 
I R B 
I nstit uti o nal Re vie w B oar d 
I R S 
I nteracti ve Res p o nse S yste m 
I R T 
I nteracti ve Res p o nse Tec h n ol o g y 
I T T 
I nte nti o n t o Treat  
I U D 
I ntra uteri ne De vice 
I U S 
I ntra uteri ne h or m o ne-releasi n g s yste m 
i. v. 
I ntra v e n o us 
I A V 
I nfl ue n za 
K M  
Ka pla n -Meier  
L D 5 0  
Let hal D ose 5 0 %  
L D H  
Lactate de h y dr o ge nase  
L L N  
L o wer Li mit of N or mal  
M D R D  
M o dificati o n of Diet i n Re n al Disease st u d y e q uati o n  
C CI

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MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliters 
NET 
Neutrophils Extracellular Traps 
NIAID-OS 
National Institute of Allergy and Infectious Disease - Ordinal Scale 
NEWS 
National Early Warning Score 
PaO2 
Partial pressure of oxygen (arterial) 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PMN 
Polymorphonuclear cell 
PP 
Per Protocol  
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcriptase-Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
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 
ULN 
Upper Limit of Normal 
VFDs 
Ventilatory-free days 
WBC 
White Blood Cell 
 
 
 
 

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1. 
STUDY SYNOPSIS  
 
CLINICAL STUDY SYNOPSIS:  
Study Number  
REP0321 
Title of Study  
Reparixin 1200 mg three times a day as add-on therapy to standard of 
care to limit disease progression in hospitalised adult patients with 
COVID-19 
and 
other 
community-acquired 
pneumonia. 
A 
multinational, multicentre, randomised, double-blinded, placebo-
controlled, parallel-group phase III trial (REPAVID-22) 
IND/EudraCT No. 
150182/ 2021-006951-32 
Study Centres (Country)  
US, EU 
Development Phase  
III 
Objective  
Primary objective. To evaluate the efficacy of oral reparixin versus 
standard care alone in limiting disease progression in adult patients 
hospitalised for infectious pneumonia acquired in the community 
(CAP), including COVID-19.  
Secondary objectives. To determine the effect of reparixin on several 
disease severity/progression measures including recovery, ventilatory 
free days and mortality.  
Safety objectives. To evaluate the safety of oral reparixin versus 
placebo in the specific clinical setting. 
Study Design and Methodology 
 
Multinational, multicentre, randomised, double-blind, placebo-
controlled, parallel-group, phase III trial. 
It will enrol 526 male and female patients >18 years, hospitalised for 
CAP (including COVID-19), assigned (1:1) to receive either oral 
reparixin (treatment group) or matched placebo (control group) three 
times a day (TID) for up to 21 days. Randomisation will be stratified 
according to disease severity and site.  
All the patients will receive the standard of care based on their clinical 
need, including COVID-19 and CAP medications, as per local standard 
therapy at the trial site and in line with international guidelines.  
The primary outcome will be evaluated at day 28, secondary will be 
evaluated from day 3 to  day 180.  
An independent external data monitoring committee (DMC) will 
oversee the study and evaluate unblinded interim data for efficacy, 
futility, and safety. 
Study procedures 
The study will consist of three periods: screening, treatment (up to 21 
days), and follow-up (up to 180 days). Potential study patients will be 
identified from those hospitalised at the participating clinical sites for 
disease management.  
Screening: screening will be performed in consented patients for 
assessment of eligibility and will include:  
• 
collection of demographic data, past medical history, disease-
specific clinical information, and previous medications 
• 
 evaluation of clinical severity scores: National Institute of 
Allergy and Infectious Disease - Ordinal Scale (NIAID-OS) 
• 
review of  available chest imaging,  
• 
measurement of SpO2 (and/or PaO2) and FiO2;  

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• 
pregnancy test (urine dipstick), in women of childbearing 
potential. Positive urine test results will be confirmed with a 
serum pregnancy test; 
• 
blood 
sampling 
for 
measurement 
of 
haematology/biochemistry and derived renal and hepatic 
function (Safety Laboratory Tests), if not already performed 
during current hospitalization. 
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. 
Randomisation: patients meeting all inclusion and none of the 
exclusion criteria will be enrolled (eligibility confirmed) and 
randomised to start study drug administration (either reparixin or 
placebo) within 24 hours from screening assessments.  
Before the administration of the first dose of study product, the 
following assessments will be performed: 
• 
12-lead ECG performed using local equipment 
• 
RT-PCR for SARS-CoV-2 from the respiratory tract 
• 
targeted examination: systolic/diastolic blood pressure (BP), 
heart rate (HR), respiratory rate (RR), body temperature, level 
of consciousness, SpO2, and use of supplemental oxygen  
• 
clinical severity scores: NIAID-OS and Pneumonia Severity 
Index (PSI) (If not already available, blood urea nitrogen 
should be measured, and PSI calculated once all laboratory 
results will be available) 
• 
blood sampling for measurement of inflammatory markers 
(lactate dehydrogenase (LDH), C-reactive protein (CRP), 
ferritin, D-dimer, procalcitonin (PCT))  
• 
blood sampling for measurement of a panel of pro-
inflammatory cytokines, such as IL-1, IL-6, IL-8 (at selected 
sites) 
Baseline is defined as the parameters prior to and including the date of 
the randomization visit. 
Treatment and post-treatment hospital stay up to day 28:  
NIAID-OS, National Early Warning Score (NEWS) and concomitant 
medications will be evaluated daily until  day 28 (or hospital 
discharge).  
The following measurements/assessments will be performed at day 3, 
7±1, 14±2, 21±2, 28±2 (or hospital discharge):  
• 
PaO2 (or SpO2) and FiO2;  
• 
blood sampling for Safety Laboratory Tests; 
• 
blood sampling for measurement of inflammatory markers 
(LDH, CRP, ferritin, D-dimer, PCT)  
• 
vital signs (can be derived by NEWS) 
At the end of treatment, the following measurements/assessments will 
be performed: 
• 
Blood sampling for measurement of inflammatory markers 
• 
Blood sampling for measurement of a panel of pro-
inflammatory cytokines (at selected sites) 
• 
ECG  

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•  
pre g na nc y test ( uri ne di pstic k), i n w o me n of c hil d beari n g 
p ote ntial. P ositi ve uri ne test res ults will be c o nfir me d wit h a 
ser u m pre g na nc y test; 
 
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: 
d urati o n of i n vasi ve 
mec ha nical ve ntilati o n (I M V) a n d/ or e xtra 
c or p oreal me m bra ne o x y ge nati o n ( E C M O ), i nte nsi ve care u nit (I C U) 
a d missi o n a n d I C U le n gt h of sta y, h os pital disc har ge h os pital le n gt h 
of sta y . At disc har ge, eti ol o gic a ge nt s (if i de ntifie d as per cli nical 
nee d ) a n d E Q -5 D -5 L  q uesti o n naire  will be c ollecte d .  
 
 
 
  
Ser u m sa m ples f or P K a nal ysis will be o btai ne d 
 
. 
At  
da y  
9 0 ± 7  
a n d  
1 8 0 ( ±1 4  
da ys),  
t he  
f oll o wi n g 
meas ure me nts/assess me nts will be perf or me d b y p h o ne: h os pital re-
a d missi o n, m ortalit y, E Q -5 D -5 L  q uesti o n nair e, occ urre nce of a n y 
a d verse e ve nt ( A E ) or seri o us a d verse e ve nt (S A E ). If re-h os pitalize d, 
it s h o ul d be als o c ollecte d: d urati o n of I M V a n d/ or E C M O, I C U 
a d missi o n a n d I C U le n gt h of sta y, h os pital le n gt h of sta y, occ urre nce 
of i nfecti o ns.  
  
N u m ber of Patie nts  
5 2 6 patie nts h os pitalise d f or C A P i ncl u di n g C O VI D -1 9 , t o tar get 5 0 0 
e val ua ble patie nts  
Dia g n osis a n d Mai n Criteria f or 
I ncl usi o n/ E xcl usi o n  
I ncl usi o n criteria 
1.  I nf or me d c o nse nt si g ne d 
2.  Male a n d fe male a d ults ≥1 8 years ol d  
3.  Patie nts h os pitalise d f or  cli nicall y s us pecte d C A P, defi ne d as t he 
occ urre nce of ( wit hi n 4 8 h fr o m h os pital a d missi o n):  
a) at least 1 of t he f oll o wi n g si g ns/s y m pt o ms: d ys p nea, 
c o u g h, p ur ule nt s p ut u m, crac kles (rales) a n d/ or r h o nc hi  
b)  b o d y te m perat ure > 3 8° C or < 3 6° C ( bef ore  or d uri n g 
a d missi o n) or le u k oc yt osis ( > l ocal U L N) 
c) ne w/i ncrease d p ul m o nar y i nfiltrate(s) b y c hest i ma gi n g  
4.  Nee d f or n o n -i n vasi ve s u p ple me ntal o x y ge n ( NI AI D-O S 5 -6)  
5.  S p O 2 < 9 2 % at r o o m air or Pa O 2  / Fi O2 (or S p O 2/ Fi O2) < 3 0 0  
6.  Fe males of c hil d -beari n g p ote ntial a n d wit h a n acti ve se x ual life 
m ust n ot wis h t o get pre g na nt wit hi n 3 0 da ys after t he e n d of t he 
st u d y a n d m ust be usi n g at least o ne of t he f oll o wi n g relia ble 
met h o ds of c o ntrace pti o n:  
a) H or m o nal c o ntrace pti o n, s yste mic, i m pla nta ble, tra ns der mal, 
or i njecta ble c o ntrace pti ves fr o m at least 2 m o nt hs bef ore t he 
scree ni n g visit u ntil 3 0 da ys after t he last I n vesti gati o nal 
Me dici nal Pr o d uct ( I M P) d ose  
b)  A n o n -h or m o nal i ntra uteri ne de vice [I U D] o r fe male c o n d o m 
wit h s per mici de or c o ntrace pti ve s p o n ge wit h s per mici de or 
dia p hra g m wit h s per mici de or cer vical ca p wit h s per mici de 
fr o m at least 2 m o nt hs bef ore t he scree ni n g visit u ntil 3 0 da ys 
after t he last I M P d ose  
c) A male se x ual part ner w h o a grees t o  use a male c o n d o m wit h 
s per mici de 
d)  A sterile se x ual part ner  
C CI
C CI

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Fe male partici pa nts of n o n -c hil d-beari n g p ote ntial or i n p ost -
me n o pa usal stat us f or at least 1 year will be a d mitte d. F or all 
fe male s u bjects, wit h c hil d-beari n g p ote ntial, pre g na nc y test 
res ult m ust be ne gati ve bef ore first dr u g i nta ke  
 
E xcl usi o n criteria  
1.  Treat me nt wit h I M V or E C M O ( NI AI D -O S  7)  
2.  He patic d ysf u ncti o n: A L T or A S T > 5 U L N; hist or y of c hr o nic 
he patic disease ( defi ne d wit h C hil d -P u g h sc ore B or C)  
3.  Re nal d ysf u ncti o n: esti mate d gl o mer ular filtrati o n rate ( e G F R; 
M D R D) < 5 0 m L/ mi n/ 1. 7 3 m
2, or nee d f or hae m o dial ysis or 
he m ofiltrati o n;  
4.  C urre nt 
use 
of 
> 2 
i m m u n os u p pressi ve 
me dicati o ns 
or 
i m m u n os u p pressi o n stat us ( AI D S, a plastic a nae mia, as ple nia, 
s yste mic c he m ot hera p y wit hi n  t he past 3 m o nt hs, ne utr o pe nia 
( A N C < l ocal L L N) , s oli d or ga n or b o ne marr o w tra ns pla nt 
reci pie nts) 
5.  Treat me nt wit h a  pr o hi bite d me dicati o n wit hi n 5 half -li ves, a n d 
i na bilit y t o st o p d uri n g treat me nt peri o d (para gra p h 5. 5. 2)  
6.  A ntici pate d disc har ge fr o m t he h os pital or tra nsfer t o a n ot her 
h os pital wit hi n 7 2 h o urs of scree ni n g  
7.  Hist or y of:  
a. 
i nt olera nce or h y perse nsiti vit y t o i b u pr ofe n t o m ore t ha n o ne 
me dicati o n bel o n gi n g t o t he class of s ulf o na mi des, s uc h as 
s ulfa met hazi ne, s ulfa met h o xaz ole, s ulfasalazi ne, ni mes uli de 
or celec o xi b ( h y perse nsiti vit y t o s ul p ha nila mi de a nti bi otics 
al o ne, e. g. s ulfa met h o xaz ole d oes n ot q ualif y f o r e xcl usi o n); 
b.  
lactase 
deficie nc y, 
galact ose mia 
or 
gl uc ose-galact ose 
mala bs or pti o n  
c. 
gastr oi ntesti nal blee di n g or perf orati o n d ue t o pre vi o us 
N S AI Ds t hera p y or rec urre nt pe ptic ulcer/ hae m orr ha ge  
d.  
aller g y t o re pari xi n  or a n y c o m p o ne nt of t he I M P f or m ulati o n  
8.  Acti ve blee di n g or blee di n g diat hesis (e xcl u di n g me nses), pri or 
i ntracra nial hae m orr ha ge 
9.  Partici pati o n i n ot her i nter ve nti o nal cli nical trials  
1 0.  Cli nical c o n diti o n n ot c o m pati ble wit h oral a d mi nistrati o n of t he 
st u d y dr u g 
1 1.  Pre g na nc y:  
a. 
p ositi ve or missi n g pre g na nc y test bef ore first dr u g i nta ke or 
da y  
b.  
pre g na nt or lactati n g w o me n  
c. 
W o me n of c hil d beari n g p ote ntial a n d fertile me n w h o d o n ot 
a gree t o use at least o ne pri mar y f or m of c o ntrace pti o n f or t he 
d urati o n of t h e st u d y 
1 2.  C urre nt h os pital sta y > 7 2 h  
1 3.  C o m plicate d 
C A P -ass ociate d 
c o n diti o ns, 
s uc h 
as 
f u n gal 
p ul m o nar y i nfecti o n, t u berc ul osis i nfecti o n, a bscess, e m p ye ma, 
si g nifica nt bilateral ple ural eff usi o n, massi ve p ul m o nar y e m b olis m 
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 
, a d mi nistere d orall y 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 hera p y t o sta n dar d of care.  
I M P ca n be ta ke n wit h a glass of water (a b o ut 2 5 0 m L) a n d a li g ht meal 
or s nac k (it is prefera ble t hat re pari xi n is ta ke n wit h f o o d). H o we ver, if 
t he patie nt is u na ble t o eat, t he st u d y dr u g ma y still be a d mi nistere d 
wit h o ut c o nc o mita nt f o o d i n gesti o n.  
D u rati o n of Treat me nt  
U p t o 2 1 da ys ( or u ntil I M V/ E C M O, if a n y)  
C CI

St u d y R E P 0 3 2 1  
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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 orall y wit h t he sa me sc he d ule as 
re pari xi n. 
Pri mar y Efficac y E n d p oi nt  
Pr o p orti o n of patie nts dea d or re q uiri n g I M V ( or E C M O) b y da y 2 8  
Sec o n dar y E n d p oi nts  
Ke y Sec o n dar y e n d p oi nts :  
- 
All -ca use m ortalit y  at da y 1 8 0  
- 
 Pr o p orti o n of patie nts ali ve a n d disc har ge d at da y 2 8  
- 
 Ve ntilat or y -free da ys at da y 2 8  
- 
Occ urre nce  of I M V ( or E C M O) b y da y 2 8  
- 
Le n gt h of pri mar y h os pital sta y  
Ot her sec o n dar y efficac y e n d p oi nts :  
- 
C li nical fail ure ( nee d f or IM V / E C M O or vas o press or , or deat h) b y 
da y 3 a n d da y 7  
- 
2 8 -da y I C U -free da ys 
- 
Da ys free of I M V/ E C M O ( n u m ber of da ys wit h NI AI D -O S 1 -6 ) at 
da y 2 8  
- 
D urati o n of anti bi otic t hera p y ( da ys) at da y 2 8  
- 
2 8 -da y h os pital free da ys  
- 
Pr o p orti o n of patie nts rec o vere d ( d o w n war d s hift fr o m scree ni n g of 
≤2 p oi nts o n t he NI AI D -O S or li ve disc har ge fr o m h os pital) at da y 
3, 7 ± 1, 1 4 ± 2, 2 1 ± 2 , 2 8  ± 2  or at h os pital disc har ge  
- 
Pr o p orti o n of patie nts w orse ni n g ( u p war d s hift fr o m scree ni n g of at 
least > 1 p oi nt of t he NI AI D -O S) at da y 3, 7 ± 1, 1 4 ± 2, 2 1 ± 2 , 2 8  ± 2 
or at h os pital disc har ge  
- 
Pa O 2/ Fi O2, at da y 3, 7± 1, 1 4 ± 2, 2 1 ± 2, 2 8 ± 2 or at h os pital disc har ge  
- 
All -ca use m ortalit y,  at b y da y 2 8, a n d da y 9 0 
- 
H os pital re -a d missi o n b y  da y 9 0 a n d 1 8 0  
- 
Ti me t o disc har ge or t o a N E W S of ≤ 2 (f or 2 4 h o urs), w hic he ver 
occ urs first   
- 
C ha n ge i n I nfla m mat or y mar kers ( L D H, C R P, ferriti n, D-di mer ; 
P C T ) a n d c yt o ki nes [ at da y 3, 7± 1, 1 4 ± 2, 2 1 ± 2, 2 8 ± 2 or at h os pital 
disc har ge ]  
- 
C ha n ge i n q ualit y of life usi n g E Q -5 D -5 L  [9 0 ± 7  a n d 1 8 0± 1 4  da ys]  
- 
d urati o n of I M V a n d/ or E C M O at 9 0 a n d 1 8 0 d  
- 
I C U a d missi o n a n d I C U le n gt h of sta y at 9 0 a n d 1 8 0 d 
- 
h os pital le n gt h of sta y at 9 0 a n d 1 8 0 d 
- 
occ urre nce of i nfecti o ns at 9 0 a n d 1 8 0 d  
 
 
 
 
 
 
 
 
 
 
 
 
P K e n d p oi nts : 
- 
Ser u m c o nce ntrati o n of re pari xi n  ( b o u n d a n d free)  
 
 
 
C CI
P P D
C CI

Study REP0321 
Reparixin in COVID-19 and other CAP (REPAVID-22) 
Page 13 of 67 
 
 
 
Protocol Version/Date: v2.0 – Final  20Jun2022  
 
 
 
 
 
 
Safety Endpoint  
- 
Incidence of Treatment Emergent AEs (TEAEs) and SAEs 
(TESAEs) from the beginning of study treatment to up to the end 
of study participation. 
- 
Incidence of lung fungal infections by 28 days 
- 
Haematology/biochemistry tests [baseline, day 3, 7±1, 14±2, 
21±2, 28±2 at hospital discharge] 
- 
BP and HR [baseline, day 3, 7±1, 14±2, 21±2, 28±2 or at hospital 
discharge] 
- 
ECG [baseline, end of treatment] 
Statistical Methods 
The sample size of the study is calculated based on results from the 
 study (phase III study) with reparixin and literature on CAP. 
Sample size has been determined to achieve an overall power of 
approximately 90% to show superiority of reparixin vs placebo in terms 
of the primary endpoint (expected effect in favour of reparixin: 
) 
and controlling the overall one-sided alpha below 0.025. An interim 
analysis, to take place when half of the planned evaluable participants 
have reached their primary endpoint, will be performed to evaluate 
efficacy and futility. 
O'Brien-Fleming’s  spending functions will be used to control the type 
I and II errors. No additional correction for multiplicity is required. The 
DMC will be involved in the evaluation of the interim analysis results 
and in the consequent decision on the continuation of the study. P-value 
boundaries are reported in the following Table: 
Analysis 
Sample 
Size 
(evaluable 
patients) 
Boundaries for primary 
endpoint 
Efficacy 
Futility 
Interim 
250 
p-value 
 
p-value 
 
Final 
500 
p-value 
 
p-value 
 
 
Assuming that 5% of patients will not be evaluable for primary 
analysis, the total number of patients to be enrolled will be 
approximately 526.  
Summary statistics have been defined for quantitative variables 
(number of observations, mean, standard deviation, median, minimum 
and maximum) and qualitative variables (number and percentage per 
category). If appropriate, confidence intervals around the mean or the 
proportions will be presented. For time-to-event variables, cumulative 
freedom from event will be evaluated using Kaplan-Meier (KM) 
method and comparison of curves among arms will be performed with 
the log-rank test. KM graphs will be presented along with the number 
of subject-at-risk at exact time points. 
The Safety (SAF) and the Full Analysis Set population will consist of 
all patients who will be randomised and received at least one dose of 
the investigational product. Safety population will be analysed 
according to the actual treatment received; FAS population will be 
analysed according to the Intention To Treat (ITT) principle, i.e. by 
treatment allocation. The Per Protocol (PP) population will consist of 
all patients in the FAS population who do not have major protocol 
deviations. Primary and secondary efficacy analyses will be conducted 
on the FAS population while SAF and PP populations will be used for 
safety and sensitivity analyses, respectively. 
CCI
CC
I
CCI
CCI
CCI
CCI

Study REP0321 
Reparixin in COVID-19 and other CAP (REPAVID-22) 
Page 14 of 67 
 
 
 
Protocol Version/Date: v2.0 – Final  20Jun2022  
 
 
 
 
 
 
The treatment policy strategy will be used for analysis of primary 
endpoint. Specifically, the primary estimand is defined by the 
following:  
 
• 
Population: adult patients hospitalized for CAP, as defined by 
the inclusion-exclusion criteria of the study.  
• 
Variable: Patients dead or requiring IMV (or ECMO) by day 
28.  
• 
Intercurrent event: The occurrence of any intercurrent event is 
irrelevant. All observed values will be used regardless of 
occurrence of these intercurrent events.  
• 
Population-level summary: Difference in proportion of 
patients dead or requiring IMV (or ECMO) by day 28.  
 
Primary endpoint will be analysed by means of logistic regression 
adjusting by pre-defined baseline factors. Missing data will be 
addressed by means of multiple imputation based on retrieved 
dropouts. Sensitivity analyses will be defined to address the robustness 
of results on primary endpoint versus deviations from the assumptions 
used in the statistical model. 
If the primary analysis of primary endpoint leads to rejection of the null 
hypotheses, key secondary endpoints will be tested in a conditional 
sequential manner to show superiority of reparixin versus placebo 
according to the pre-defined ranking sequence to control the type I error 
at 0.025. Estimands for key secondary endpoints will be described in 
the Statistical Analysis Plan. Independently of the results on primary 
endpoints, all secondary endpoints will be analysed 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 descriptively in 
nature.  
TEAEs and TESAEs will be presented in terms of the number and 
incidence of TEAEs and TESAEs. Other safety parameters will be 
summarised 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 
finalised before interim analysis. Any deviation from the original 
statistical plan will be described in the Clinical Study Report 
 
 
 
 
 
 

Study REP0321 
Reparixin in COVID-19 and other CAP (REPAVID-22) 
Page 15 of 67 
 
 
 
Protocol Version/Date: v2.0 – Final  20Jun2022  
 
 
 
 
 
 
2. 
SCHEDULE OF EVALUATION 
 
The grid below summarizes the study schedule and the patient visits 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. 
 
Study procedures 
Screening 
 day -1 or 1 
Baseline3 
Day 1 
Day 3 
Day 7 
(±1) 
Day 14 (±2) 
Day 21 (±2)11 
Day 28 (±2) 
  
Hospital 
discharge 20 
Day 90 (±7) 
Day 180 (±14) 
ELIGIBILITY 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X1 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics, 
Medical History  
X 
 
 
 
 
 
 
 
 
 
Previous medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY 
INTERVENTION 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study product 
administration4 
 
<--------------------- daily --------------------> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY 
PROCEDURES 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR 
 
X12 
 
 
 
 
 
 
 
 
Clinical severity score 
(NIAID-OS) 
X 
<-------------------------- daily15 ----------------------------> 
 
 
Physiological 
parameters (NEWS)18 
 
<-------------------------- daily ------------------------------> 
 
 
PSI 
 
X12 
 
 
 
 
 
 
 
 
PaO2/FiO219 
X12 
 
X 
X 
X 
X 
X 
 
 
 
Chest imaging review 
X13 
Adverse events 
evaluation 
 
<-------------------------------------------------------------------------------------> 
Concomitant 
medications 
<--------------------------------------------------------------------> 
 
 
Additional Clinical 
Findings10 
 
 
 
 
 
 
X 
X 
 
 
EQ-5D-5L2 
 
 
 
 
 
 
 
X 
X 
X 
Follow-up16 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
SAFETY 
PROCEDURES 
 
 
 
 
 
 
 
 
 
 
Safety Laboratory 
Tests6 
X12 
 
X 
X 
X 
X 
X 
 
 
 
Pregnancy Test7 
X 
 
 
 
 
X 
 
 
 
 
Vital signs14 
 
X 
X 
X 
X 
X 
X 
X 
 
 
ECG 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
Cytokines8 
 
X 
 
 
 
X 
 
 
 
 
Inflammatory markers9 
 
X12 
X 
X 
X 
X 
X 
X 
 
 
Serum PK 
 
 
X17 
 
 
 
 
 
 
 
CCI

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1 
I nf or me d c o nse nt m ust b e d oc u me nte d bef ore a n y st u d y-s pecific scree ni n g pr oce d ure  
2  
  Tele p h o ne i nter vie w versi o n  
3 
Scree ni n g a n d baseli ne  ( pre-treat me nt assess me nt) ma y c oi nci de ( b ot h as Da y 1)  
4 
St u d y pr o d uct will be a d mi nistere d TI D u p t o  2 1 da ys  
5 
 
6 
I ncl u des Hae mat ol o g y (R B C c o u nt , hae mat ocrit, hae m o gl o bi n, W B C c o u nt a n d  differe ntial c o u nt [ ne utr o p hils , 
e osi n o p hils, bas o p hils, m o n oc ytes, l y m p h oc ytes], platelets c o u nt) a n d Bi oc he mistr y (s o di u m, p otassi u m, 
c hl ori de, calci u m, gl uc ose, creati ni ne  [t o calc ulate e G F R usi n g M D R D], al b u mi n, A S T, A L T, t otal a n d direct 
bilir u bi n).  
7  
F or w o me n of c hil d beari n g p ote ntial. P ositi ve uri ne test res ults will be c o nfir me d wit h a ser u m pre g na nc y test. 
St u d y dr u g m ust n ot b e a d mi nistere d u nless pre g na nc y test res ult is ne gati ve.  
8 
S uc h as I L -1, I L -6, I L -8 (i n selecte d ce ntres) , t o be c hec ke d  pri or t o first I M P a d mi nistrati o n a n d at t he e n d of 
treat me nt  
9 
L D H, ferriti n, C R P, D -di mer , P C T 
1 0 
I ncl u de fi nal e v al uati o n of da ys of h os pitalisati o n, eti ol o gic a ge nts (if i de ntifie d),  I C U a d missi o n a n d t otal days 
i n I C U, occ urre nce a n d d urati o n of I M V a n d/ or E C M O,  if a n y. 
1 1 
Or e n d of treat me nt     
1 2 
Dia g n ostic a n d L a b orat or y tests perf or me d at t he site d uri n g c urre nt h os pitalizati o n  will be acce pte d f or 
deter mi nati o n of eli gi bilit y  a n d / or use d  as baseli ne data  
1 3 
Scree ni n g c h est  i ma gi n g, alrea d y perf or me d per cli nical nee ds,  s h o ul d be re vie we d t o c o nfir m ne w / w orse ni n g 
l u n g i nfiltrate(s) 
1 4 
S yst olic / diast olic bl o o d press ure ( B P ; m m H g); heart  rate ( H R; b/ mi n), res pirat or y rate ( R R; n/ mi n) 
1 5 
E ver y m or ni n g d uri n g h os pitalizati o n  
1 6 
 P h o ne f oll o w -u p t o assess re -h os pitalizati o n , all-ca use m ortalit y  (healt h re gistr y  ma y be use d ). If re-
h os pitalize d, it s h o ul d be als o c ollecte d: d urati o n of I M V a n d / or E C M O, I C U a d missi o n a n d I C U le n gt h of 
sta y, h os pital disc h ar ge a n d h os pital le n gt h of sta y, occ urre nce of i nfecti o ns.  
 
 
 
1 8 
I n a sc ore d s yste m, N E W S i ncl u des Bl o o d Press ure ( B P), Heart Rate ( H R), Res pirat or y Rate ( R R), b o d y 
te m perat ure, le vel of c o nsci o us ness ( A, V, P, U), S p O2 a n d use of s u p ple me ntal o x y ge n  (see 1 4. 4. 4) 
1 9 
If Arterial Bl o o d Gas (A B G ) a nal ysis is n ot rea dil y a vaila ble, S p O2 ca n be use d t o esti mate Pa O 2  (see a p pe n di x 
1 4. 4. 6 ) 
2 0 
 It ca n occ ur bef ore or after 2 8 d 
2 1  If not alrea d y a vaila ble, bl o o d urea nitr o ge n s h o ul d be meas ure d t o calc ulate P SI. I n case t he la b orat or y 
res ults are n ot rea dil y a vaila ble, a n d P SI calc ulate d o nce all la b orat or y res ults will be a vaila ble  
 
 
 
 
 
 
 
 
C CI
C CI

St u d y R E P 0 3 2 1  
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2 . 1. 
B A C K G R O U N D I N F O R M A TI O N  
Re pari xi n  is a s pecific i n hi bit or of I L-8 ( C X C L 8) bi ol o gical acti vit y, ste m mi n g fr o m a pr o gra m of dr u g 
desi g n of m olec ules i nte n de d t o m o d ulate c he m o ki ne acti o n. Re pari xi n  is t he first l o w m olec ular wei g ht 
bl oc ker of I L 8 bi ol o gical acti vit y i n cli nical de vel o p me nt.  
Base d o n its mec ha nis m of acti o n, earl y pre -cli nical c haracterizati o n of re pari xi n was s pecificall y tar gete d t o 
e val uate t he i n hi biti o n of P M N recr uit me nt a n d t he pre ve nti o n of Isc he mia/ Re perf usi o n i nj ur y. Ori gi nal 
de vel o p me nt was f oc use d t o s oli d or ga n tra ns pla ntati o n, w here re pari xi n was i nf use d i. v. f or u p t o 7 da ys. I n 
t his file d, re pari xi n has recei ve d t he or p ha n dr u g desi g nati o n i n E U i n Se pte m ber 2 0 0 1 a n d i n U S A i n Ja n uar y 
2 0 0 3 f or pre ve nti o n of dela ye d graft f u ncti o n  after s oli d or ga n tra ns pla ntati o n. M ore rece ntl y, or p ha n dr u g 
desi g nati o n has bee n gra nte d i n E U ( Se pte m ber 2 0 1 1) f or t he “ pre ve nti o n of graft l oss i n pa ncreatic islet 
tra ns pla ntati o n” a n d i n t he U S ( Se pte m ber 2 0 1 2) f or t he “ pre ve nti o n of graft l oss i n islet cell tra ns pla ntati o n”.  
Si milarl y, o nc ol o g y st u dies i n h u ma n breast ca ncer ste m cells i n vitr o a n d i n xe n o grafts e vi de nce d  of t he r ole 
of I L-8 i n t u m or metastasis a n d i n tiss ue da ma ge i n d uc e d b y c he m ot hera pe utic a ge nts a n d s u p p orte d t he 
cli nical de vel o p me nt of oral re pari xi n i n breast ca ncer patie nts. 
Gi ve n t he pr o mi ne nt r ole pla ye d b y C X C L 8 a n d P M N i n C O VI D 1 9 p ul m o nar y i nfla m mati o n, oral re pari xi n 
is bei n g st u die d i n t he i n dicati o n of se vere C O VI D-1 9 p ne u m o nia .  
 
2. 2  
R E L E V A N T N O N -C LI NI C A L P H A R M A C O L O G Y  
Re pari xi n is i n vitr o  a p ote nt a n d s pecific i n hi bit or of C X C L 8 bi ol o gical acti vit y. I n vitr o e x peri me nts ha ve 
s h o w n t hat re pari xi n i n hi bits C X C L 8-i n d uce d c he m ota xis of h u ma n p ol y m or p h o n uclear le u k oc ytes (P M N ) 
i n t he l o w na n o m olar ra n ge. St u dies t o el uci date t he mec ha nis m of acti o n ha ve s h o w n t hat re pari xi n is a n o n-
c o m petiti ve all osteric i n hi bit or of t he C X C L 8 rece pt ors C X C R 1 a n d C X C R 2. I nteracti o n of re pari xi n wit h 
C X C L 8 rece pt ors i n hi bits t he i ntracell ular si g nal tra ns d ucti o n e ve nts acti vate d b y bi n di n g of C X C L 8 t o 
C X C R 1 a n d C X C R 2 
1 -2. I n vi v o, re pari xi n pre ve nte d P M N i nfiltrati o n i nt o t he tra ns pla nte d ki d ne y a n d 
re d uce d creati ni ne le vels i n a rat m o del of ki d ne y tra ns pla ntati o n. Si milarl y, i n a rat m o del of l u n g 
tra ns pla ntati o n, re pari xi n i m pr o ve d is olate d graft o x y ge nati o n, decrease d p ul m o nar y oe de ma, a n d 
si g nifica ntl y re d uce d ne utr o p hil i nfiltrati o n i nt o tra ns pla nte d l u n gs. M ore o ver, re pari xi n pre ve nte d P M N 
i nfiltrati o n a n d tiss ue da ma ge i n ot her a ni mal m o dels of isc he mia/re perf usi o n i nj ur y of li ver, brai n, i ntesti ne, 
heart a n d s pi nal c or d. I n t hese m o dels, i n viv o i n hi biti o n of P M N recr uit me nt ra n ge d fr o m 4 0 t o 9 0 %, a n d 
i n hi biti o n of tiss ue da ma ge ra n ge d fr o m 5 0 t o 8 0 %. 
 
  
I n a m uri ne m o del of L P S -i n d uce d A LI, re pari xi n ( 1 5 μ g g −1 ) re d uce d ne utr o p hil recr uit me nt i n t he l u n g b y 
a p pr o xi matel y 5 0 % , t he acc u m ulati o n of ne utr o p hils i n t he i nterstitial c o m part me nt a n d vasc ular 
per mea bilit y. B ot h pr o p h ylactic a n d t hera pe utic a p plicati o n of re pari xi n i m pr o ve d gas e xc ha n ge a n d re d uce d 
ne utr o p hil recr uit me nt a n d vasc ular per mea bilit y i n a cli nicall y rele va nt m o del of aci d -i n d uce d A LI3.  
I n t he cat da n der e xtract (C D E ) si n gle c halle n ge m o del, a d mi nistrati o n of re pari xi n  ( 1 5 m g/ k g) s u p presse d 
ne utr o p hil recr uit me nt i nt o t he l u n gs. I n t he C D E m ulti ple challe n ge m o del, re pari xi n i n hi bite d e osi n o p hil, 
ne utr o p hils, a n d t otal cell n u m bers i n B A L  fl ui d, ser u m le vels of t otal I g E a n d C D E s pecific I g E, air wa y 
e pit helial m uci n sec reti o n, le vels of T h 2 i nfla m mati o n‐ass ociate d ge nes peri osti n  a n d m uc 5ac, a n d t he B A L  
fl ui d le vels of IL‐ 4 , IL‐ 1 3 , IL‐ 3 3, a n d T S L P.  P har mac ol o gical i n hi biti o n of C X C R 1/ 2‐ a xis b y a d mi nistrati o n 
of re pari xi n i n hi bits aller ge n i n d uce d i n nate a n d aller gic air w a y i nfla m mati o n i n mice 4.  
I n a 
m uri ne 
m o del of ble o m yci n-i n d uce d p ul m o nar y fi br osis, in hi biti o n of C X C R 2 wit h re pari xi n 
a meli orate d p artic ulate m atter -i n d uce d i ncrease d se verit y of p ul m o nar y fi br osis. C o-treat me nt wit h re pari xi n 
i n mice recei vi n g p artic ulate m atter a n d ble o m yci n re d uce d ne utr o p hil n u m ber a n d ne utr o p hil elastase 
c o nce ntrati o n of da y 2  B A L  fl ui d. M ore o ver, re pari xi n i m pr o ve d l u n g f u ncti o n a n d a meli orate d p ul m o nar y 
fi br osis as assa ye d b y t otal c olla ge n c o nte nt a n d hist oc he mical stai ns of fi br osis mar kers o n da y 1 4 l u n g 
tiss ues5. 
T he r ole of C X C R 1/ 2 i n hi biti o n d uri n g i nfl ue nza, p ne u m oc occal, a n d p ost -i nfl ue nza p ne u m oc occal 
i nfecti o ns was als o i n vesti gate d. M ost e x peri me nts were c o n d ucte d usi n g D F 2 1 6 2, a Re pari xi n a nal o g ue, 
bel o n gi n g t o t he sa me fa mil y of n o n -c o m petiti ve all osteric i n hi bit ors of C X C R 1 a n d C X C R 2. Re pari xi n a n d 
D F 2 1 6 2 e x hi bit si milar p ote nc y i n t he i n hi biti o n of t he tar get rece pt ors C X C R 1 a n d C X C R 2 (I C 5 0s i n I L-8 -
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Re p arixi n i n C O VI D-1 9  a n d ot her C A P ( R E P A VI D -2 2 ) 
Pa ge 1 8  of  6 7  
 
 
 
Pr ot o c ol Versi o n/ Date: v 2. 0  –  Fi nal  2 0 J u n 2 0 2 2  
 
 
 
 
 
 
i n d uce d c he m ota xis i n t he ra n ge of 1 n M). T he m olec ular mec ha nis m of acti o n has bee n dee pl y c haracterize d 
b y p oi nt -m uta ge nesis st u dies o n C X C R 1 a n d C X C R 2 s h o wi n g t hat Re pari xi n a n d D F 2 1 6 2 bi n d t he rece pt ors 
i n t he sa me all osteric site i n t he Tra ns -Me m bra ne re gi o n, w hic h is hi g hl y c o nser ve d i n t he t w o rece pt or 
s u bt y pes. F or t his reas o n, D F 2 1 6 2 has bee n use d t o assess t he r ole of C X C R 1/ 2 d uri n g i nfl ue nza (I A V), 
p ne u m oc occal, a n d p ost -i nfl ue nza p ne u m oc occal i nfecti o ns in t he m o use m o dels.  Mice were i nfecte d wit h 
I A V or Stre pt oc occ us p ne u m o niae a n d t he n treate d dail y wit h D F 2 1 6 2. T o st u d y sec o n dar y p ne u m oc occal 
i nfecti o n, mice were i nfecte d wit h a s u blet hal i n oc ul u m of I A V t he n i nfecte d wit h S. p ne u m o niae 1 4 da ys 
later. DF 2 1 6 2 was gi ve n i n a t hera pe utic sc he d ule fr o m da ys 3 t o 6 after i nfl ue nza i nfecti o n. Let halit y, wei g ht 
l oss, i nfla m mati o n, vir us/ bacteria c o u nt, a n d l u n g i nj ur y were assesse d. C X C L 1 a n d C X C L 2 were pr o d uce d 
at hi g h le vels d uri n g I A V i nfecti o n. D F 2 1 6 2 treat me nt decrease d m or bi dit y a n d t his was ass ociate d wit h 
decrease d i nfiltrati o n of ne utr o p hils i n t he l u n gs a n d re d uce d p ul m o nar y da ma ge a n d viral titres. D uri n g S. 
p ne u m o niae i nfecti o n, D F 2 1 6 2 treat me nt decrease d ne utr o p hil recr uit me nt, p ul m o nar y da ma ge, a n d  let halit y 
rates, wit h o ut affecti n g bacteria b ur de n. T hera pe utic treat me nt wit h D F 2 1 6 2 d uri n g s u blet hal I A V i nfecti o n 
re d uce d t he m or bi dit y ass ociate d wit h vir us i nfecti o n a n d als o decrease d t he ma g nit u de of i nfla m mati o n, 
l u n g da ma ge, a n d n u m ber of bacteria i n t he bl o o d of mice s u bse q ue ntl y i nfecte d wit h S. p ne u m o niae. T hese 
data s u g geste d t hat m o d ulati o n of t he i nfla m mat or y res p o nse b y bl oc ki n g C X C R 1/ 2 i m pr o ves disease 
o utc o me d uri n g res pirat or y i nfl ue nza a n d p ne u m oc occal i nfecti o ns, wit h o ut c o m pr o misi n g t he a bilit y of t he 
m uri ne h ost t o deal wit h i nfecti o n
6. T o i n vesti gate t he r ole of C X C R 1/ 2 d uri n g i nfl ue nza i nfecti o n, mice were 
i nfecte d wit h 1  ×  1 0 4 P F U of I A V a n d t he n treate d t hree ti mes a da y (fr o m da y 0— at t he ti me of t he 
i nfecti o n— t o da y 5 p ost-i nfecti o n) wit h re pari xi n at 1 5 m g/ k g. Si milarl y. t o D F 2 1 6 2, treat me nt wit h re pari xi n 
decrease d m or bi dit y, as see n b y t he re d ucti o n of wei g ht l oss, re d uce d le u k oc yte i nfiltrati o n i nt o t he air wa ys, 
i ncl u di n g ne utr o p hils, a n d t he le vels of t he pr o-i nfla m mat or y c yt o ki nes T N F-α a n d C X C L 1 a n d re d uce d t he 
l u n g i nj ur y ass ociate d wit h I A V i nfecti o n meas ure b y hist o pat h ol o gical sc ore. I n c o ncl usi o n, e ve n t h o u g h 
t he e xte nsi ve c haracterizati o n w or k wit h i nfecti o us a ge nts was c o n d ucte d wit h D F 2 1 6 2, preli mi nar y 
e x peri me nts s h o we d a si milar be ha vi o ur usi n g re pari xi n i n t he si n gle I A V m o del lea di n g t o c o m para ble 
res ults. 
A rece nt st u d y has s h o we d t hat C O VI D -1 9 ne utr o p hils are c haracterize d b y I L -8 -i n d uce d de gra n ulati o n a n d 
dri ve a s yste mic pr ot hr o m b otic p he n ot y pe. It als o s h o we d t hat t hera pe utic bl oc ka de of I L -8 b y re pari xi n 
re d uces 
C O VI D-1 9 -ass ociate d h u ma n ne utr o p hil act i vati o n i n vitr o a n d atte n uates 
A R D S-relate d 
micr ot hr o m b osis i n vi v o i n t he tra ns ge nic h A C E 2 m o use m o del of C O VI D -1 9 ass ociate d res pirat or y fail ure, 
w here re pari xi n treat me nt le d t o decrease d fi bri n o ge n bi n di n g b y i ntra vasc ular ne utr o p hils a n d a n atte n uati o n 
of p ul m o nar y micr o -t hr o m b osis7. 
 
2 .3 . 
A 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 oxic 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. a d mi nistrati o n t o d o gs f or 2 wee ks res ulte d i n a safe d ose of 
. C o nti n u o us i. v. i nf usi o n of re pari xi n t o t he male a n d fe male rat 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 t o be use d 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 n or der t o pr o vi de e vide 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 
 hi g her t han  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 a ver y 
c o m pre he nsi ve t o xic ol o gical i n vesti gati o n i n vitr o a n d i n a ni mal s pecies.  
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2.4. 
PHARMACOKINETICS AND PRODUCT METABOLISM 
Pharmacokinetic (PK) studies by i.v. injection revealed that reparixin is very rapidly eliminated in rats and 
humans 
 whereas elimination is slower in dogs 
 The 
PK of reparixin was linear in rats and in dogs but linearity was less evident in humans. Reparixin undergoes 
complete metabolism (oxidation + conjugation) in all the species tested. The in vitro human hepatic, phase I 
metabolism of reparixin is catalysed by CYP2C9 and to a lesser extent by CYP2C19. DF2243Y, DF2188Y, 
methanesulfonamide and ibuprofen are the metabolites detected in human plasma and urine, with DF2243Y 
being the major metabolite. Exposure to ibuprofen after administration of reparixin 
 
(the highest dose tested in humans) was similar or lower than that obtained after a standard therapeutic single 
dose of ibuprofen (300mg). Preliminary PK data obtained in a few patients undergoing islet transplantation 
shows that plasma levels of reparixin (total and unbound) and its major metabolite DF2243Y appears to be 
within the expected range according to the dose administered. Due to extensive metabolism, unchanged 
reparixin was poorly or not excreted into the urine of rats, dogs and humans so that the PK profile of reparixin 
is not influenced by renal impairment. In vitro protein binding of [14C]-reparixin showed that reparixin is 
highly bound (approximately 99%) to plasma proteins in rats, dogs, rabbits, cynomolgus monkeys and 
humans. Albumin is likely to be the major binding protein in plasma in all species, accounting for 99.2% in 
humans.  
In clinical trials with oral tablets reparixin was administered for 
 followed by 
 
 before the next cycle. Reparixin was rapidly absorbed (median Tmax 1 hr). Reparixin systemic 
exposure (Cmax and AUClast) did not change from day 1 to day 
 indicating the absence of accumulation 
over the dosing period. Also, t1/2 did not change from day 1 to day 
 with a median value of about 2 hrs. 
Once absorbed, reparixin is highly bound to proteins as only <0.1% to 0.2% of total reparixin is available as 
unbound (free) drug. Reparixin was rapidly metabolized to DF2243Y, DF2188Y and ibuprofen. For all three 
metabolites systemic exposure was similar on both day 1 and day 
 within the observed intersubject 
variability. The t1/2 of all three metabolites appeared to remain about the same from day 1 to day 
 
To investigate the PK/PD characteristics of reparixin, we assessed the effect of the drug in inhibiting IL-8-
mediated Neutrophils Extracellular Traps (NET) release by hPMN in whole blood of healthy volunteers. 
Reparixin blocked IL-8-induced NET formation in a concentration dependent manner, being the inhibition 
(40%) statistically significant at 
 and reaching the almost complete inhibition (about 90%) at
 
. This finding supports that the total blood concentration of 
 (corresponding to a free unbound 
concentration of 
), as that reached at the steady state (Css) by i.v. infusion or by repeated oral 
administration, is coherent with the objective to reach the drug exposure necessary to maximize the potential 
clinical efficacy of the compound. 
Reparixin has some potential in vitro for a non-competitive inhibition of the human hepatic enzyme CYP3A4 
that is involved in the metabolism of cyclosporine A, tacrolimus and rapamycin. However, since inhibition 
is evident at concentration far higher than the free plasma concentration of reparixin at steady state in humans, 
it is predicted that the clinical relevance of such inhibition is remote. Indeed, reparixin does not affect to a 
clinically relevant extent the activity of CYP3A4 and CYP2C9 (enzyme involved in reparixin metabolism), 
as revealed by an interaction study where the PK of midazolam and tolbutamide (probe substrates for these 
enzymes) was evaluated in healthy subjects receiving single oral doses of the probes alone or in combination 
with reparixin. 
 
2.5. 
A SUMMARY OF CLINICAL DATA 
To date, several clinical studies (from Phase I to Phase III) with a total of 627 subjects exposed to the drug, 
of whom 342 and 337 received oral tablets and i.v. formulation, respectively were performed. 
During the Phase I studies a total of 166 subjects of whom 103 normal volunteers and 17 patients with 
different grade of renal impairment, 16 patients undergoing cardiopulmonary bypass and 30 patients with 
metastatic breast cancer were exposed to reparixin. 
In Phase II and III studies, a total of 318 patients have been treated with reparixin I.V. (in phase II only) and 
oral tablets. For I.V. administration: 46 undergoing lung transplantation, 48 patients undergoing kidney 
transplant, 85 patients undergoing intrahepatic islet transplantation, 22 undergoing orthotopic liver 
transplantation and 4 patients with severe COVID-19 pneumonia (under compassionate use). 
For oral administration: 122 patients with breast cancer, 220 patients hospitalized for COVID-19 pneumonia 
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were treated. 
In all studies, reparixin has shown a good safety profile with both I.V. and oral administration routes. 
Data with oral tablets include treatments repeated monthly cycles of 21 days continuous treatment in breast 
cancer patients, which exceed the duration of the treatment in the COVID-19 studies, which require a single 
cycle only of 21 days. 
 
2.5.1. Efficacy in patients with Covid-19 
To date three studies were performed with reparixin in COVID-19 patients. They were represented by:  
a. Compassionate use with reparixin i.v. infusion,  
b. Phase II open-label study 
),  
c. Phase III double-blind study 
).  
 
In particular: 
 
1. In March 2020, IRCCS Ospedale San Raffaele, a reference center in Italy for COVID-19 pandemic 
emergency, utilized reparixin under a compassionate use application. Four patients with ARDS caused by 
COVID-19 pneumonia with the clinical indication for intubation and invasive mechanical ventilation 
(IMV) were treated with reparixin i.v. infusion
 via high-flow central 
vein for 5 days. An article on these patients was published (Piemonti et al., 2020), reporting that 1 out of 
the 4 patients was never intubated and discharged from the hospital, and 3 were intubated: 1 in stable 
condition and 2 with improving lung function.  
From a haemato-chemical standpoint, there was an improvement or stabilization of the inflammatory 
markers [C-reactive protein (CRP), procalcitonin (PCT), and ferritin] during treatment with reparixin, as 
per tissue damage markers [lactate dehydrogenase (LDH), ALT, AST]. As per the last update in March 
2021, 3 of the 4 patients treated were intubated, and all patients were discharged alive from hospital.  
2. Phase II open-label study 
. In 2020 Dompé concluded the Phase II segment of an adaptive 
Phase II/III, randomized, controlled multicenter study on the efficacy and safety of reparixin in the 
treatment of hospitalized patients with COVID-19 pneumonia. Fifty-six patients were randomized 2:1 to 
receive 1200 mg (2x 600 mg tablets) oral reparixin three times daily (37 pts) or standard of care (SOC) 
(19 pts) for up to 21 days. Results suggested that Reparixin may prevent the progression to severe disease, 
as it significantly decreased the incidence of at least one clinical event of the composite endpoint including 
supplemental oxygen requirement, invasive mechanical ventilation use, admission to ICU, and use of a 
rescue medication for any reason. Treatment with Reparixin was well tolerated in terms of treatment-
emergent adverse events, laboratory tests and vital signs parameters. 
3. Phase III double-blind study 
. The Phase II study
 results informed the design of 
a subsequent double-blind, placebo-controlled clinical study 
), approved in Italy (EudraCT 
Number:
) and in the US; nonetheless, due to a late activation of the three centers in US, 
that coincided with a lowering incidence of new COVID-19 infections, the study enrolled only in Italy. 
Study 
 title was 
 
 
” and its objective was to evaluate efficacy and safety of oral reparixin as compared to placebo 
(both on top of standard treatment). A planned primary analysis on efficacy endpoint up to Day 28 was 
recently completed. To maintain study integrity, results were disclosed to the study Sponsor in an 
aggregate way, study personnel remained blinded to patient-level information, and analyses were 
conducted by an independent statistician. From February 2021 to June 2021, patients with RT-PCR-
confirmed severe COVID-19 were randomized in a 2:1 fashion to receive oral reparixin 1200 mg (2x 600 
mg tablets) three times a day (TID) or placebo for 21 days. Schedule and regimen were consistent with 
the previous trial. Follow-up information on the patient’s clinical condition and survival are collected until 
day 90. Briefly, patients were considered for inclusion if they needed oxygen support with a PaO2/FiO2 
between 100 and 300 (or SpO2 >95% at room air, or RR ≥24 breaths/min at room air), abnormal chest 
imaging, and laboratory signs of inflammation (LDH >normal range, CRP ≥100 mg/L or IL-6 ≥40 pg/mL, 
serum ferritin ≥900 ng/mL, XDP >20 mcg/mL). The primary efficacy outcome was the proportion of 
patients alive and with no respiratory failure at day 28, defined as no need for IMV, extracorporeal 
membrane oxygenation (ECMO), or admission to ICU due to worsening respiratory status. Among 278 
randomized patients, all enrolled in Europe, 179/183 (97.8%) in the reparixin group and 88/95 (92.6%) in 
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the placebo group received at least one dose of investigational product and were included in the primary 
intention-to-treat (ITT) analysis of efficacy. All participants had a positive RT-PCR assay for SARS-CoV-
2 RNA from the upper respiratory tract. At baseline, the cohort was well-balanced across the two groups: 
mean age 60.8 (SD 11.9) years, 73% were males, 27% had a Hispanic origin, and 30% with a BMI>30 
Kg/m2. All participants had the typical features of acute respiratory failure, such as abnormal findings at 
the chest imaging, need for oxygen therapy either low flow or HFNC/NIV (HFNC/NIV, 49.2% in the 
reparixin and 50.0% in the placebo group), with a mean PaO2/FiO2 of 200.2 (SD 67.5). The treatment 
was discontinued more frequently in placebo (33 patients [18.0%] vs. 21 [22.1%]), with good compliance 
to study medication during treatment in both arms (median 95.8% in the reparixin group and 96.5% in the 
placebo group). According to ITT principle, all randomized and treated patients were considered for the 
efficacy analysis, using retrieve dropouts’ information to handle missing data at Day 28. 
 
 
 
Patients in both 
treatment arms received the standard supportive care based on the patient’s clinical need as per local 
standard therapy: 85.2% of patients in the placebo group received glucocorticoids (82.7% in reparixin), 
35.2% received remdesivir (29.6% in reparixin), and 2.3% received tocilizumab (3.4% in reparixin). The 
mortality at 28 days was
 in the placebo group and
 in the reparixin group (OR 0.543 [95%IC 
0.185-1.592], p=0.265). Nonetheless, there was a strong signal in favour of reparixin in limiting the 
worsening of respiratory failure at day 28. In fact, the proportion of ICU admission due to a deterioration 
of respiratory failure (followed by IMV, or ECMO, or death) was lower in the treatment group, 9 (5.9%) 
in the reparixin group and 11 (13.8%) in the placebo group, OR 0.372 [95%IC 0.144-0.960], p=0.041. 
The incidence of IMV/ECMO was also lower in the treatment group: 8 patients (5.3%) in reparixin vs. 10 
(12.7%) in placebo group, p = 0.048. This is also corroborated by physiological parameters, as the 28-d 
trajectory of PaO2/FiO2 was significantly better in patients receiving oral reparixin: PaO2/FiO2 mean 
change from baseline: 145.0 [SD 146.5] in reparixin vs. -27.9 [SD 130] in the control group, p=0.008. 
Once again, there was a strong safety signal even as the number of adverse events was steadily higher in 
the control group.  
 
2.5.2. Safety  
In all studies, reparixin has shown a good safety profile with both i.v. and oral administration routes. 
A total of 448 subjects have been exposed to reparixin in the clinical studies completed up to the start of the 
phase II in COVID-19. Of these, 337 and 112 received i.v. formulation and oral tablets, respectively.  
The patient population exposed to i.v. formulation includes 103 adult healthy subjects (100M/3F), 17 patients 
with different grades of renal impairment (12M/5F), 16 patients undergoing cardiopulmonary by-pass 
(10M/6F), 46 patients undergoing lung transplantation (23M/23F), 48 patients undergoing kidney transplant 
(31M/17F), 22 undergoing liver transplant (18M/4F) and 85 receiving intrahepatic pancreatic islet infusion 
(32M/53F), with 22 patients in this group receiving reparixin twice. Exposure included short or prolonged 
i.v. infusion up to 
 over 30min or 
 over 48h and, in pancreatic islet and liver 
transplantation studies,
 i.v. continuous infusion for 7 days. Overall, reparixin 
was safe and well tolerated in both healthy subjects and critically ill patients. In phase 1 studies, no deaths, 
Serious Adverse Events (SAE) or Adverse Events (AE)-related withdrawals were reported. The majority of 
AEs reported were of mild intensity. All subjects had recovered completely or had ongoing adverse events 
of mild intensity when they were discharged. The safety of reparixin was confirmed also in patients with 
different grades of renal impairment. In the interaction study no safety concerns were raised during co-
administration of midazolam/tolbutamide with reparixin. During phase II and III studies, AE and SAE profile 
was similar for both placebo and reparixin groups and no particular safety concerns were raised. Data 
obtained in the trials in islet transplantation further support the safety profile of the proposed dose, even after 
a 7-day administration, repeated 
 in several patients. Most frequent Adverse Drug Reactions (ADRs) 
were nausea, headache, and vomiting; great majority of these were mild to moderate in nature and none 
required discontinuation of the investigational product. Tachycardia occurred in one patient from Days 5 to 
38 after 1st islet infusion was judged probable in relation to the investigational product. Vomiting, nausea 
and headache on Day 5 and 6 after 2nd islet infusion in one patient and erythema, nausea and headache on 
Days 2 to 6 after 1st islet infusion in another patient were judged highly probable in relation to the 
investigational product. Nausea, vomiting and severe gastrointestinal bleeding associated with anaemia 
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developed in a female patient early after the beginning of reparixin infusion because the patient received a 
dose of reparixin 3 times as high as that foreseen in the protocol (medical error). These events were assessed 
as serious by the investigator and by the Sponsor. 
The most frequent (>10%) ADRs observed in studies on i.v. formulation were:  
Gastrointestinal disorders (about 26% of the total number of reports), including abdominal pain lower, 
abdominal pain NOS, abdominal pain upper, constipation, diarrhoea, dyspepsia, flatulence, gastroesophageal 
reflux disease, gastrointestinal haemorrhage, intra-abdominal haemorrhage, nausea and vomiting.  
Nervous system disorders (about 19%), including headache, dizziness, hypoesthesia, somnolence.  
General disorders and administration site conditions (about 16%), including cannula site reaction, fatigue, 
implant site haemorrhage, injection site thrombosis, infusion site oedema, lethargy, malaise, oedema, oedema 
peripheral, and pyrexia  
The patient population exposed to reparixin oral tablets consists of 111 female patients receiving either single 
agent reparixin 
, operable breast cancer: 20 patients) or the combination of reparixin and weekly 
paclitaxel in metastatic breast cancer 
 30 patients; 
: 61 
patients). In these studies, reparixin was generally well tolerated at all doses studied. Overall, 505 ADRs 
were reported in 78 patients in the safety population. 
70.9% of the ADRs were grade 1 (mild), 22.9% were grade 2 (moderate) and 4.3% were grade 3 (severe). 
One grade 4 ADR was reported overall 
). In addition, one patient in clinical trial REP0114 
experienced serious ADRs including grade 4 peritonitis and grade 5 intestinal perforation. 
The most frequent (>10%) ADRs observed in the three studies were:  
Gastrointestinal disorders (31.8%), including nausea, vomiting, abdominal pain, discomfort or distension, 
dyspepsia, flatulence, constipation;  
General disorders and administration site conditions (16.4%), including fatigue and peripheral oedema. 
Further data can be found in the Investigator’s Brochure. 
Preliminary safety data derived from the 
 trial confirmed the tolerability of reparixin in patients 
with COVID-19, with treatment emergent adverse events/treatment emergent serious adverse event 
(TEAEs/TESAEs) profile similar in both treatment groups. A total of 161 TEAEs were reported in 71 patients 
(39.7%) in the reparixin group and 100 TEAEs were reported in 42 patients (47.7%) in the placebo group. 
Similarly, TESAEs were reported in 18 patients (10.1%) in the reparixin group (22 TEAEs) and in 12 (13.6%) 
in the placebo (15 TEAEs) and were related to treatment in 1 patient (1.1%) in the placebo group (1 TEAE). 
Eighteen TEAEs leading to discontinuation of the Investigational Medicinal Product (IMP) were reported in 
15 patients (8.4%) in the reparixin group and 12 TEAEs leading to discontinuation of IMP were reported in 
11 patients (12.5%) in the placebo group. One patient (0.6%) in the reparixin group discontinued the study 
due to a TEAE. Thirteen TEAEs leading to death were reported in 11 patients (6.1%) in the reparixin group 
and 9 TEAEs leading to death were reported in 7 patients (8.0%) in the placebo group. 
 
2.6. 
DISEASE REVIEW AND STUDY RATIONALE 
COVID-19 is the disease caused by a new coronavirus called SARS-CoV-2. WHO first learned of this new 
virus on 31 December 2019, following a report of a cluster of cases of “viral pneumonia” in Wuhan, People’s 
Republic of China. The most common symptoms of COVID-19 are fever, dry cough, fatigue. Other 
symptoms that are less common and may affect some patients include loss of taste or smell, nasal congestion, 
conjunctivitis, sore throat, headache, muscle or joint pain, skin rash, nausea or vomiting, diarrhoea, dizziness. 
Symptoms of severe COVID‐19 disease include shortness of breath, loss of appetite, confusion, persistent 
pain or pressure in the chest, high fever above 38 °C8.  
NIH published criteria for Therapeutic Management of Hospitalized Adults With COVID-199. 
Noteworthy, a considerable percentage of COVID-19 cases have rapidly progressed to severe and critical 
type, among which acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the most 
common complications, resulting in a large number of pneumonia hospitalized patients requiring 
supplemental oxygen, mechanical ventilation, or even Extracorporeal membrane oxygenation (ECMO). 
Pulmonary oedema is a detrimental feature as well as a key causal factor of ALI/ARDS.  
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One of the most significant findings in COVID-19 patients who require admission to ICU, as compared to 
less severe patients, is prominent neutrophilia10. Excessive recruitment of neutrophils and their release of 
neutrophil extracellular traps (NETs) can aggravate tissue injury in several disease conditions11. In severe 
COVID-19 infection, greater neutrophilia may drive elevated pulmonary influx of neutrophils and stimulate 
excessive NET release, leading to signs and symptoms of ARDS. In keeping with this hypothesis, elevated 
NET breakdown products were found in sera of severely ill COVID-19 patients12. Neutrophil recruitment to 
the lung parenchyma requires chemoattraction. In patients with severe clinical course of COVID-19 infection, 
statistically significantly higher levels of IL-8 were detected as compared to non-severe patients13. Binding 
of IL-8 to its receptors on neutrophils mediates recruitment, activation and NET release. Two CXC 
chemokines 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 CXC chemokines (GRO-α, GRO-β, 
GRO-γ, CXCL1, CXCL2, CXCL3), ENA-78 (CXCL5) and CXCL714. Thus, inhibition of IL-8 receptors 
(CXCR1 and CXCR2) is being pursued as a therapeutic strategy for severe COVID-19 infections.  
To a similar extent, there is a strong rationale to reduce the inflammatory response in all infectious 
pneumonia, as a dysregulation inflammatory response may contribute to morbidity and mortality in CAP.23  
Pathogenic organisms other than SARS-CoV-2 may similarly contribute to pneumonia pathogenesis and 
progression, as neutrophils play a significant role in its development and progression. IL-8 primarily mediates 
neutrophil activation, migration, and NETosis. A dysregulated IL-8 axis may trigger a prothrombotic 
neutrophil phenotype, excessive degranulation, NET formation, cytotoxic effect, microvascular occlusion, 
and fibrosis.20 Indeed, in some patients, the initial systemic inflammatory response can become dysregulated, 
leading to tissue injury and organ dysfunction which may result in clinical manifestations such as acute 
respiratory distress syndrome (ARDS), sepsis, and multiple organ dysfunction syndrome.21 Nonetheless, 
available trails have been mainly focused on glucocorticoids, and constitute insufficient evidence to 
recommend their routine use in CAP (ATS/IDSA guidelines).22 This critical unmet clinical need may 
represent a key benefit of reparixin in patients suffering from an acute lung infection, which still constitutes 
a leading cause of morbidity and mortality worldwide. Thus, inhibition of IL-8 receptors (CXCR1 and 
CXCR2) is being pursued as a therapeutic strategy for CAP. 
Since the beginning of 2021, when vaccination plan started, the in-hospital fatality rate in Europe has declined 
over the pandemic, mainly due to improvement in clinical knowledge, patient management, and treatments15-
16. Changes in respiratory support and steroids have played a crucial role, accounting for 22.2% in-hospital 
mortality risk reduction (OR 0.95 [95%CI 0.94–0.95], p<0·0001)17. However, there are still limited approved 
and adequate medications to prevent disease progression. The healthcare resource allocation for respiratory 
failure, IMV and ICU is still challenged in some geographic areas, and the low vaccination rate in some EU 
countries and the uncertainty on SARS-Cov-2 variants spread still represent a high level of risk for pandemic 
management. Interventions for reducing respiratory failure, the need for IMV and access to ICU would 
significantly improve patients’ care and healthcare resource allocation. To a similar extent, community-
acquired pneumonia (CAP), including all acute pneumonia acquired outside the hospital, still represents a 
leading cause of morbidity and mortality worldwide. Despite advancements in clinical and therapeutic 
management, CAP is the second most common cause of hospitalization and the most common infectious 
cause of death, representing a pressing unmet clinical need.23 
In preclinical studies, CXCR1/2 inhibition improves disease outcomes during respiratory influenza and 
pneumococcal infections, two primary pathogens of CAP.24 Of foremost importance, the ability of the murine 
host to deal with the infection was not impaired.24  Clinical data obtained in the compassionate use, as well 
as in the phase II and III trials in COVID-19 patients support the potential clinical efficacy of reparixin in 
limiting the progression of the disease in patients with established COVID-19. These findings, coupled with 
the safety shown in phase I to III clinical trials, provide strong rationale supporting further testing of reparixin 
in CAP including COVID-19, and the conduct of this new phase III clinical study.  
The comparable pathophysiologic mechanism of acute lung infection, the preclinical data on reparixin in 
infectious diseases, the continuity of target populations and the prominent clinical needs support the extension 
of the current disease target to a broader umbrella of acute infection of the pulmonary parenchyma acquired 
outside of the hospital, including COVID-19 among the CAP infections. 
 

St u d y R E P 0 3 2 1  
Re p arixi n i n C O VI D-1 9  a n d ot her C A P ( R E P A VI D -2 2 ) 
Pa ge 2 4  of  6 7  
 
 
 
Pr ot o c ol Versi o n/ Date: v 2. 0  –  Fi nal  2 0 J u n 2 0 2 2  
 
 
 
 
 
 
2. 6 . 1. Alter n ati ve tre at me nts  
T here are p har mac ol o gic treat me nts a p pr o ve d f or  C O VI D -1 9  a n d ot her i nfecti o us p ne u m o nia , ot her t ha n 
s u p p orti ve a n d i n vasi ve care ma na ge me nt . T he c urre nt trial will n ot i nterfere wit h t he us ual ma na ge me nt of 
t he patie nts, as re pari xi n/ place b o will be use d as a n a d d-o n t hera p y . T he e val uati o n, t he assess me nt , a n d 
ma na ge me nt of t he patie nts (s uc h as decisi o ns o n a nti -i nfecti ve me dicati o ns, a dj u ncti ve t hera p y, s u p p orti ve 
t hera p y, a n d site a n d le vel of care) will n ot be deter mi ne d or i nfl ue nce d b y st u d y pr oce d ures,  a n d will be 
e ntirel y u n der t he c o ntr ol of t he tre ati n g p h ysicia ns as all patie nts, re gar dless of gr o u p all ocati o n or st u d y 
partici pati o n, will recei ve t he sta n dar d of o pti mal care.   
 
 
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 s u p p ort 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 was c o nfir me d i n t he p hase II trial 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 nts.  As i m m u n o m o d ulat o r, t here is p ossi ble ris k of hi g her sec o n dar y i nfecti o n. 
N o net heless, rece nt cli nical a n d precli nical data s u g gest t hat re pari xi n d o n ot i ncrease t he ris k of sec o n dar y 
i nfecti o n. M ore o ver, t o mi ni mize t he ris k i n C A P, patie nts wit h f u n gal i nfecti o ns a n d i m m u n os u p press i o n 
will n ot be i ncl u de d i n t he trial . 
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 i ncl u de la b orator y tests a n d dail y cli nical 
o bser vati o ns.  
E ve n if re pari xi n i n vitr o 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), it 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 
as re ve ale 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 ( Re pari xi n I n vesti gat or’s Br oc h ur e, 2 0 2 1).  
 
2. 6. 2. 2.  Bl o o d sa m pli n g  
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 (a b o ut 
 m L) will be o btai ne d t o e val uate hae mat ol o g y a n d cli nical c he mistr y ( Safet y 
La b orat or y Tests , baseli ne, da y 3, 7 ± 1, 1 4 ± 2, 2 1 ± 2, 2 8 ± 2 or h os pital disc har ge ) 
•  
bl o o d sa m ples f or i nfla m mat or y mar kers (a b o ut 
 m L)  will be ta ke n baseli ne, da y 3, 7 ± 1, 1 4 ± 2, 
2 1 ± 2, 2 8 ± 2 or h os pital disc har ge  
•  
i n selecte d ce nters, bl o o d sa m ples f or c yt o ki nes  (a b o ut 
 m L) at baseli ne a n d at t he e n d of treat me nt, 
a n d P K  
  
T hese sa m pl i n gs mi g ht be at ris k of 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 he mat o ma, i nfecti o n, a rterial sa m pli n g. 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. Als o, m ult i ple p u nct ures mi g ht be re q uire d t o 
i de ntif y t he vei ns.  
F or t he arterial bl o o d gas ( A B G ) a nal ysis , a s mall s yri n ge a n d s mall nee dle (t o pic 1 % li d ocai ne, if a vaila ble) 
will be utilize d t o wit h dra w at least 1-2 m L  of bl o o d  fr o m a n arter y ( prefera bl y ra dial).   
Ti me of IM P  a d mi nistrati o n a n d act ual sa m pli n g ti mes f or eac h patie nt will be rec or de d i n t he i n di vi d ual 
e C R F.  
 
2. 6. 2. 3.  P ote ntial be nefit  
T he rati o nale f or treati n g patie nts wit h C A P  i ncl u di n g C O VI D-1 9  is t o re d uce t he i nfla m mat or y res p o nse t o 
p ne u m o nia, w hic h ma y c o ntri b ute t o its m or bi dit y a n d m ortalit y. N o net heless, a vaila ble trails i n C A P ha ve 
C CI
C
CI
C
CI
C
CI

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been mainly focused on glucocorticoids, and constitute insufficient evidence to recommend their routine use 
(ATS/IDSA guidelines). This critical unmet clinical need may represent a key benefit of reparixin in patients 
suffering from an acute lung infection, which still constitutes a leading cause of morbidity and mortality 
worldwide.  
In summary, given the cumulative knowledge for the safety profile of reparixin in patients with COVID-19, 
and the significant unmet need for a treatment to prevent the progression in lung infections, the benefit/risk 
balance for this study is assessed to be favourable. 
 
To the patients: half of the patients will be assigned to the placebo arm and will therefore obtain no benefit. 
Patients receiving reparixin treatment may possibly benefit, but this is to be ascertained.  
To society: This study may identify a useful medication that may help limiting disease progression in severe 
COVID-19 and CAP adult patients. 
 
2.6.3. Description of the Investigational Products 
In this study the IMP will be either reparixin 600 mg oral tablet or matched placebo. The proposed dose in 
this clinical study is 1200 mg oral reparixin TID for up to 21 days. Placebo will be administered with the 
same schedule. 
The oral route and the dose regimen have been selected based on the clinical data from previous clinical study 
in the same COVID-19 population.  
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 and the dose regimen proposed for this study, a 
treatment schedule already used for the previous phase II and phase III trials in COVID-19 adult patients.  
 

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3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN  
3.1. 
STUDY OBJECTIVES 
The primary objective of this trial is to evaluate the efficacy of oral reparixin plus standard of care versus 
placebo plus standard of care in limiting disease progression in adult patients hospitalized for infectious 
pneumonia acquired in the community (CAP), including severe COVID-19.  
The effect of reparixin on recovery, ventilatory free days and mortality will be addressed.  
The safety of oral reparixin versus placebo in the specific clinical setting will be evaluated. 
 
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 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 a multinational, multicentre, randomized, double-blind, placebo-controlled, parallel-group, 
phase III trial. 
It will enrol approximately 526 adult patients hospitalized for CAP (including severe COVID-19) that meet 
the entry criteria (sections 4.1 and 4.2), randomly assigned at 1:1 ratio to receive either oral reparixin 1200 
mg (treatment group) or matched placebo (control group) TID for up to 21 days. All patients must receive 
standard and supportive care according to their clinical status and local guidelines during the whole study 
period.  
Each patient will be involved in the study for up to 180 days. This period consists of informed consent 
acquisition and screening, randomization and baseline assessments, and a post-randomization study period 
of up to 28 days from the first IMP dose (or hospital discharge). Subjects will be assessed daily while 
hospitalized up to 28 days from first IMP administration (or hospital discharge). Detailed evaluations and 
their timing are presented in sections 2 and section 6.1. Follow-up information on the patient’s clinical 
condition and survival will be collected until day 180, regardless of hospitalization.  
An interim analysis for efficacy and futility is planned when half of the planned patients is evaluable for the 
primary endpoint. The end of this study is defined as the date of the last patient’s last visit.  
 
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. 

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A double-blind, randomized study design is being adopted as the gold standard to minimize systematic bias 
and increase baseline comparability between treatment groups. So, the study will include a control group 
receiving a placebo. Despite significant unmet needs for the selected study population, the standard and 
supportive care in severe COVID-19 includes dose corticosteroids and, depending on local guidelines, 
additional immunomodulators or anti-viral agents. The use of corticosteroids in other form of CAP, although 
less recognized, will not be prohibited and it will be decided by the treating physicians. Thus, in this rapidly 
evolving scenario, this study should involve patients treated with the current standard care plus placebo. 
 
3.4. 
STUDY TIME-TABLE.  
Overall planned study timelines are reported below 
Study period         First Patient First Visit: April 4, 2022 
 
Last Patient First Visit: Sep 2023 
  
 
Last Patient Last Visit: March2024 
Detailed assessments and schedule are presented in sections 2 and section 6.1. 

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4. 
SELECTION OF STUDY POPULATION 
Number of patients: approximately 526 adult patients hospitalized for suspected CAP (including established 
COVID-19) will be enrolled to target 500 evaluable patients. A patient is considered enrolled if, after 
signature of consent and screening, (s)he provides 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 fulfil the following inclusion criteria: 
1. 
Informed consent signed  
2. 
Male and female ≥18 years old; 
3. 
Patients hospitalized for clinically suspected CAP, defined as the occurrence of (within 48h from 
hospital admission): 
a. at least 1 of the following signs/symptoms: dyspnea, cough, purulent sputum, crackles 
(rales) and/or rhonchi 
b. body temperature > 38°C or <36°C (before or during admission) or leucocytosis (> local 
ULN) 
c. new/increased pulmonary infiltrate(s) by chest imaging  
4. 
Need for non-invasive supplemental oxygen (NIAID-OS 5-6; Appendix 14.4.1); 
5. 
SpO2 <92% at room air, or PaO2/FiO2 (or SpO2/FiO2) <300; 
6. 
Females of child-bearing potential and with an active sexual life must not wish to get pregnant within 
30 days after the end of the study and must be using at least one of the following reliable methods 
of contraception: 
a. Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives for at 
least 2 months before the screening visit until 30 days after the last IMP dose 
b. A non-hormonal intrauterine device [IUD] or female condom with spermicide or contraceptive 
sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 
months before the screening visit until 30 days after the last IMP dose 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. A sterile sexual partner  
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. 
 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria are NOT eligible for inclusion in the study: 
1. 
Treatment with IMV or ECMO (NIAID-OS 7); 
2. 
Hepatic dysfunction: ALT or AST > 5 ULN; history of chronic hepatic disease (defined with Child-
Pugh score B or C); 
3. 
Renal dysfunction: estimated glomerular filtration rate (eGFR, MDRD) <50 mL/min/1.73 m2, or 
need for haemodialysis or hemofiltration; 
4. 
Current use of >2 immunosuppressive medications or immunosuppression status (AIDS, aplastic 
anaemia, asplenia, systemic chemotherapy within the past 3 months, neutropenia (ANC < local 
LLN), solid organ or bone marrow transplant recipients) 
5. 
Treatment with prohibited medication within 5 half-lives, and inability to stop during treatment 
period (see section 5.5.2); 
6. 
Anticipated discharge from the hospital or transfer to another hospital within 72 hours of screening 
7. 
History of:  
a. intolerance or hypersensitivity to ibuprofen to more than one medication belonging to the class of 
sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib 
(hypersensitivity to sulphanilamide antibiotics alone, e.g. sulfamethoxazole does not qualify for 
exclusion) 
b. lactase deficiency, galactosemia or glucose-galactose malabsorption 

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c. gastrointestinal bleeding or perforation due to previous NSAIDs therapy or recurrent peptic 
ulcer/haemorrhage 
d. allergy to reparixin or any component of the IMP formulation 
8. 
Active bleeding or bleeding diathesis (excluding menses), prior intracranial haemorrhage 
9. 
Participation in other interventional clinical trials 
10. Clinical condition not compatible with oral administration of the study drug 
11. Pregnancy: 
a) positive or missing pregnancy test before first drug intake or day 1; 
b) pregnant or lactating women; 
Women of childbearing potential and fertile men who do not agree to use at least one primary form of 
contraception for the duration of the study 
12. Current hospital stay >72h  
13. Complicated CAP-associated conditions, such as fungal pulmonary infection, tuberculosis infection, 
abscess, empyema, significant bilateral pleural effusion, massive pulmonary embolism 
 
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 numbers 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. 

St u d y R E P 0 3 2 1  
Re p arixi n i n C O VI D-1 9  a n d ot her C A P ( R E P A VI D -2 2 ) 
Pa ge 3 0  of  6 7  
 
 
 
Pr ot o c ol Versi o n/ Date: v 2. 0  –  Fi nal  2 0 J u n 2 0 2 2  
 
 
 
 
 
 
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 NA 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 O R 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 f or oral a d mi nistrati 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 f or e ac h u nit re p ari xi n (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 
 
 
 
I n-h o use s pecificati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.  
Batc h release certificate  will be pr o vi de d t o get her wit h t he I M P.  
 
5 . 1. 2. M a n uf act uri n g, P ac k a gi n g a n d L a belli 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 
 S ec o n dar y 
pac ka gi n g a n d la belli n g will be  perf or me d b y
 or  alter nati vel y, mi g ht be 
perf or me d 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 
 wit h 
 ta blets eac h, f or a t otal 
of 
 ta blets, a n  a m o u nt sli g htl y i n e xcess of t hat re q uire d f or a wee k treat me nt c o urse ( 4 2 ta blets).  
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 belli n g are 
re p orte d i n A p pe n di x 1 4. 3 . 
 
5 . 1. 3. S u p pl y, St or a ge a n d H a n dli n g of I M P 
A n a p pr o priate n u m ber of pac ka ges will be i nitiall y se nt t o t he site as s o o n as all esse ntial d oc u me nts a n d 
re g ulat or y/et hics a p pr o vals ha ve bee n o btai ne d. I M P re-s u p pl y will be pla n ne d o n de ma n d, acc or di n g t o 
e nr ol me nt rate.  
T he I M P m ust be ke pt at a te m perat ure n ot e xcee di n g 3 0° C a n d m ust n ot be fr oze n .  
A te m perat ure pr o be will acc o m pa n y t he dr u g o n s hi p me nt. Te m perat ure ra n ge reac he d d uri n g s hi p me nt will 
be verifie d o n recei pt at site, s o t hat p ote ntial sta bilit y c o ncer ns d uri n g s hi p me nt ca n be i n vesti gate d a n d 
a p pr o priate acti o n ta ke n.  
O nce recei ve d at t he site, t he P har macist ( or desi g nee) will c hec k t he pac ka ge f or acc urate deli ver y a n d 
ac k n o wle d ge recei pt; a n y de viati o ns fr o m e x pecte d pac ka ge c o nte nt (i nc o nsiste nc y, da ma ges) s h o ul d be 
i m me diatel y re p orte d t o D o m pé ( or a p p oi nte d C R O) a n d t he use of t he dr u g s us pe n de d u ntil a ut h orizati o n 
f or its c o nti n ue d use has bee n gi ve n b y D o m pé ( or a p p oi nte d C R O).   
T he I M P m ust be st ore d at site i n a sec ure l ocati o n, i n a te m perat ure -c o ntr olle d r o o m. Te m perat ure rec or ds 
m ust be a vaila ble f or t he cli nical researc h a ss ociate (C R A ) t o re vie w at m o nit ori n g visits; a n y de viati o ns 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C
CI
C
CI

St u d y R E P 0 3 2 1  
Re p arixi n i n C O VI D-1 9  a n d ot her C A P ( R E P A VI D -2 2 ) 
Pa ge 3 1  of  6 7  
 
 
 
Pr ot o c ol Versi o n/ Date: v 2. 0  –  Fi nal  2 0 J u n 2 0 2 2  
 
 
 
 
 
 
fr o m t he rec o m me n de d st ora ge c o n diti o ns s h o ul d be i m me diatel y re p orte d t o D o m pé ( or a p p oi nte d C R O) 
a n d t he use of t he dr u g s us pe n de d u ntil a ut h orizati o n f or its c o nti n ue d use has bee n gi ve n b y D o m pé ( or 
a p p oi nte d C R O).  
 
5 . 1. 4. Bl i n di n g 
A p peara nce, i ncl u di n g pac ka gi n g a n d la belli n g, of t he I M P will n ot all o w t o rec o g nize act ual treat me nt 
(eit her re pari xi n or place b o).  
F or eac h ra n d o mize d s u bject, i n di vi d ual c o de brea ks will be accessi ble i n t he e ve nt of a me dical e mer ge nc y 
re q uiri n g k n o wle d ge of t he treat me nt assi g ne d t o t he s u bject. O nl y t he res p o nsi ble i n vesti gat or, or a ut h orize d 
dele gates, ca n brea k t he c o de via t he I nteracti ve Res p o nse Tec h n ol o g y (I R T). 
I n vesti gat ors will be all o we d t o u n bli n d st u d y me dicati o n directl y t hr o u g h t he I R T s yste m; a n y e mer ge nc y 
u n bli n di n g  m ust be n otif ie d t o t he C R O’s me dical m o nit or. Trai ni n g is pr o vi de d t o i n vesti gat ors pri or t o 
a ut h orizati o n t o use t he I R T s yste m a n d t he u n bli n di n g f u ncti o n is o utli ne d i n t he st u d y s pecific user g ui de.  
T he s p o ns or’s pers o n nel fr o m t he P har mac o vi gila nce De part me nt of D o m p é ma y brea k t he treat me nt c o de 
f or s u bjects w h o e x perie nce a S us pecte d U ne x pecte d Seri o us A d verse Reacti o n ( S U S A R), i n or der t o 
deter mi ne if t he i n di vi d ual case re q uires e x pe dite d re g ulat or y re p orti n g.  
Wit h t he e xce pti o n of t he a b o ve -me nti o ne d e pis o des, t he  i de ntit y of t he treat me nts will re mai n u n k n o w n t o 
t he s u bject, I n vesti gat or, site staff, C R O a n d D o m pé’s pers o n nel u ntil t he st u d y c o m pleti o n a n d f or mal 
u n mas ki n g.  O nl y t he D M C  will ha ve access t o gr o u p -u n bli n de d a n d/ or f ull y u n bli n de d D M C re p orts.  
F or a n al ysis p ur p oses, t he ra n d o mizati o n c o des will be br o ke n w he n t he last e nr olle d patie nt has c o m plete d 
t hera p y, a n d o nce t he data base has bee n l oc ke d. 
 
5 .2 . 
D O S E, R O U T E A N D S C H E D U L E  O F I M P A D MI NI S T R A TI O N  
Re pari xi n  will be a d mi nistere d orall y at t he d ose of 1 2 0 0  m g ( 2 x 6 0 0 m g ta blets) TI D ( 6 ta blets dail y) f or 
u p t o 2 1 da ys. Place b o will be a d mi nistere d wit h t he sa me treat me nt sc he d ule.  
T he t hree dail y d oses will be a d mi nistere d mai ntai ni n g a n i nter val bet wee n d os es of a b o ut 
. It is 
a d visa ble t o ta ke t he 2  ta blets wit h a glass of water t o facilitate s wall o wi n g.   
I M P ca n be ta ke n wit h a glass of water (a b o ut 2 5 0 m L) a n d a li g ht meal or s nac k, as it is prefera ble t hat 
re pari xi n is ta ke n wit h f o o d. H o we ver, if t he patie nt is u na ble t o eat, t he st u d y dr u g ma y still be a d mi nistere d 
wit h o ut c o nc o mita nt f o o d i n gesti o n.  
 
F or patie nts w h o are u n willi n g or u na ble, i n t he o pi ni o n of t he i n vesti gat or, t o c o m pl y wit h t he oral ta blet 
treat me nt, is p ossi ble t o c o nti n ue t he re g ular a d mi nistrati o n of t he st u d y dr u g b y a d mi nisteri n g t he me dici ne 
t hr o u g h a nas o-gastric t u be, f oll o wi n g t his pr oce d ure: f or eac h a d mi nistrati o n, dis perse t w o re pari xi n 6 0 0 m g 
ta blets i n 2 5 m L of dri n ki n g water i n a s uita ble c o ntai ner (e. g. c o nical t u bes f or 5 0 m L Falc o n ce ntrif u ge). 
Dis gre gate t he ta blets (s ha ki n g ma n uall y or wit h t he ai d of a pla netar y s ha ker or a r oc ker) u ntil o btai ni n g a 
h o m o ge ne o us mil k y s us pe nsi o n (ti me re q uire d 7 - 1 0 mi n utes). Kee p t he pre pare d s us pe nsi o n at r o o m 
te m perat ure a n d pr otecte d fr o m li g ht f or u p t o 2 4 h o urs. I m me diatel y bef ore a d mi nistrati o n, ma n uall y s ha ke 
t he s us pe nsi o n a gai n u ntil c o m plete a n d h o m o ge ne o us res us pe nsi o n, wit h dra w usi n g a 5 0 m L nee dle-free 
s yri n ge a n d a d mi nister t o t he patie nt usi n g a nas o -gastric t u be. After a d mi nistrati o n, r u n 2 5 m L  of dri n ki n g 
water t hr o u g h t he gastric t u be.  
 
5 .3 . 
C RI T E RI A F O R S C H E D U L E A D J U S T M E N T/ D O S E -M O DI FI C A TI O N O R 
DI S C O N TI N U A TI O N O F T H E I M P 
5 .3 . 1. Criteri a f or sc he d ule a dj ust me nt/ d ose -m o dific ati o n   
N o sc he d ule a dj ust me nt a n d/ or d ose m o dificati o n is f oresee n, e xce pt f or disc o nti n uati o n of I M P as detaile d 
bel o w.  
C CI

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5.3.2. Criteria for discontinuation of the IMP  
The IMP must be discontinued in the case: 
➢ The patient develops renal (eGFR < 50 mL/min) or hepatic (increased ALT/AST > 5 x ULN) 
dysfunction;  
➢ The patient is discharged from the hospital ; 
➢ The patient develops clinical condition not compatible with oral administration of the study drug, or  
IMV/ECMO; 
➢ Pregnancy occurs 
➢ Any medical condition may threaten the safety of the patient if they continue to receive study 
treatment (as per investigator or Sponsor evaluation)  
➢ Initiation of a prohibited medication (paragraph 5.5.2) 
➢ CAP diagnosis ruled out, and/or any complicated CAP-associated conditions such as fungal 
pulmonary infection, abscess, tuberculosis infection, empyema, significant bilateral pleural effusion, 
massive pulmonary embolism (as in exclusion criterion n13) 
Occurrence of renal or hepatic disfunction will be specifically monitored through safety laboratory tests 
obtained at day 3, 7±1, 14±2, 21±2 during treatment, and at 28±2 or hospital discharge. The other criteria 
that qualify the patient to treatment discontinuation will be monitored daily. 
In addition, the IMP will be immediately discontinued in the event of any other possibly drug related 
occurrences that the study physician believes might compromise patient’s safety.   
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 but will be asked to complete safety and efficacy observations as per the protocol, unless 
otherwise they withdraw their consent. 
 
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 centre.   
When the IMP is received at the site, designated member of site staff 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 for 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 

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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 monitoring personnel of the study during on-site monitoring visits, as 
per records in the specific study eCRF and actual tables remaining in the Patient Kits. Compliance, calculated 
on the TID regimen, will be assessed based on the actual duration of treatment (up to 21 days).  
 
5.5. 
PRIOR AND CONCOMITANT MEDICATION 
5.5.1. Reporting of prior and concomitant medication  
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 Day 28 / end of study 
visit. All such medications will be reported in the appropriate section of the eCRF. Anticoagulants, as per 
local standard dose, are recommended for all the patients without major contraindications. 
All the details as per the eCRF fields (sequential number, drug name, indication, starting dose, start/stop date, 
route of administration) will be recorded. Change in dose will be tracked. 
 
5.5.2 
Prohibited medications  
Not allowed medications (either at screening or introduced during the trial) include concomitant drugs for 
which a significant drug-drug interaction leading to metabolic alterations is suspected based on the respective 
metabolic pathways. Reparixin is catalysed by CYP2C9 and to a lesser extent by CYP2C19. Reparixin has 
some potential in-vitro for a non-competitive inhibition of the human hepatic enzyme CYP3A4. However, at 
the present time, clinically significant untoward pharmacological interactions are not known for reparixin. 
Patients should remain under close observation during the days of administration of drugs with similar 
metabolic pathway if given concomitantly with reparixin.  
The following medications should not be used from within 5 half-lives from screening to day 28:  
1) Treatment with any not authorized investigational agent (except for off-label use of anti-COVID-19 agents, 
with approval of Medical Monitor) 
2) T cell or B cell-targeted therapies, interferon, or convalescent plasma 
3) CYP2C9 inducers (rifampin, carbamezapine, aprepitant, bosentan, phenobarbital, St. John’s Wort) or 
CYP2C9 inhibitors (amiodarone, fluconazole, miconazole, oxandrolone, capecitabine, cotrimoxazole, 
etravirine, fluvastatin, fluvoxamine, metronidazole, sulfinpyrazone, tigecycline, voriconazole, zafirlukast). 
 
 

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6. 
STUDY PROCEDURE AND ASSESSMENT 
During the course of the study, visits and 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 three study periods: screening, treatment (up to 21 days), and follow-up (up to 180 
days). Potential participants will be identified from those hospitalized at the participating clinical sites to 
manage CAP including COVID-19. 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 
Written 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:  
• 
collection of demographic data, past medical history, disease-specific clinical information, and 
previous medications 
• 
evaluation of NIAID-OS 
• 
review of available chest imaging  
• 
measurement of SpO2, PaO2, and FiO2 (if ABG is not readily available, SpO2 can be used to 
estimate PaO2, see appendix 14.4.6);  
• 
pregnancy test (urine dipstick), in women of childbearing potential. Positive urine test results will be 
confirmed with a serum pregnancy test; 
• 
blood sampling for measurement of hematology/biochemistry and derived renal and hepatic function 
(Safety Laboratory Tests), , if not already performed during current hospitalization.; 
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, the subject may be rescreened once (immediately or later) if deemed 
appropriate by the investigator. In that case, the subject must be re-consented. A new rescreening period will 
start, and all screening procedures must be repeated. 
 
6.1.2 Randomization and Baseline (Day 1) assessment 
Patients meeting all inclusion and none of the exclusion criteria will be enrolled (eligibility confirmed) and 
randomized (see sections 4.1 and 4.2). No time limit has been posed for the time from the onset of symptoms 
and hospitalization. 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 randomisation 
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 Interactive 
Response Technology (IRT). Investigators will have to remain blind throughout the whole study duration. 
Information for unblinding is provided in section 5.1. 
The following additional baseline assessments, to be completed within 24 hours from screening, should be 
performed before the first administration of the study drug (Day 1):  
• 
12-lead ECG performed using local equipment 
• 
systolic/diastolic Blood Pressure (BP), Heart Rate (HR), Respiratory Rate (RR), body temperature, 
level of consciousness (A, V, P, U), SpO2, and use of supplemental oxygen (utilized as physiological 
parameters using NEWS and vital signs)  
• 
RT-PCR for SARS-CoV-2 from the respiratory tract (if not already performed during the current 
hospitalization) 
• 
Clinical severity score (NIAID-OS) and Pneumonia Severity Index (PSI) 

St u d y R E P 0 3 2 1  
Re p arixi n i n C O VI D-1 9  a n d ot her C A P ( R E P A VI D -2 2 ) 
Pa ge 3 5  of  6 7  
 
 
 
Pr ot o c ol Versi o n/ Date: v 2. 0  –  Fi nal  2 0 J u n 2 0 2 2  
 
 
 
 
 
 
o  If n ot alrea d y a vaila ble, bl o o d urea nitr o ge n s h o ul d be meas ure d t o calc ulate P SI. I n case 
t he la b orat or y res ults are n ot rea dil y a vaila ble, P SI ca n be calc ulate d  later o n (o nce all 
la b orat or y res ults are a vaila ble ) t o d o n ot st o p recr uit me nt  
•  
bl o o d sa m pli n g f or meas ure me nt of i nfla m mat or y mar kers (lactate de h y dr o ge nase ( L D H), C -
reacti ve pr otei n ( C R P), ferriti n, D-di mer, pr ocalcit o ni n ( P C T))  
•  
bl o o d sa m pli n g f or meas ure me nt of c yt o ki nes   
 
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 2 8  ( or disc h ar ge) 
NI AI D -O S, N E W S a n d c o nc o mita nt me dicati o ns will be e val uate d dail y u p t o da y 2 8  (or disc har ge ).  
T he f oll o wi n g meas ure me nts/assess me nts will be perf or me d at da y 3, 7 ± 1, 1 4 ± 2, 2 1 ± 2, 2 8 ± 2 (or h os pital 
disc har ge):  
•  
Pa O 2 a n d Fi O 2  (if A B G is n ot rea dil y a vaila ble, S p O 2 ca n be  c ollecte d a n d  use d t o esti mate Pa O 2, 
see a p pe n di x 1 4. 4. 6);  
•  
bl o o d sa m pli n g f or Safet y La b orat or y Tests;  
•  
bl o o d sa m pli n g f or meas ure me nt of i nfla m mat or y mar kers: L D H, C R P, ferriti n, D -di mer, P C T  
•  
vital si g ns  (ca n be deri ve d b y N E W S ) 
At t he e n d of treat me nt, t he f oll o wi n g meas ure me nts/assess me nts will be perf or me d:  
•  
Bl o o d sa m pli n g f or meas ure me nt of i nfla m mat or y mar kers a n d c yt o ki nes  
•  
E C G  
•  
Pre g na nc y test   
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:  d urati o n of I M V a n d/ or E C M O, I C U 
a d missi o n a n d I C U le n gt h of sta y, h os pital disc har ge a n d h os pital le n gt h of sta y . At disc har ge,  eti ol o gic 
a ge nts (if i de ntifie d), a n d E Q -5 D -5 L  q uesti o n naire will be c ollecte d/ perf or me d.  
 
 
 
I n selecte d ce ntres, ser u m sa m ples f or P K a nal ysis will be o btai ne d 
. 
I n case of treat me nt ter mi nati o n will occ ur < 2 1  d a ys (Secti o n 5. 3. 2 ), patie nt will u n der g o t he assess me nt 
pla n ne d as per da y 2 1.  
If h os pital disc har ge will occ ur bef ore da y 2 8, i n -pers o n visits will be pla n ne d at da y 1 4 ± 2 a n d 2 8 ± 2 
(de pe n di n g o n t he disc har ge ti me p oi nt ), as t he preferre d m o dalit y t o o btai n b ot h safet y la b orat or y tests a n d 
cli nical data ( N E W S a n d NI AI D -O S). H o we ver, restricti o ns d uri n g t he pa n de mic ma y li mit o ut patie nt 
visits d ue t o h os pital restricti o ns a n d tra vel li mitati o ns. If s o, p h o ne visit will be perf or me d als o at da y 1 4 ± 2 
a n d 2 8 ± 2 t o assess NI AI D -O S o nl y.  
 
6. 1. 4 9 0 -d a y  a n d  1 8 0 -d  f oll o w-u p  
After disc har ge fr o m h os pital, s u bjects will be c o ntacte d f or a f oll o w -u p c hec k o n t heir healt h stat us at Da y 
9 0  a n d da y 1 8 0 b y i nter vie w via a tele p h o ne call  ( or ot her telec o m m u nicati o n net w or ks), u nless t he patie nt 
als o wit h dra ws t he c o nse nt t o t he f oll o w-u p.  I n s o me cases, healt h re gistr y ma y be als o use d. 
T he f oll o wi n g meas ure me nts/assess me nts will be perf or me d b y p h o ne  at da y 9 0 ± 7  a n d 1 8 0 ± 1 4 da ys : 
•  
E Q -5 D -5 L  q uesti o n naire  
•  
re-h os pitalizati o n, all -ca use m ortalit y . If re-h os pitalizati o n , d urati o n of I M V a n d/ or E C M O, I C U 
a d missi o n a n d I C U le n gt h of sta y, h os pital disc har ge a n d h os pital le n gt h of sta y  
•  
Occ urre nce of a n y A E or S A E  
E n d of St u d y ( E o S) partici pati o n is defi ne d as t he last da y w he n a patie nt c o m pletes t he last st u d y assess me nt 
(i ncl u di n g t he f oll o w-u p assess me nts), or wit h dra ws t he c o nse nt t o partici pate i n t he st u d y. S u bjects wit h E o S 
bef ore Da y 2 8 s h o ul d u n der g o a f ull e val uati o n as re q uire d o n Da y 2 8. S u bjects wit h E o S after Da y 2 8 b ut 
earlier t ha n Da y 9 0  s h o ul d u n der g o e val uati o n as re q uire d o n Da y 9 0  
 
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6.2. 
EARLY PATIENT WITHDRAWAL 
6.2.1. Withdrawal criteria 
Patients will be informed that they have the right to withdraw from the study at any time (withdrawal of 
consent), without prejudice to their medical care, and are not obliged to state their reasons.   
The primary, actual, reason of withdrawal should be recorded, especially if there is suspect of withdrawal 
due to adverse events (“withdrawal of consent” is a definition to be used if the patient does not give reasons). 
Safety laboratory tests should be performed whenever possible at patient withdrawal.  
Patients who discontinue the treatment with the IMP (Section 5.3.2) will not be withdrawn from the study 
but will be asked to complete observations as per the protocol, unless otherwise they withdraw their consent. 
It is important that any randomized patient remains in the study and is followed for both efficacy and safety 
outcomes, regardless he/she has completed or discontinued the study treatment.  
Investigators will be trained about the importance of patient retention through the duration of the trial. 
In case of pregnancy, the patient will be withdrawn from the study, but she will be monitored for safety and 
pregnancy outcomes, unless she withdraws her consent. 
Any withdrawals must be fully documented in the eCRF. 
 
6.2.2. Replacement procedures 
There are no plans to replace discontinued subjects. 
 
6.3. 
END OF STUDY 
For the purpose of this trial, the End of Study is defined as the date of the last assessment of the last patient. 
 
6.4. 
PATIENT MANAGEMENT AFTER STUDY COMPLETION OR TERMINATION 
After completion of the 180-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  
- 
allergy, with a particular focus on IMP-related allergy/intolerance 
- 
past (no / yes) or current tobacco use (no / yes, < or ≥ 10 cigarettes daily) 
- 
past (no / yes) or current alcohol consumption (no / yes, < or ≥ one litre of wine 
daily, or equivalent)  
- 
recent test for influenza (no / yes, positive / negative) 
- 
vaccination for COVID-19 (no / yes: number of doses) 
- 
vaccination for influenza (no / yes: number of doses) 
- 
date of onset of COVID-19/CAP signs and symptoms 

St u d y R E P 0 3 2 1  
Re p arixi n i n C O VI D-1 9  a n d ot her C A P ( R E P A VI D -2 2 ) 
Pa ge 3 7  of  6 7  
 
 
 
Pr ot o c ol Versi o n/ Date: v 2. 0  –  Fi nal  2 0 J u n 2 0 2 2  
 
 
 
 
 
 
- 
date of h os pital/ E D a d missi o n  
- 
disease s pecific  cli nical i nf or mati o n  (i ncl u di n g ele me nts of i ncl usi o n criteri o n 
3)  
C hest i ma gi n g 
C hest X -ra y/
l u n g U S will be re vie we d 
Fi n di n gs t o be rec or de d ( m ulti ple a ns wers all o we d):  
•  
c o ns oli dati o n 
•  
gr o u n d -glass o pacities  
•  
Air br o nc h o gra ms  
•  
Ple ural a n d I nterl o b ular se ptal t hic ke ni n g  
•  
Ot her  fi n di n g(s): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
NI AI D -O S  
 
 
L a ncet Res pir Me d. 2 0 2 1 Dec; 9( 1 2): 1 4 0 7 – 1 4 1 8  
 
 
P SI  
 
 
N E W S  
N ati o n al E arl y W ar ni n g Sc ore ( N E W S)  
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Royal College of Physicians. National Early Warning Score (NEWS): Standardising 
the assessment of acute-illness severity in the NHS. Report of a working party. 
London: RCP, 2012 
 
Safety 
Laboratory 
Tests 
Hematology  
• 
RBC count (n x106/µL), haematocrit (%), haemoglobin (g/dL) 
• 
WBC count and differential count: neutrophils, eosinophils, basophils, 
monocytes, lymphocytes (n x103/µL) 
• 
platelets 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., nkat/L or U/L)  
• 
creatinine (µmol/L or mg/dL) 
• 
estimated Glomerular Filtration Rate (eGFR; MDRD formula, ml/min/1.73m2) 
GFR (MDRD) = 175 × Serum Cr –1.154 × age–0.203 × (0.742, if female) × (1.212, 
if black) 
• 
INR (units) 
• 
serum glucose (mmol/L or mg/dL); specify if fasting or fed 
• 
sodium (mmol/L or mEq/L), potassium (mmol/L or mEq/L), chloride (mmol/L 
or mEq/L), calcium (mmol/L or mg/dL) 
• 
albumin (mmol/L or g/dL) 
 
(units may change as per local lab standard) 
Inflammatory 
markers 
• 
C-reactive protein (hs-CRP or CRP; nmol/L or mg/L),  
• 
ferritin (nmol/L or ng/mL) 
• 
D-dimer  
• 
LDH (nkat/L or U/L) 
• 
PCT 
Prior and 
Concomitant 
medications  
 
At screening: recording of drug name, indication, total daily dose, dose unit, route, 
start and end dates. 
During study: recording of any change of already recorded, or new concomitant 
medications. 

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Specific anti-COVID-19 and anti-CAP therapy may include anti-infective 
medications, and authorized or off-label medications, such as glucocorticoids, 
baricitinib and JAK inhibitors, remdesivir, tocilizumab, other interleukin inhibitors. 
Vital signs 
- 
systolic / diastolic blood pressure (BP; mmHg);  
- 
heart rate (HR; b/min) 
- 
respiratory rate (RR; n/min) 
- 
BP and HR measurements to be done with an electronic automated device, with 
the patient resting for at least 5 minutes 
Lung function 
- 
peripheral arterial oxygen saturation (SpO2; %) 
- 
arterial partial pressure of oxygen (PaO2; mmHg) 
- 
fraction of inspiration O2 (FiO2; 0.21 to 1) 
- 
PaO2/FiO2 (mmHg), SpO2 may be used in place of FiO2 if ABG not available , 
(see appendix 14.4.6) 
Cytokines  
Panel of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8 (in selected centers) 
Supplemental 
oxygen 
- 
requirement (no / yes) 
- 
if yes, < 6 L/min, 6 - 10 L/min, >10 L/min (daily average)  
- 
Liters per day 
Non-invasive 
supplemental 
oxygen 
- 
low-flow (via e.g. nasal cannula, simple mask, partial rebreathing mask; other) 
- 
high-flow (via e.g. high-flow nasal cannula, HFNC; other) 
- 
non-invasive ventilation (via e.g. non-invasive positive pressure ventilation, 
NIPPV, such as CPAP or BiPAP; other) 
Duration of any non-invasive supplemental oxygen to be recorded (days) 
IMV/ECMO 
- 
endotracheal intubation  
- 
tracheostomy tube 
- 
Extracorporeal Membrane Oxygenation (ECMO) 
Duration of any invasive mechanical ventilation or ECMO to be recorded (days) 
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 (b/min) 
- 
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 
 

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7. 
STUDY ENDPOINTS 
7.1.  
EFFICACY ENDPOINTS 
Primary endpoint: The primary study endpoint is the proportion of patients dead or requiring IMV (or 
ECMO) by day 28. 
 
Key secondary endpoints: 
The following key secondary endpoints will be considered: 
1. All-cause mortality at day 180 
2. Proportion of patients alive and discharged at day 28 
3. Ventilatory-free days (VFD) at  day 28 
o Number of days from Day 0 to Day 28 when the patient will alive and free of invasive 
ventilation. In case of multiple periods of IMV during the first 28 days, the total duration of 
ventilation considered all periods of ventilation during the index admission. Patients who 
will die within 28 days or will be still on invasive ventilation after 28 days will score zero 
VFDs18. 
4. Occurrence of IMV (or ECMO) by day 28 
5. Length of primary hospital stay 
 
Other secondary endpoints: 
In addition, the following secondary endpoints will be assessed: 
- 
Clinical failure by day 3 and day 7 
o Clinical failure will be defined as the occurrence of IMV/ECMO or vasopressor, or death 
- 
28-day ICU-free days 
- 
Days free of IMV/ECMO (number of days with NIAID-OS 1-6) at day 28  
- 
Duration of antibiotic therapy (days) at day 28 
- 
Hospital free days [timeframe: day 28] 
- 
Proportion of patients recovered (downward shift from screening of ≤2 points on the NIAID-OS or live 
discharge from hospital) [timeframe: day 3, 7±1, 14±2, 21±2, 28 ±2 or at hospital discharge] 
- 
Proportion of patients worsening (upward shift from screening of at least >1 point of the NIAID-OS) 
[timeframe: day 3, 7±1, 14±2, 21±2, 28 ±2 or at hospital discharge] 
- 
 PO2/FiO2 [timeframe: day 3, 7±1, 14±2, 21±2, 28 ±2 or at hospital discharge] 
- 
All-cause mortality [day 28, and 90] 
- 
Hospital re-admission by day 90 and 180 
- 
Time to discharge or to a NEWS of ≤ 2 (for 24 hours), whichever occurs first [timeframe: day 28] 
- 
Change in inflammatory markers (LDH, CRP, ferritin; D-dimer, PCT) and cytokines [at day 3, 7±1, 
14±2, 21±2, 28±2 or at hospital discharge]  
- 
Change in quality of life using EQ-5D-5L [90±7 and 180±14 days] 
- 
duration of IMV and/or ECMO at 90 and 180d 
- 
ICU admission and ICU length of stay at 90 and 180d 
- 
hospital length of stay at 90 and 180d 
- 
occurrence of infections at 90 and 180d 
 
 

St u d y R E P 0 3 2 1  
Re p arixi n i n C O VI D-1 9  a n d ot her C A P ( R E P A VI D -2 2 ) 
Pa ge 4 1  of  6 7  
 
 
 
Pr ot o c ol Versi o n/ Date: v 2. 0  –  Fi nal  2 0 J u n 2 0 2 2  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
7. 3.  
S A F E T Y E N D P OI N T S  
- B P a n d H R [ti mefra me:  baseli ne  a n d da y 3, 7 ± 1, 1 4 ± 2, 2 1 ± 2, 2 8 ± 2 or at h os pital disc har ge]  
- Hae mat ol o g y (R B C, hae mat ocrit, hae 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 o c he mistr y ( s o di u m, p otassi u m, c hl ori de, calci u m, gl uc ose, creati ni ne, e G F R 
al b u mi n, A S T, A L T, t otal a n d direct bilir u bi n ) [ Ti mefra me: da y 3, 7 ± 1, 1 4 ± 2, 2 1 ± 2, 2 8 ± 2 or at h os pital 
disc har ge ]; 
- E C G [baseli ne  - e n d of treat me nt]  
- I nci de nce of l u n g bacterial a n d/ or f u n gal i nfecti o ns (t hat d oes n ot a p pear t o be i nc u bati n g at t he ti me 
of i ncl usi o n, c o nfir me d micr o bi ol o gicall y)  b y da y 2 8  
- I nci de nce of T E A E s a n d Treat me nt E mer ge nt Seri o us A d verse E ve nts ( T E S A Es ) [T i mefra me: fr o m 
t he be gin ni n g of I M P a d mi nistrati o n  u p t o t he e n d of st u d y partici pati o n] 
 
7. 4  P H A R M A C O KI N E TI C E N D P OI N T  
Ser u m c o nce ntrati o n of re pari xi n ( bi n d a n d free) 
 
 
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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 covers also medication errors and uses 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 was at risk of death at the time of the event.  It does not refer to an 
event which hypothetically might have caused death if it were more severe), 
• 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, diarrhoea, influenza, or accidental trauma (e.g., sprained 
ankle, back pain) which may interfere or prevent everyday life functions, but do 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 that based 
upon appropriate medical judgment, 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. 

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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, considering that current early clinical development status in the indication investigated, where each 
adverse event has to be carefully evaluated, 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 DSUR for 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, after the patient has had the opportunity to spontaneously 
mention any problem, the Investigator or appropriate designee should inquire/monitor daily about the 
occurrence of an AEs.  
AEs should be reported for any clinically relevant change in concomitant condition(s) that is the result of an 
untoward (unfavorable and unintended) change in a patient’s medical health. 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. 
Worsening of an already recorded Adverse Event shall be reported as a new AE, filling in the relevant AE 
page in the CRF, with the new information, including the onset date and action taken. 
 
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 

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be followed-up to determine 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 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 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 
with 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. 

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Severity of the Adverse Event 
Mild 
Grade 1 - Does not interfere with patient’s usual function (awareness of symptoms or 
signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with patient’s usual function (enough discomfort to 
interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with patient’s usual function (incapacity to work or to 
do usual activities [unacceptable]) 
 
8.4. 
SERIOUS ADVERSE EVENT REPORTING 
8.4.1. Reporting Procedure for the Investigator to Dompé/CRO 
The Principal Investigator must report all SAEs occurring during patient participation in the study, regardless 
of presumed causal relationship, to the appropriate Sponsor/CRO Pharmacovigilance contact by e-mail 
(preferred) or fax 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).   
The Investigator should also report information on SAEs that continue after patient has completed his/her 
participation in the study (whether study completion or withdrawal) unless 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 to the appropriate Pharmacovigilance or 
directly to the Dompé Global Pharmacovigilance,  Safety and Surveillance Department, should the whole 
study have been ended.  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 
e-mailed/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, along with 
their relatedness to the Investigational Product, should identify which adverse events are serious and which 
are non-serious.  In any case, the Investigator is requested to record his/her opinion about the relatedness of 
the observed event(s) with the investigational medication. 
 
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 to 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: 

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• 
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 active 
treatment will be considered expeditable 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 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 periodical 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).  
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 active treatment will be 
considered expeditable for regulatory reporting, in line with law requirements. 
The blind should ordinarily be broken for IND safety reports submitted to FDA and all participating 
investigators. 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. 

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-  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 periodical safety 
updates, as per applicable local requirements and regulations.     
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. 
Prior to enrolment in the clinical trial, female patients of childbearing potential and their partners must be 
advised of the importance of avoiding pregnancy during the entire course of the study treatment and for the 
30 days after the end of IMP administration and of the potential risks associated with an unintentional 
pregnancy. During the trial (treatment period or follow up period), female patients are to be instructed to 
contact the Investigator immediately if they suspect they might be pregnant. In the same way, male patients 
who become aware that the partner might be pregnant, are to be instructed to contact the Investigator 
immediately. 
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. 
 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
SAMPLE SIZE 
The sample size of the study is calculated based on results from the phase III randomized controlled trial 
 and literature on CAP. Considering a randomization ratio 1:1 (reparixin:placebo) and a one-sided 
alpha of 0.025, a total of 500 evaluable patients will allow to achieve an overall power of 90% to detect a 
group difference
 in proportion of patients dead or requiring IMV (or ECMO) by day 28 in favour of 
reparixin, assuming that the proportion of patients dead or requiring IMV (or ECMO) in the placebo group 
by day 28 will be approximately 
. 
Sample size has been adjusted in order to take into consideration an interim analysis during the study. Details 
on interim analysis are provided in section 9.4. No additional multiplicity correction of alpha is required. 
Assuming that 5% of subjects will not be evaluable for primary analysis after enrolment, a total of 
approximately 526 patients is expected to be enrolled.  
 
9.2. 
RANDOMIZATION 
Enrolled patients will be randomized in a 1:1 ratio to either reparixin or placebo according to the stratified 
randomization list. Dropouts after randomization will not be replaced. 
Randomization list will be stratified by disease severity (NIAID-OS 5 vs. NIAID-OS 6) and site to ensure 
balanced assignment across treatment groups. The stratified 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 of 
IMP packaging/labelling will also receive appropriate randomization codes for the purpose of IMP 
preparation. 
Randomization will be performed through IRS. Each Patient Kit number will be randomly associated with a 
treatment group. Access to individual patient treatment code 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:  
- Interim analysis for efficacy or futility: this analysis will be conducted by an independent statistician when 
half of the planned evaluable patients has reached Day 28 or IMV/ECMO or an intercurrent event;  
- Final analysis: this analysis will be conducted when all enrolled subjects have completed the study and 
the study database has been unblinded and locked;  
- Analyses for the Data Monitoring Committee: these analyses will be produced periodically according to 
the DMC Charter.  
9.4. 
INTERIM ANALYSIS 
An interim analysis is planned when half of the planned evaluable patients has reached the primary endpoints 
at Day 28 (i.e., first 250 randomized patients who meet the FAS definition reaching Day 28 or primary 
endpoint definition) for identification of early superiority of reparixin (efficacy) or for early stop of the trial 
for futility. 
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O'Brien-Fleming’s  spending functions will be used to control the type I and II errors for analyses of primary 
endpoints. P-values boundaries for efficacy and futility at interim and final analyses are reported in the next 
table: 
Analysis 
Sample Size 
(evaluable patients) 
Boundaries for primary endpoint 
Efficacy 
Futility 
Interim 
250 
p-value
 
p-value 
 
Final 
500 
p-value 
 
p-value
 
The interim analysis will be conducted by an independent statistician who will share the results on primary 
endpoint (full list of interim outputs will be detailed in the SAP) with the DMC. On the basis of the interim 
results, DMC will communicate to the Sponsor the consequent recommendation on the continuation of the 
study. The following scenarios may emerge: 
- Scenario 1: The communication will be “Not enough evidence for demonstrate superiority of Reparixin”. 
In this case, since results are not considered enough to draw conclusions on primary endpoints, the 
enrolment shell continue up to the final analysis step, and treatments and follow-ups will proceed without 
modifications. Key first efficacy analysis and final analysis will be performed according to the rules 
described in section 9.3.  
- Scenario 2: The communication will be “Superiority of Reparixin is shown”. In this case, enrolment of 
subjects shell be stopped and considered completed. Already-enrolled subjects continue their residual 
treatment and follow-up as planned. Key first efficacy analysis and final analysis will be performed 
according to the rules described in section 9.3.  
- Scenario 3: The communication will be “Superiority of Reparixin is excluded”. In this case, the enrolment 
(if still ongoing) shell be stopped and all subjects will discontinue the treatment and will be followed-up 
until the next scheduled visit where they will be notified of the termination of the study. When database 
is closed, final analysis will be performed and the clinical study report will be written and released.  
 
9.5. 
ANALYSIS POPULATION 
The following populations will be defined: 
- The Safety (SAF) population will consist of all randomized patients who received at least one dose of the 
IMP. SAF population will be analysed 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. 
- The Per Protocol (PP) population will consist of all patients in the FAS population who do not have major 
protocol deviations. Primary and secondary efficacy analyses will be conducted on the FAS population 
while SAF and PP populations will be used for safety and sensitivity analyses, respectively. 
 
9.6. 
ESTIMANDS 
9.6.1. Primary estimand 
The primary estimand is defined by the following:  
- Population: Adult patients hospitalized for CAP, as defined by the inclusion-exclusion criteria of the 
study. 
- Variable: Patients dead or requiring IMV (or ECMO) by day 28. 
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- Intercurrent event: The occurrence of an intercurrent event is irrelevant. All observed values will be used 
regardless of occurrence of an intercurrent event. Retrieved dropouts will be used for data imputation of 
missing data. 
- Population-level summary: Difference in proportion of patients dead or requiring IMV (or ECMO) by day 
28. 
 
9.6.2. Key secondary estimands 
 
• 
Key secondary endpoint #1 (see section 7.1) will be analyzed according to the following estimand: 
- Population: Adult patients hospitalized for CAP, as defined by the inclusion-exclusion criteria of the 
study. 
- Variable: Any death up to day 180. 
- Intercurrent event: The occurrence of an intercurrent event is irrelevant. All observed values will be used 
regardless of occurrence of an intercurrent event. Retrieved dropouts will be used for data imputation of 
missing data. 
- Population-level summary: Difference in proportion of patients dead by day 180. 
• 
Key secondary endpoint #2 (see section 7.1) will be analyzed according to the following estimand: 
- Population: Adult patients hospitalized for CAP, as defined by the inclusion-exclusion criteria of the 
study. 
- Variable: Patients alive and discharged at day 28. 
- Intercurrent event: The occurrence of an intercurrent event is irrelevant. All observed values will be used 
regardless of occurrence of an intercurrent event. Retrieved dropouts will be used for data imputation of 
missing data. 
- Population-level summary: Difference in proportion of patients alive and discharged at day 28. 
• 
Key secondary endpoint #3 (see section 7.1) will be analyzed according to the following estimand: 
- Population: Adult patients hospitalized for CAP, as defined by the inclusion-exclusion criteria of the 
study. 
- Variable: Ventilatory free days up to day 28. 
- Intercurrent event: The occurrence of an intercurrent event is irrelevant (Ventilatory free days definition 
already include death occurrence). All observed values will be used regardless of occurrence of an 
intercurrent event. Retrieved dropouts will be used for data imputation of missing data. 
- Population-level summary: Difference in means of Ventilatory free days up to day 28. 
• 
Key secondary endpoint #4 (see section 7.1) will be analyzed according to the following estimand: 
- Population: Adult patients hospitalized for CAP, as defined by the inclusion-exclusion criteria of the 
study. 
- Variable: Patients requiring IMV (or ECMO) by day 28. 
- Intercurrent event: In case of death before day 28, an unfavorable value will be imputed to the secondary 
endpoint. Instead, the occurrence of other intercurrent events is irrelevant: all observed values will be used 
regardless of occurrence of these intercurrent events (retrieved dropouts will be used for data imputation 
of missing data). 
- Population-level summary: Difference in proportion of patients requiring IMV (or ECMO) by day 28. 
• 
Key secondary endpoint #5 (see section 7.1) will be analyzed according to the following estimand: 
- Population: Adult patients hospitalized for CAP, as defined by the inclusion-exclusion criteria of the 
study. 
- Variable: Length of hospital stay. 

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- Intercurrent event: In case of death before hospital discharge, an unfavorable value will be imputed to the 
secondary endpoint (hospital stay will be set as 28 days or date of death if later than 28 days). Instead, the 
occurrence of other intercurrent events is irrelevant: all observed values will be used regardless of 
occurrence of these intercurrent events (retrieved dropouts will be used for data imputation of missing 
data). 
- Population-level summary: Difference in means of length of hospital stay (days). 
 
9.7. 
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, 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. If appropriate, confidence intervals around the mean or the proportions 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 event 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 event 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. 
The significance level used for primary and key secondary analysis will be 0.025 one-sided. Unless otherwise 
specified, the significance level used for other statistical testing will be 0.05 and two-sided tests will be used. 
All patient data collected on the CRF will be listed by patient and centre.  
The Statistical Analysis Plan (SAP) will be issued before the interim analysis and 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.   
 
9.7.1. Analysis of efficacy variables 
9.7.1.1. Primary analysis   
The following null hypothesis is defined: the proportion of patients dead or requiring Invasive Mechanical 
Ventilation (or ECMO) by day 28 in reparixin group is higher or equal than control: 
H0: TREPARIXIN ≥ TCONTROL 
H1: TREPARIXIN < TCONTROL 
where TREPARIXIN and TCONTROL are the proportions of patients dead or requiring Invasive Mechanical 
Ventilation (or ECMO) by day 28 for reparixin and control groups, respectively. The null hypothesis H0 will 
be rejected, and superiority of reparixin declared if primary analysis p-value will be lower than pre-specified 
thresholds reported in section 9.4, depending at which analysis (interim or final) the test is performed. 
Primary endpoint will be analyzed by means of logistic regression adjusting by pre-defined baseline factors 
(stratification factors, gender and presence of concomitant disease (yes, no)) and a one-sided test will be used 
to test for differences between treatment groups.  

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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.  
 
9.7.1.2. Sensitivity analysis   
The following sensitivity analyses are defined to assess the robustness of results on primary endpoint versus 
assumptions used in the statistical model for the main estimator (additional analyses may be added in the 
SAP): 
- The comparison between treatment and control will be performed in the FAS population by means of MI 
under MAR assumption instead of missing not at random (MNAR).  
- A tipping point strategy will be used as a sensitivity analysis for missing data for assessment of superiority 
(if shown) of reparixin. Tipping point will assess how departures from MI under MNAR assumptions 
must be in order to overturn conclusions from the primary superiority analysis. Tipping point will be based 
on iterative application of MI-RD (or MI under wash-out approach), where the imputed values for the 
reparixin arm are shifted at a constant Δ to represent a worse effect in each iteration. The tipping points 
are the smallest Δs at which no statistical significance is shown (p≥0.025).  
In addition, for supportive purposes the primary analysis described in previous section will be performed: 
- by considering complete cases only (i.e. without considering patients with missing primary endpoint);  
- on the PP set instead of FAS; 
- by including in the logistic regression model further clinical relevant variables such as PSI, etiology, or 
other factors that may result imbalanced at baseline (for example specific comorbidities). 
Details on sensitivity and supportive analyses will be provided in the SAP. 
9.7.1.3. Secondary analyses 
If the primary analysis of primary endpoint leads to rejection of the null hypotheses, key secondary endpoints 
will be tested in a conditional sequential manner to show superiority of reparixin versus placebo according 
to the pre-defined ranking sequence (see section 7.1).  
This hierarchical test strategy protects the family-wise false positive error rate at the overall one-sided 0.025 
level.  
Key secondary endpoints #1, #2, and #4 will be analyzed by means of a logistic regression model, while key 
secondary endpoints #3 and #5 by means of an ANOVA model. All models will include the covariates 
described in section 9.7.1.1. 
In case of futility at interim analysis or in case of not rejection of null hypothesis, the above testing strategy 
will not be performed. Instead, independently of results on primary endpoint, descriptive in nature analyses 
will be performed on all secondary endpoints at each available timepoints by means of descriptive statistics 
and by appropriate parametric tests depending on the nature of the variable and its distribution. Data 
transformation might be used in order to satisfy the assumption of normality requested by parametric 
statistical tests. In case such assumptions are not met, non-parametric counterpart tests will be used. Details 
will be provided in the SAP. Change from baseline value (for continuous variables) and shift tables versus 
baseline (for categorical variables) may also be summarized for all post-baseline visits. 
 

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9.7.3. Analysis of safety variables 
TEAEs and TESAEs will be presented by treatment arms in terms of number of TEAEs and TESAEs and 
incidence by System Organ Class and Preferred Term using MedDRA. Analyses will be provided also by 
severity and relationship to the study drug. 
Vital signs, laboratory, eGFR and ECG parameters will be summarised by treatment at each available 
timepoint by means of descriptive statistics.  
 
9.7.4. Intermediate analyses for the DMC 
Safety data will be reviewed on an ongoing basis by a Data Monitoring Committee (DMC). Full details of 
the activities and responsibilities of the DMC are provided in the study DMC Charter (see additional details 
in Section 12.5). 
The DMC will give careful consideration to the appropriateness of trial continuation if there is emerging 
evidence that reparixin is harmful. Except for interim analysis (it will be involved in the evaluation of the 
interim analysis results and in the consequent decision on the continuation of the study), the DMC does not 
monitor primary endpoint for early efficacy termination, so no Type I error adjustment is necessary. Anyhow, 
access to unblinded information on the primary endpoint is allowed to balance patient safety risk against a 
possible gain in efficacy. 
 
9.7.5. Specification of subgroups for analysis 
In the presence of congruous numbers, subgroup analyses of primary and key secondary endpoints will be 
performed on the following subgroups defined by baseline characteristics: 
- Age class (<40 yrs, 40 - 64 yrs, ≥ 65 yrs), 
- Race, 
- Ethnicity. 
Statistical tests for interaction (between subgroup variable and treatment arm) will be performed before 
investigating further subgroups: analyses will be performed if interaction tests between treatment and variable 
is statistically significant at 15% nominal level. Variables that may be evaluated after test for interaction are: 
- Region (EU, US, other), 
- Clinical severity score (NIAID-OD 5 vs. NIAID-OD 6), 
- Concomitant medication. 
Statistical details and potential new subgroups definitions will be reported in the SAP. 
9.7.6. 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 9.7.1.1. 
 
 
 
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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 theIEC/ 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 to 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 21CFR 
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. 
PATIENT INFORMATION AND CONSENT 
No study-related procedures (including non-invasive and diagnostic procedures) will be undertaken prior to 
completion of the consenting process.   
Each potentially eligible patient will be informed of the study’s objectives and overall requirements. The 
Investigator or delegate personnel according to site procedures, will explain the study fully to him/her using 
the ICF. Although patients will be informed that they can withdraw consent at any time, the Investigator will 
also emphasize that missing data diminish the scientific value of all patients’ contributions. Similarly, patients 
will be informed that safety data might have to be collected after their participation in the study has been 

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completed. If the patient is willing to participate in the study, (s)he will be requested to give written informed 
consent after being given sufficient time to consider his/her participation and the opportunity to ask for further 
details. 
The ICF will be signed and personally dated by both the patient and the Investigator or delegate personnel 
according to site procedures. A copy of the signed form will be provided to the patient, and the original signed 
ICF will be retained and filed in the Investigator Site File. Patient 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.   
 
10.4. 
CONFIDENTIALITY 
All information obtained during the conduct of the study will be regarded as confidential. An agreement for 
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. 
 
 
 
 
 
 
 

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11. 
DATA HANDLING AND RECORD-KEEPING 
11.1. 
CASE REPORT FORM (CRF) 
All data relating to the study will be recorded on Electronic CRFs (eCRF) to be provided by the CRO, through 
the EDC system. eCRF should not be made available in any form to third parties, except for authorized 
Dompé’ designee 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 enrolment. 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 centre Initiation Visit. 
The eCRF must be available for review to designated Dompé’s 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 database will be performed in ongoing basis and the 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, 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 guidances for electronic records. Also, data will be stored and evaluated in such a way as to 
guarantee patient confidentiality in accordance with the legal stipulations applying to confidentiality of data. 
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, and Regulatory Inspection by 
Regulatory Authority.  
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/coworkers. Updates 
should be provided at least every two years. 
- 
Confidential disclosure agreement Form in accordance also with European data protection 
Regulation (EU) No. 679/2016 (GDPR) 

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- 
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. 
 
 

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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 as “new protocol” under IND 150182, 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  
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. 
 
12.3  
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 
Inspection by Regulatory Authority.  
      
12.4 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. 
 
12.5  
DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (DMC) will be established and will be responsible for 
safeguarding the interests of trial participants, and for enhancing the integrity and credibility of the trial. The 
DMC will assess the safety of the interventions during the trial and will monitor the overall conduct of the 
clinical trial. The DMC will provide recommendations to Dompé about stopping or continuing the trial on 
safety basis. The DMC will be involved in the evaluation of the interim analysis efficacy results and in the 
consequent decision on the continuation of the study. 

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The DMC will operate independently of Dompé, and its members will not have connections to Dompé except 
for the compensation to DMC members related to their activities.  
The DMC will comprise at least three members. They will be a multidisciplinary group that will include: 
• At least two Clinicians, expert in respiratory diseases, e.g. pulmonologists and/or intensivists and/or 
internal medicine physician, with extensive experience in the diagnosis and management of patients with 
COVID-19, mainly with a severe disease presentation to require hospitalization; 
• A Biostatistician with substantial experience in the DMC process. 
The DMC: 
• Will review unblinded data. To this purpose, an Independent Statistician will liaise with the CRO 
statistician and will have access to those components of the database necessary to generate the reports 
to the DMC. 
• Will be responsible for the ongoing review of safety data throughout the trial.  Primary among the safety 
data that will be reviewed are Serious AEs.  
• Will have also access to unblinded information on the primary analysis to enable the assessment of the 
acceptability of safety in the context of emerging evidence about efficacy. 
• Will be advisory to Dompé and make recommendations to Dompé regarding the continuation of the trial 
and potential modifications to the design and conduct of the trial. These recommendations will be made 
in a manner to maintain confidentiality of emerging information about efficacy and safety, unless access 
to certain data is needed to enable Dompé to make decisions about the DMC recommendations. Dompé 
will be 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 
All details of the conduct and responsibilities of the DMC will comply with Guidance for Clinical Trial 
Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees and will be described 
in the ‘DMC Charter’ to be finalized during the set-up phase of the study and prior to the initiation of 
treatment. 
 
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 centre involved. 
Any written amendment will be sent to all recipients of the protocol. 
 
12.7. 
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. 

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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. 
 
12.8. 
 PUBLICATIONS 
As this study is part of a multicentre 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. Criteria for selection of authors will be agreed. After the initial publication or one year after 
completion of the study, whichever occurs first, an Investigator and/or his/her colleagues may publish the 
results of Investigator’s part of the study independently.  
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 the 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 publishing in peer reviewed journals; presenting results at 
scientific congresses; and posting information and results on internet-based public registers and databases. 
In any case, 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 a data could, in some circumstances, prevents or negatively impacts patentability. 
 
 
 
 

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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. https://www.who.int/medical_devices/priority/Chapter_1_20167_WHO_Priority_medical_devices_list_for_
COVID_19_response.pdf?ua=1; 
9.  NIH (National Institutes of Health) COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 
(COVID-19) Treatment Guidelines. 
https://www.covid19treatmentguidelines.nih.gov/. Accessed 27 
December 2021; 
10.  Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, 
China [published correction appears in Lancet. 2020 Jan 30]. Lancet. 2020; 395:497-506; 
11. Narasaraju T, Tang BM, Herrmann M, et al. Neutrophilia and NETopathy as Key Pathologic Drivers of 
Progressive Lung Impairment in Patients With COVID-19. Front Pharmacol 2020; 11:870; 
12. Zuo Y, Yalavarthi S, Shi H, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020; 5:e138999 
13. Qin C, Zhou L, Hu Z, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-
19) in Wuhan, China. Clin Infect Dis. 2020; 71:762-768; 
14. 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; 
15. Docherty AB, Mulholland RH, Lone NI et al. Changes in in-hospital mortality in the first wave of COVID-19: 
a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK. 
Lancet Respir Med 2021;9:773-785;  
16. Presanis AM, Kunzmann K, Grosso FM, et al. Risk factors associated with severe hospital burden of 
COVID‑19 disease in Regione Lombardia: a cohort study. BMC Infect Dis 2021; 21:1041; 
17. Docherty AB, Mulholland RH, Lone NI et al. Changes in in-hospital mortality in the first wave of COVID-19: 
a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK. 
Lancet Respir Med 2021;9:773-785; 
18. Yehya N, Harhay MO, Curley MAQ, et al. Reappraisal of Ventilator-Free Days in Critical Care Research. Am 
J Respir Crit Care Med 2019; 200:828–836; 
19. Lancet Respir Med. 2021 Dec; 9(12): 1407–1418 
20. Cesta MC et al, “The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management 
of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome”, Front Pharmacol. 2022 Jan 
12;12:808797. doi: 10.3389/fphar.2021.808797  
21. Metlay JP, Waterer GW, Long AC, et al. “Diagnosis and Treatment of Adults with Community-acquired 
Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases 
Society of America”, Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67  
22. Xu J, et al. Deaths: final data for 2013. National vital statistics reports: from the Centers for Disease Control 
and Prevention, National Center for Health Statistics, National Vital Statistics System. 2016; 64(2):1–119 
23. Ramirez, JA. (2018) "A Continuum of Disease from Community-Acquired Pneumonia to Multiple Organ 
Dysfunction Syndrome," The University of Louisville Journal of Respiratory Infections: Vol. 2 : Iss. 2 , Article 
1. DOI: 10.18297/jri/vol2/iss2/1  Available at: https://ir.library.louisville.edu/jri/vol2/iss2/1). 
 

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14. 
APPENDICES 
14.1. 
APPENDIX 1 - SPONSOR APPROVAL PAGE 
 
 
 
 
Medical Expert: __
 
 
 
 
 
 
 
 
 
Clinical Operation Manager: 
 
  
 
 
 
 
 
Development Director 
 
  
 
 
PPD
PPD
PPD

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14.2. 
APPENDIX 2 - INVESTIGATOR’S SIGNATURE PAGE 
 
Investigator’s Statement 
 
I have read study protocol REP0321 (Reparixin 1200 mg three times a day as add-on therapy to standard of care to 
limit disease progression in hospitalised adult patients with COVID-19 and other community-acquired pneumonia. A 
multinational, multicentre, randomised, double-blinded, placebo-controlled, parallel-group phase III trial 
(REPAVID-22) 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: 
Dat
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD

St u d y R E P 0 3 2 1  
Re p arixi n i n C O VI D-1 9  a n d ot her C A P ( R E P A VI D -2 2 ) 
Pa ge 6 4  of  6 7  
 
 
 
Pr ot o c ol Versi o n/ Date: v 2. 0  –  Fi nal  2 0 J u n 2 0 2 2  
 
 
 
 
 
C O N FI D E N TI A L  
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  
 
  
S a 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 :  
Patie nt Kit N o. X X Y Y  
 
Patie nt N o. _ _ _ _ _ _ _ _  
 
I n vesti gat or: _ _ _ _ _ _ _ 
 
 
T he f oll o wi n g re prese nt 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  
S T U D Y R E P 0 3 2 1  
S p o ns or  D o m pé far mace utici s. p.a.; Via Sa n ta L ucia 6 , Mila n –  Ital y  
Tele p h o ne: 
 
 
 
I N V E S TI G A T O R: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
P A TI E N T 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: re p ari xi n ( 60 0  m g) or pl ace b o or al t a blets  
 
C O N T AI N S : 
 
 
c o de d B A T C H N o. 
c o de 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 : Dis pe nse t h e Patie nt Kit, 
 
 
F or a n y q uesti o ns, please c o ntact <t o be i de ntifie d i n t h e fi n al la bel >  
 
F o r cli nic al tri al use o nl y. C a uti o n:  Ne w Dr u g -Li mite d b y Fe der al l a w t o i n vesti g ati o n al use .*  
* F or U S l a bels o nl y  
 
C o nte nt of t he L a bel 
  
S T U D Y R E P 0 3 2 1  
S p o ns or  D o m pé far mace utici s. p.a.; Via Sa n Marti n o 1 2, Mila n –  Ital y 
I N V E S TI G A T O R: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
P A TI E N T 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: re p ari xi n ( 60 0  m g) or pl ace b o or al t a blets  
 
C O N T AI N S : 
 
 
c o de d B A T C H N o. 
c o de 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 : Ta ke t h e dr u g t hree ti mes a da y, 2 ta blets f or eac h a d mi nistrati o n  ( 2 ta blets at a ti me a b o ut 
).  
F o r cli nic al tri al use o nl y.  
C a uti o n:  Ne w Dr u g -Li mite d b y Fe der al l a w t o i n vesti g ati o n al use*  
*f or U S l a bel o nl y  
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

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14.4. 
METHODOLOGICAL DETAILS 
14.4.1. National Institute of Allergy and Infectious Disease - Ordinal Scale (NIAID-OS) 
COVID-19 disease severity score will be evaluated according to the following scale19  
 
 
14.4.2. Calculation of eGFR 
Renal function will be evaluated by estimated Glomerular Filtration Rate (eGFR), calculated using the 
Modification of Diet in Renal Disease study equation (MDRD)  as per the following formula:  
 
 
Levey AS et al. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000; 11: A0828 
 
14.4.3. Handling of samples for assays 
Local laboratories will be involved for the assay haematology/biochemistry (Safety Laboratory Tests) and 
inflammatory markers (LDH, CRP, ferritin, D-dimer, PCT and cytokines). 
All steps will be tracked to ensure correct data reporting.   
All samples submitted to these labs will be destroyed after the CSR has been issued or after the patient has 
withdrawn his/her consent. 
 

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14.4.4 National Early Warning Score (NEWS) 
 
Royal College of Physicians. National Early Warning Score (NEWS): Standardising the assessment of acute-
illness severity in the NHS. Report of a working party. London: RCP, 2012 
 
14.4.5. Pneumonia Severity Index (PSI) 
 
 
 
14.4.6 SpO2/FiO2 - PaO2/FiO2, and SpO2 - PaO2 conversion tables 

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Adapted from Severinghaus JW. Simple, accurate equations for human blood O2 dissociation computations. 
J Appl Physiol Respir Environ Exerc Physiol. 1979 Mar;46(3):599-602