A Phase 3, Double-blind, Randomized, Placebo-controlled, Multicenter Study on the Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients With Severe COVID-19 Pneumonia
Phase: PHASE3
Conditions: Pneumonia, Viral
Sponsor: Dompé Farmaceutici S.p.A

Dompé Farmaceutici S.p.A.                      Clinical Study Report REPAVID-19 Phase 3                        Appendix 16.1.1 
 
16.1.1 Protocol and protocol amendments 
Protocol REP0220 – Final Version 3.0, 09 April 2021 
 

 
 
 
 
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REP0220_Final Version No. 3.0_09/APR/2021 
EudraCT number 2020-005919-51 
 
TABLE OF CONTENTS 
 
1. 
SIGNATURES ........................................................................................................ 5 
2. 
CONTACT INFORMATION ................................................................................ 8 
3. 
LIST OF ABBREVIATIONS ................................................................................ 9 
4. 
PROTOCOL SYNOPSIS ..................................................................................... 11 
1. 
INTRODUCTION ................................................................................................ 21 
1.1 
Background ............................................................................................................. 21 
1.2 
Mechanism of action of Reparixin .......................................................................... 21 
1.3 
Toxicology data ...................................................................................................... 24 
1.4 
Pharmacokinetics and product metabolism ............................................................ 24 
1.5 
Clinical development .............................................................................................. 25 
1.7 
Phase 2 study .......................................................................................................... 28 
1.8 
Phase 3 study .......................................................................................................... 28 
2. 
STUDY OBJECTIVES AND ENDPOINTS ....................................................... 28 
2.1 
Study objectives ...................................................................................................... 28 
2.2 
Primary Endpoint .................................................................................................... 28 
2.3 
Key Secondary Endpoints ....................................................................................... 28 
2.4 
Additional Secondary Endpoints ............................................................................ 29 
2.5 
 ............................................................................................ 29 
2.6 
Safety Endpoints ..................................................................................................... 30 
3. 
STUDY DESIGN AND METHODOLOGY ....................................................... 30 
3.1 
Study design ............................................................................................................ 30 
3.2 
Study population ..................................................................................................... 31 
3.3 
Study duration ......................................................................................................... 31 
3.4 
Description of the study .......................................................................................... 31 
4. 
STUDY POPULATION ....................................................................................... 32 
4.1 
Number of patients.................................................................................................. 32 
4.2 
Inclusion/exclusion criteria ..................................................................................... 33 
4.2.1 
Inclusion Criteria: ................................................................................................... 33 
4.2.2 
Exclusion Criteria: .................................................................................................. 33 
5. 
TREATMENTS .................................................................................................... 34 
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5.1 
Investigational products .......................................................................................... 34 
5.1.1 
Dose regimen and administration ........................................................................... 34 
5.1.2 
Randomization ........................................................................................................ 35 
5.1.3 
Unblinding .............................................................................................................. 35 
5.1.4 
Compliance to Treatment ........................................................................................ 36 
5.2 
Other treatments ...................................................................................................... 36 
5.2.1 
Additional therapy .................................................................................................. 36 
5.2.3 
Concomitant and not allowed medications ............................................................. 37 
5.3  
Preparation, Handling, Storage and Accountability of the study drugs .................. 38 
5.3.1 
Reparixin ................................................................................................................. 38 
5.3.2 
Placebo .................................................................................................................... 38 
5.3.3 
Management, Packaging and Labelling of Investigational Products ...................... 38 
6. DISCONTINUATIONS ........................................................................................................ 39 
7. ASSESSMENTS AND PROCEDURES .............................................................................. 40 
7.1 
Procedures ............................................................................................................... 40 
7.2  
Screening and Baseline assessments ....................................................................... 41 
7.3 
On-treatment assessments ....................................................................................... 42 
7.4 
Follow-up ................................................................................................................ 42 
7.5 
 ......................................................................... 43 
8. EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION ................. 45 
8.1 
Definitions .............................................................................................................. 45 
8.2 
Monitoring for adverse events ................................................................................ 47 
8.3  
Recording of adverse events ................................................................................... 47 
8.4 
Relationship and severity of AEs to the Investigational product ............................ 47 
8.5 
Follow-up of patients with adverse events ...... Errore. Il segnalibro non è definito. 
8.6 
Serious adverse events reporting ............................................................................ 49 
8.7  
Exposure to investigational product during pregnancy........................................... 50 
8.8 
Adverse events causing treatment discontinuation ................................................. 51 
8.9 
Overdose ................................................................................................................. 51 
9. DATA MONITORING  COMMITTEE ............................................................................. 51 
10. STATISTICAL CONSIDERATIONS ............................................................................... 52 
10.1 
Sample size ............................................................................................................. 52 
10.2 
Overview of planned statistical analyses ................................................................ 52 
10.3 
Analysis Population ................................................................................................ 52 
10.4 
Intermediate analyses .............................................................................................. 53 
10.4.1 
Interim analysis ....................................................................................................... 53 
10.4.2 
Key first efficacy analysis ....................................................................................... 53 
10.5 
Statistical Methodology .......................................................................................... 54 
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10.5.1 
General Considerations ........................................................................................... 54 
10.5.2 
Analysis of efficacy variables ................................................................................. 54 
10.5.2.1 
Primary analysis ...................................................................................................... 54 
10.5.2.2 
Sensitivity analyses ................................................................................................. 55 
10.5.2.3 
Secondary Analyses ................................................................................................ 55 
10.5.3 
Safety Analysis ....................................................................................................... 56 
10.5.4 
 ........................................................................... 56 
10.5.5 
Intermediate analyses for DMC .............................................................................. 56 
10.5.6 
Specification of subgroups for analysis .................................................................. 56 
10.5.7 
Missing data ............................................................................................................ 57 
11 
STUDY ORGANIZATION .................................................................................. 58 
11.1 
Study documentation and record keeping ............................................................... 58 
11.2 
Ethical considerations, quality assurance and monitoring ...................................... 58 
11.3 
Informed consent .................................................................................................... 58 
11.4  
Data collection ........................................................................................................ 59 
11.5 
Confidentiality and data protection ......................................................................... 59 
11.6 
Unique subject identifier ......................................................................................... 59 
11.7 
Database management ............................................................................................ 60 
11.8 
Coding dictionaries ................................................................................................. 60 
11.9 
Publication policy ................................................................................................... 60 
11.10 
Administrative aspects ............................................................................................ 60 
12 
REFERENCES...................................................................................................... 61 
13 
APPENDICES ....................................................................................................... 66 
Appendix 1. Investigator’s Brochure (IB) ................................................................................... 66 
Appendix 2. Investigational Drug Labels .................................................................................... 66 
Appendix 3. Severe Adverse Event (SAE) reporting form and completion guideline ................ 66 
Appendix 4. Pregnancy reporting form and completion guideline ............................................. 66 
Appendix 5. Informed consent form ........................................................................................... 66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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REP0220_Final Version No. 3.0_09/APR/2021 
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INVESTIGATOR’S SIGNATURE PAGE 
 
A phase 3, double-blind, randomized, placebo-controlled, multicenter study on the efficacy and safety of Reparixin 
in the treatment of hospitalized patients with severe COVID-19 pneumonia 
Version 3.0 09 April 2021  
 
Investigator’s Statement 
 
I have read this study protocol and agree to conduct the study as outlined in the protocol, and in accordance with 
the Declaration of Helsinki, ICH-GCP E6 (R2) and any local regulations, being responsible for personally 
supervise the study conduct and ensure study staff complies with protocol requirement. 
 
 
Name of Principal Investigator (block letters):____________________________________________ 
 
 
 
Signature:  _______________________________  
Date: 
 _________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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3. LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALI 
Acute Lung Injury 
ALP  
Alkaline Phosphatase 
ALT  
Alanine Aminotransferase 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BAL 
Broncho-Alveolar Lavage 
CDE 
Cat Dander Extract 
CIF 
cumulative incidence function  
Cmax 
Maximum concentration 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
COVID 
Corona Virus Disease 
Css 
Concentration, steady state 
CT 
Computerized Tomography 
CXC 
Cisteina X Cisteina (chemochine) 
CYP 
Cytochrome P450  
DB 
Data Base  
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee  
 
 
ECMO 
Extracorporeal Membrane Oxygenation  
eCRF 
electronic Case Record Form 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
EoS 
End of Study 
EoT 
End of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspiration O2  
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit  
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
CCI

 
 
 
 
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IRS 
Interactive Response System 
ITT 
Intentio to Treat  
 
 
KM 
Kaplan-Meier  
LD50 
Lethal Dose 50% 
LDH 
Lactate dehydrogenase  
LLN 
Lower Limit of Normal 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
ml 
Milliliters 
NCI-CTCAE 
National Cancer Institute, Common Terminology Criteria for Adverse Events 
OATP 
Organic-Anion-Transporting Polypeptides 
PaO2 
Partial pressure of oxygen  
PCR 
Polymerase Chain Reaction 
P/F 
PaO2 / FiO2 
Pk 
Pharmacokinetic 
 
 
PMN 
Polymorphonuclear cell 
PP 
Per Protocol  
PT 
Preferred Term 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee 
SCM 
Single Challenge Model 
SmPC 
Summary of Product Characteristics 
SpO2 
peripheral capillary oxygen saturation 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TID 
Three times daily 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
XDP 
Cross-Linked Fibrin Degradation Product 
yrs 
years 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WHO-OS 
WHO Ordinal Scale 
 
 
 
 
 

 
 
 
 
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o 
Proportion of patients alive and free of respiratory failure at Day 28, i.e. with no need of 
invasive mechanical ventilation or Extracorporeal Membrane Oxygenation (ECMO) or 
admission to Intensive Care Unit (ICU) linked to worsening of respiratory parameters 
compared to baseline.  
 
Key Secondary Endpoints: 
o 
Proportion of patients alive and free of respiratory failure (as described for the primary 
endpoint) at Day 60.  
o 
Mortality rates up to Day 28, 
o 
Incidence of ICU admission until Day 28,  
o 
Time to recovery (category 1 - 2 - 3 of the 7-point WHO Ordinal Scale of clinical 
improvement (WHO-OS) until Day 28. 
 
 
Additional Secondary Endpoints: 
o 
Proportion of subjects alive and free of respiratory failure (as described for the primary 
endpoint) at fixed time-points: days 3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) -60 (±2) after 
randomization (randomization = day 1),  
o 
Mean changes in clinical severity score based on the 7-point WHO-OS as measured at days 
3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) - 60 (±2) - 90 (±2) after randomization, 
o 
Time to clinical improvement 1 (decline of 1 category in the 7-point WHO-OS) up to Day 
28,  
o 
Time to clinical improvement 2 (decline of 2 categories in the 7-point WHO-OS) up to Day 
28, 
o 
Time to discharge from hospital (up to day 28), 
o 
Clinical status at days 3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) - 60 (±2) - 90 (±2)  either in 
hospital or at home (7-point WHO-OS). When patient is at home, his/her clinical status can 
be assessed by phone, 
o 
Dyspnea severity (Likert scale and VAS scale) at days 3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 
(±2) or until discharge, 
o 
Duration of supplemental oxygen treatment (days) up to Day 28, 
o 
Incidence of invasive mechanical ventilation use, or ECMO up to Day 60, 
o 
Duration of invasive mechanical ventilation, or ECMO (days) up to Day 60, 
o 
Duration of non-invasive mechanical ventilation (days) up to Day 28, 
o 
Duration of ICU admission (days) up to Day60,  
o 
Duration of hospitalization since randomization (days) up to Day 28, 
o 
Partial pressure of oxygen (PaO2): change from baseline to the firstly available daily value 
at days 3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) or until discharge, 
o 
Pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2): change 
from baseline to the firstly available daily value at days 3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 
(±2) or until discharge, 
o 
P/F ratio [partial arteriolar oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) ratio] 
from baseline to days 3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) or until discharge, 
o 
Hs-CRP: change from baseline to days 3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) or until 
discharge (alternatively, CRP), 
o 
Mortality rates up to Day 60 and Day 90, 
o 
Freedom from (time to) death or respiratory failure (as described for the primary end-point). 
 
 

 
 
 
 
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Inclusion Criteria: 
1. Age 18 to 90, male and female subject of any race 
2. Reverse transcriptase Polymerase Chain Reaction (rt-PCR)-confirmed COVID-19 infection based on a 
nasal / oropharyngeal swab within 10 days before randomization 
3. At least one of the following: 1) Respiratory distress with tachypnea (RR ≥ 24 breaths/min without 
oxygen); 2) Partial arterial oxygen pressure (PaO2) / Fraction of inspiration O2 (FiO2) >100 and <300 
mmHg (1mmHg = 0.133kPa), 3) SpO2 ≤ 94% while breathing ambient air.  
Calculation through validated Sat/FiO2 scales is allowed. 
P/F value of reference if the last available before the signature of consent 
4. Need of supplemental oxygen (i.e. new use of supplemental oxygen, or increased oxygen requirement if 
on chronic oxygen) requiring low- or high-flow oxygen or non-invasive mechanical ventilation (7-point 
WHO-OS category 4 or 5) 
5. Radiological chest imaging (X-rays, CT scan) confirms lung involvement and inflammation (presence of 
ground-glass opacities, and/or inter/intra lobular septal thickening, and/or consolidations in a patchy 
distribution).  
6. Inflammatory status as documented by at least one of the following: Lactate dehydrogenase (LDH) > 
normal range, C-reactive protein (CRP) ≥ 100 mg/L or IL-6 ≥ 40 pg/mL, serum ferritin ≥ 900 ng/mL, 
XDP > 20 mcg/mL.  
7. 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:  
i) 
Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives for at least 
2 months before the screening visit until 30 days after final visit  
ii) 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 final visit  
iii) A male sexual partner who agrees to use a male condom with spermicide  
iv) 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. 
 
Exclusion Criteria: 
1. Cannot obtain informed consent. 
2. hepatic dysfunction with Child Pugh score B or C, or ALT or AST > 5 times the upper limit;  
3. renal dysfunction with estimated glomerular filtration rate (MDRD) < 50 mL/min/1.73 m2 or patient 
receiving continuous renal replacement therapy, hemodialysis, or peritoneal dialysis. 
4. Bacterial sepsis (besides COVID-19 sepsis) 
5. Positive test for influenza virus, if tested during the current illness (note: influenza testing is not required 
by protocol) 
6. Known congenital or acquired immune deficiency,  
7. Patients with hypersensitivity to ibuprofen or to more than one non-steroidal anti-inflammatory drug or 
to more than one medication belonging to the class of sulfonamides (e.g. sulfamethazine, 
sulfamethoxazole, sulfasalazine, nimesulide or celecoxib 
Hypersensitivity to sulphanilamide antibiotics, e.g. sulfamethoxazole, does not qualify for exclusion).  
Know allergy to any medication (either investigational or non-investigational) which is planned at study 
entry for use during the study. 
8. Patients receiving other not allowed medications (see Section: Not allowed medications) 

 
 
 
 
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9. Severe, active bleeding such as hemoptysis, gastrointestinal bleeding, central nervous system bleeding, 
and nosebleeds within 1 month before enrollment. 
10. Evidence of COVID-19 disease progression during previously initiated treatment with remdesivir (alone 
on in any combination with other antiviral treatments), protease inhibitors (e.g. ritonavir, lopinavir, 
darunavir – atazanavir), tyrosine kinase inhibitors (e.g. baricitinib, imatinib, gefitinib), convalescent 
plasma or intravenous immunoglobulin for COVID-19, or investigational treatments 
11. More than three infusions of remdesivir, including the loading dose, prior to randomization 
12. Subject participating in other interventional clinical trials. Subject having received investigational therapy 
in the previous 3 days, or at least 5 half-lives.  
13. At the time of enrollment, patients not in a clinical condition compatible with the oral administration of 
the study drug.  
14. P/F < 100 mmHg 
15. 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 
 
 
Study treatments:  
Patients who satisfy the predefined inclusion and exclusion criteria for this trial will be randomized 2:1 to one of 
the following groups for in-hospital treatment: 
 
Group 1: Reparixin oral tablets 1200 mg TID (2 tablets, 600 mg each, TID) for up to 21 days or until decision of 
discharge from the hospital, on top of standard supportive care.   
 
Group 2 (control): placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of 
discharge from the hospital, on top of standard supportive care.  
 
Randomization will be performed through an Interactive Response System (IRS). Each Patient’s Kit number will 
be randomly associated with a treatment group. The randomization list will be provided to the facility responsible 
for IMP packaging/labelling for the purpose of IMP preparation. Each randomized patient will be allocated with 
randomization number according to the stratified randomization list. Dropouts after randomization will not be 
replaced.  
Randomization will be stratified by site, gender and age class (<65 yrs vs ≥ 65 yrs) to ensure balanced assignment 
across treatment groups. The stratified permuted block randomization list will be generated with a computer 
procedure by an independent statistician not involved in the conduct of the study. 
 
 
Unblinding:   
For each randomized subject, individual code breaks will be accessible in the event of a medical emergency 
requiring knowledge of the treatment assigned to the subject. Only the responsible investigator, or authorized 
delegates, can break the code via the IRT. 
Any breaking of the treatment code by the investigational staff must be reported immediately to the Sponsor and 
must include an explanation for breaking the code. The sponsor should be contacted to discuss the case, if possible, 
prior to unblinding.  
A general rule is that breaking the code is only allowed if the knowledge of the actual treatment is necessary for 
an appropriate decision on actions / treatments for the safety of the patient.  
The DMC will have access to group-unblinded and/or fully unblinded DMC reports. 

 
 
 
 
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The sponsor’s personnel from the Pharmacovigilance Department of Dompé may break the treatment code for 
subjects who experience a Suspected Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the 
individual case requires expedited regulatory reporting. 
 
 Additional therapy : 
Any additional  therapy must be considered as local standard of care treatment, and it must be able to be 
administered to all patients enrolled in the study. Investigators are allowed to provide any medications having 
received final or conditional approval for the treatment of the COVID-19 infection, or used off-label at the 
Investigator’s discretion and justified by scientific evidence of effectiveness against the COVID-19 infection 
without to stop study treatment. 
 
 
 
Not allowed 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.  
For remdesivir (recently receiving conditional approval for the treatment of COVID-19; June 2020) no clinical 
interaction studies have been performed and the overall potential of this drug for interactions is currently unknown. 
However, reparixin is not a substrate of the microsomal enzymes of which remdesivir is an in-vitro inhibitor 
(CYP3A4, OATP1B1, OATP1B3) or inducer (CYP1A2, CYP3A).  
Patients should remain under close observation during the days of remdesivir administration if given concomitantly 
with reparixin. 
 
 
Study duration:  
The treatment duration will be up to a maximum of 21 days, with a follow-up period lasting up to 90 days since 
baseline.  
The treatment will be interrupted upon the Investigator’s clinical judgment of the patient’s improvement, even if 
the patient is still hospitalized but no longer requiring supplemental oxygen or significant medical care. 
The treatment is not foreseen to be continued at home.  
For subjects discharged home before the completion of the 21-day treatment period, follow-up visits (preferably 
in person at the Center, or via a telephone call) will be held at days 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) -60 (±2) 
and/or 90 (±2) depending on the discharge time point.   
 
 
End of study (EOS) definition: EOS is defined as the last day the last patient completes the last study assessment 
(including the follow-up assessments), or withdraws the consent to participate in the study including refusal to 
undergo follow-up, or is deceased or otherwise lost to follow-up.  
 
End of treatment (EOT) definition: EOT is defined as the last treatment day in a randomized patient. EOT occurs 
upon completion of the scheduled treatment period (up to 21 days) for clinical judgment of improvement, or at the 
time of discharge from hospital, or at any time the treatment is interrupted early for any reason (e.g. for adverse 
events, ineffectiveness, withdrawal of consent for treatment). Patients randomized but with no actual treatment 
initiated, will have their EOT on the date of randomization. 

 
 
 
 
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Stopping criteria for individual subjects:  
Subjects should be prematurely discontinued from study treatment for any of the following reasons: 
• 
subject no longer consents to participate in the treatment phase of the study, yet consenting for the 
continuation of the collection of information in the follow-up phase of the study (specific consent to be 
signed). Patient may eventually decide to withdraw the consent for the study continuation including the 
collection of information in the follow-up phase, 
• 
physician decision that it is in the best interest of the subject to be discontinued from study treatment, 
• 
physician decision because of poor efficacy or poor tolerability of the investigational treatment 
• 
the treatment will be interrupted in case of significant worsening of the renal function with eGFR 
(MDRD) falling to below 30 ml/min/1.75m2 or an increase of serum creatinine by more than 50% since 
randomization  
• 
severe protocol deviations 
All study subjects, including ‘treatment’ drop-outs for any reason, will have to be followed up until the End of 
Study, unless the patient withdraws his/her consent to the study continuation including the follow-up.  
 
 
Stopping criteria for the clinical trial:   
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, for reasonable cause 
provided that written notice is submitted in advance of the intended termination. Advance notice is not required if 
the study is stopped due to safety concerns.  
The recommendations of the Data Monitoring Committee will be taken into consideration in this regard.  
If the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the investigator and 
subsequently provide written instructions for study termination.  
 
 
Data Monitoring Committee (DMC):  An independent Data Monitoring Committee (DMC) will be appointed 
with the responsibility of safeguarding the interests of trial participants, assessing the safety and efficacy of the 
interventions during the trial, and monitoring the overall conduct of the clinical trial. These tasks will be 
accomplished on an ongoing basis throughout the trial. The DMC will provide recommendations about stopping 
or continuing the trial. In order to contribute to enhancing the integrity of the trial, the DMC may also formulate 
recommendations relating to the selection/recruitment/retention of participants, their management, improving 
adherence to protocol- specified regimens and retention of participants, and the procedures for data management 
and quality control.  
The DMC will be advisory to the clinical trial leadership group (the Scientific Committee of the study). The 
Scientific Committee will be comprised of the sponsor’s study team and lead study investigators, who jointly will 
have responsibility for the design, conduct and analysis of the clinical trial. The Scientific Committee 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. 
 
Statistical plan:  
The sample size of the study is calculated based on results from the REPAVID-19 study (phase II, open label 
study) with Reparixin.  
Each patient will be randomly allocated to Reparixin or Control according to a randomization ratio of 2:1 and 
followed for the entire treatment and follow-up duration for collecting the efficacy endpoints. 
Considering a randomization ratio 2:1 (Reparixin:placebo) and a one-sided alpha of 0.025, a total of 264 evaluable 
patients will allow to achieve an overall power of 90% to detect a group difference ≥20% in proportion of patients 

 
 
 
 
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alive and free of respiratory failure at Day 28 in favor of reparixin, assuming that the proportion of patients alive 
and free of respiratory failure in the placebo group will be approximately 60%. Assuming that 15% of subjects 
will not be evaluable for primary analysis, a total of approximately 312 subjects is expected to be enrolled.  
An interim analysis for efficacy and futility is planned when half of the planned patients has reached the primary 
endpoints. O’Brien-Fleming 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. 
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. 
Primary endpoint will be analyzed by means of logistic regression adjusting by pre-defined baseline factors.  Since 
patients who discontinue the IMP will not be withdrawn from the study but will be asked to complete safety and 
efficacy assessments, missing data will be addressed by modeling patients with missing data after retrieved drop-
outs, assuming that missing data would have been like retrieved drop-outs if they were assessed. 
Results of primary analysis will be assessed in sensitivity analyses to assess the robustness of results on primary 
endpoint versus adherence to protocol and presence of missing data. 
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. Independently of the results on primary endpoints, all secondary endpoints will be 
analyzed at each available time points by means of summary statistics and by appropriate parametric tests 
depending on the nature of the variable and its distribution. All analyses will be descriptively in nature. 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. Change from baseline 
value (for continuous variables) and shift tables versus baseline (for categorical variables) will also be summarized 
for all post-baseline visits. 
AEs will be presented in terms of the number of AEs and incidence. Other safety parameters will be summarized 
by treatment at each available visit by means of descriptive statistics.  
The Safety and the Full Analysis Set population will consist of all patients who will be randomized and received 
at least one dose of the investigational product. Safety population will be analyzed according to the actual treatment 
received; Full Analysis Set population will be analyzed according to 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. 
The Study Statistical Analysis Plan (SAP) with more technical and detailed elaboration of the principal features 
of statistical analyses will be finalized before interim analysis. Any deviation from the original statistical plan will 
be described in the Clinical Study Report.  
 
SCHEDULE OF ASSESSMENTS 
 

 
 
 
 
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1. INTRODUCTION 
1.1 
Background  
IN DECEMBER 2019, A NEW IDENTIFIED CORONAVIRUS (SARS-COV-2) OUTBREAK IN WUHAN CAUSED PUBLIC HEALTH 
CRISIS IN CHINA AND SPREAD WORLDWIDE. On February 11, 2020, the World Health Organization officially named 
the disease caused by the new coronavirus: "COVID-19". The symptoms of human infection with SARS-CoV-2 
are generally fever, fatigue, dry cough and dyspnea. Noteworthy, a considerable percentage of COVID-19 cases 
have rapidly progressed to a severe and critical condition with acute lung injury (ALI), acute respiratory distress 
syndrome (ARDS) and pulmonary edema as the most common complications, resulting in a large number of 
pneumonia hospitalized patients requiring supplemental oxygen, mechanical ventilation, or even ECMO.  
 
LUNG EDEMA, ENDOTHELIAL AND EPITHELIAL INJURY ARE ACCOMPANIED BY AN INFLUX OF NEUTROPHILS INTO THE 
INTERSTITIUM AND BRONCHEOALVEOLAR SPACE. Activation and transmigration of neutrophils are considered to 
play a key role in the progression of ALI and ARDS (1). Proof for the importance of neutrophils in ALI comes 
from clinical data and animal models. In patients with ARDS, the concentration of neutrophils in the 
bronchoalveolar lavage (BAL) fluid correlates with severity of ARDS and outcome (2; 3), whereas the severity of 
lung injury has been reduced by neutrophil depletion in mice. Furthermore, after blocking interleukin-8 (IL-8), a 
major chemoattractant for neutrophils, rabbits have been protected from acid aspiration-induced lung injury. A 
multitude of experimental and clinical data point at the causative role of neutrophils in lung injury (1-57). Although 
neutrophil activation is vital for the host defense, overzealous activation leads to tissue damage by release of 
cytotoxic and immune cell–activating agents such as proteinases, cationic polypeptides, cytokines, and reactive 
oxygen species.  
 
1.2 
Mechanism of action of Reparixin 
 
NUMEROUS STUDIES HAVE CONFIRMED A KEY ROLE OF CXCR1/CXCR2 RECEPTOR AS POTENTIAL THERAPEUTIC 
TARGET IN ACUTE LUNG INJURY (ALI) AND ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS). Neutrophil 
infiltration of the lung is controlled by a complex network of chemokines that are released by a variety of cell 
types. Alveolar macrophages are a major source of chemokines in the alveolar space and produce IL-8, growth-
regulated oncogene (GRO)-related peptides and CXCL5 (also known as epithelial neutrophil-activating protein 
[ENA]-78) (58; 59) (60; 61). High concentrations of IL-8 in BAL fluid from ARDS patients are associated with 
increased neutrophil influx into the airspace (62; 63). Recent studies have revealed that IL-8 in BAL fluid is bound 
to IL-8 autoantibodies (anti-IL-8:IL-8 complexes) (64; 65) and BAL fluid concentrations of these complexes 
correlate with development and outcome of ALI (66; 67). In particular, this complex exhibits chemotactic and 
proinflammatory activity (68). Moreover, intratracheal application of IL-8 induces lung injury which can be 
attenuated by inhibition in different models of ALI (69). In rodents, the most relevant chemokines for neutrophil 
recruitment into the lung are keratinocyte-derived chemokine (KC, also named CXCL1) or cytokine-induced 
neutrophil chemoattractant (CINC; the rat homolog to KC) and macrophage inflammatory protein-2 (MIP-2, also 
named CXCL2). Similar to IL-8, CXCL1, CXCL2, lipopolysaccharide-induced CXC chemokine (LIX, also named 
CXCL5) and lungkine (CXCL15) bind to CXCR2. Inhibition or knockout of CXCR2 receptor diminishes 

 
 
 
 
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neutrophil influx into the lung (70-77). In contrast to the multiple CXC chemokines only 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 and CXCL8 (IL-8) with a high affinity, human CXCR2 
binds also to CXCL6 and IL-8 as well as several CXC chemokines (GRO-α,GRO-β, GRO-γ, CXCL1, CXCL2, 
CXCL3), ENA-78 (CXCL5) and (CXCL7) (78).  
 
MECHANISM OF ACTION OF REPARIXINAS MODULATOR OF THE INFLAMMAYORY CASCADE. Reparixin (DF1681Y) is 
a specific inhibitor of CXC ligand 8 [CXCL8; formerly interleukin (IL)-8] biological activity, stemming from a 
program of drug design of molecules intended to modulate chemokine action. Reparixin is in vitro a potent and 
specific inhibitor of CXCL8 biological activity. In vitro chemotaxis experiments have shown that reparixin inhibits 
CXCL8-induced chemotaxis of human polymorphonuclear leukocytes (PMN) in the low nanomolar range. Studies 
to elucidate the mechanism of action have shown that reparixin is a non-competitive allosteric inhibitor of the 
CXCL8 receptors CXCR1 and CXCR2. Interaction of reparixin with CXCL8 receptors inhibits the intracellular 
signal transduction events activated by binding of CXCL8 to CXCR1 and CXCR2 (85, 86). In vivo, reparixin 
prevented PMN infiltration into the transplanted kidney and reduced creatinin levels in a rat model of kidney 
transplantation. Similarly, in a rat model of lung transplantation, reparixin improved isolated graft oxygenation, 
decreased pulmonary oedema, and significantly reduced neutrophil infiltration into transplanted lungs. Moreover, 
reparixin prevented PMN infiltration and tissue damage in other animal models of ischemia/reperfusion injury of 
liver, brain, intestine, heart and spinal cord. In these models, in vivo inhibition of PMN recruitment ranged from 
40 to 90%, and inhibition of tissue damage ranged from 50 to 80%. Efficacy was seen in all models at reparixin 
dose of 9.90 mg/kg.  
Recently, reparixin lysine salt was evaluated in different models of intrahepatic pancreatic islet transplantation in 
mice, which include syngeneic and allogeneic settings. Reparixin was administered by s.c. continuous infusion for 
7 or 14 days starting from day -1 of islet transplantation. A dose of 5.28 mg/kg/hour was administered in all 
experiments. Reparixin was able to significantly improve islet engraftment, as demonstrated by its ability to 
increase the likelihood of and to reduce the time to gain non-fasting blood glucose levels less than 200 mg/dl 
(normo-glycaemia) in marginal mass syngeneic islet transplantation model. In the fully mismatched allogeneic 
model, reparixin not only protected islets from early graft failure, but was also able to increase the time to rejection, 
as shown by post-transplant prolongation of normo-glycaemia. Graft function was indefinitely prolonged in 
20/30% of mice treated with reparixin and rapamycin, suggesting possible tolerance induction. In parallel, 
reparixin treatment reduced intrahepatic infiltration of PMNs, macrophages, T helper and dendritic cells 
 
REPARIXIN EFFECTS ON ACUTE LUNG INJURY (ALI) MODELS. The therapeutic potential of reparixin in murine 
models of LPS-induced pulmonary inflammation and acid-induced ALI was studied. Reparixin (15 μg g−1) 
reduced neutrophil recruitment in the lung by approximately 50% in an in vivo model of LPS-induced ALI. 
Reparixin also reduced accumulation of neutrophils in the interstitial compartment and vascular permeability in 
LPS-induced ALI. Both prophylactic and therapeutic application of Reparixin improved gas exchange, and 
reduced neutrophil recruitment and vascular permeability in a clinically relevant model of acid-induced ALI (70).  
In the CDE (cat dander extract) single challenge model (SCM), administration of Reparixin (15 mg/kg) suppressed 
neutrophil recruitment into the lungs. In the CDE Multiple Challenge Model, Reparixin inhibited eosinophil, 
neutrophils, and total cell numbers in BALF, serum levels of total IgEand CDE specific IgE, airway epithelial 
mucin secretion, levels of Th2 inflammation‐associated genes periostinand muc5ac, and the BALF levels of IL‐4, 
IL‐13, IL‐33, and TSLP in BALF. 
 
REPARIXIN SUPPRESSES ALLERGEN CHALLENGE INDUCED NEUTROPHILIC INFLAMMATION AND ALLERGIC AIRWAY 
INFLAMMATION. In the CDE (cat dander extract) single challenge model (SCM), administration of reparixin (15 
mg/kg) suppressed neutrophil recruitment into the lungs. In the CDE Multiple Challenge Model, reparixin 
inhibited eosinophil, neutrophils, and total cell numbers in BALF, serum levels of total IgEand CDE specific IgE, 
airway epithelial mucin secretion, levels of Th2 inflammation‐associated genes periostin and muc5ac, and the 

 
 
 
 
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BALF levels of IL‐4, IL‐13, IL‐33, and TSLP in BALF. Pharmacological inhibition of CXCR1/2‐axis by 
administration of reparixin  inhibits allergen induced innate and allergic airway inflammation in mice (79). 
 
REPARIXIN AMELIORATES THE INCREASED SEVERITY OF PULMONARY FIBROSIS CAUSED BY PARTICULATE MATTER 
In a murine model of bleomycin-induced pulmonary fibrosis, pharmaceutical inhibition of CXCR2 with reparixin 
ameliorated Particulate Matter-induced increased severity of pulmonary fibrosis. Co-treatment with reparixin in 
mice receiving Particulate Matter and bleomycin reduced neutrophil number and neutrophil elastase concentration 
of day 2-BALF. Moreover, reparixin improved lung function and ameliorated pulmonary fibrosis as assayed by 
total collagen content and histochemical stains of fibrosis markers on day 14-lung tissues. (80) 
 
REPARIXIN ANALOGUES RESULTED A VALID THERAPEUTIC STRATEGY FOR TREATING LUNG INFECTIONS CAUSED BY 
INFLUENZA A VIRUS OR STREPTOCOCCUS PNUEMONIAE. 
The role of CXCR1/2 during influenza, pneumococcal, and post-influenza pneumococcal infections was 
investigated. Mice were infected with influenza A virus (IAV) or Streptococcus pneumoniae and then treated daily 
with the CXCR1/2 antagonist DF2162. To study secondary pneumococcal infection, mice were infected with a 
sublethal inoculum of IAV then infected with S. pneumoniae 14 days later. DF2162 was given in a therapeutic 
schedule from days 3 to 6 after influenza infection. Lethality, weight loss, inflammation, virus/bacteria counts, and 
lung injury were assessed. CXCL1 and CXCL2 were produced at high levels during IAV infection. DF2162 
treatment decreased morbidity and this was associated with decreased infiltration of neutrophils in the lungs and 
reduced pulmonary damage and viral titers. During S. pneumoniae infection, DF2162 treatment decreased 
neutrophil recruitment, pulmonary damage, and lethality rates, without affecting bacteria burden. Therapeutic 
treatment with DF2162 during sublethal IAV infection reduced the morbidity associated with virus infection and 
also decreased the magnitude of inflammation, lung damage, and number of bacteria in the blood of mice 
subsequently infected with S. pneumoniae. These data suggested that modulation of the inflammatory response by 
blocking CXCR1/2 improves disease outcome during respiratory influenza and pneumococcal infections, without 
compromising the ability of the murine host to deal with infection (81). 
DF2162, a Reparixin analogue, belongs to the same family of non competitive-allosteric inhibitors of CXCR1 and 
CXCR2 widely characterized in our research labs in terms of structure activity relationship and mechanism of 
action. 
The two molecules belong to the chemical class of 2-(R)- phenyl propionamide derivatives thus sharing the same 
chemical moiety.  
Reparixin and DF2162 exhibit similar potency in the inhibition of the target receptors CXCR1 and CXCR2 (IC50s 
in CXCL8 induced-chemotaxis in the range of 1 nM). The molecular mechanism of action has been deeply 
characterized by point-mutagenesis studies on CXCR1 and CXCR2 showing that Reparixin and DF2162 bind the 
receptors in the same allosteric site in the Trans-Membrane region, highly conserved in the two receptor subtypes. 
(83-86) 
The different pharmacokinetic profile of the two molecules account for a bid (15 mg/Kg) oral administration of 
DF2162 as compared to a tid (15 mg/Kg) administration (on continuous infusion) for reparixin. 
For this reason, DF2162 has been used to assess the role of CXCR1/2 during influenza (IAV), pneumococcal, and 
post-influenza pneumococcal infections in mice models. Even though the extensive characterization work was 
conducted with DF2162, preliminary experiments showed a similar behaviour using reparixin in the single IAV 
model leading to comparable results.  
To investigate the role of CXCR1/2 during influenza infection, mice were infected with 1 × 104 PFU of IAV and 
then treated three times a day (from day 0 - at the time of the infection - to day 5 post-infection) with reparixin at 
15 mg/Kg. Similarly to DF2162, treatment with reparixin decreased morbidity, as seen by the reduction of weight 
loss, reduced leukocytes infiltration into the airways, including neutrophils, and the levels of the pro-inflammatory 
cytokines TNF-α and CXCL1 and reduced the lung injury associated with IAV infection measure by 
histopathological score. 
 

 
 
 
 
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1.3 
Toxicology data 
 
Reparixin was tested for toxicity in rodent and non-rodent animal species after single and repeated i.v. doses. The 
repeated dose administration studies were conducted by i.v. continuous infusion, according to the intended human 
administration route. The general toxicological profile of i.v. Reparixin, in the studies conducted to date, is 
characterized by a low toxicity after single or repeated dose administrations in rats (LD50 = 229.68 mg/kg i.v.; 
660.00 mg/kg/day as No Observed Adverse Effect Level from 4-week studies) and mice (401.94 mg/kg i.v.). 
Continuous i.v. administration to dogs for 2 weeks resulted in a safe dose of 39.60 mg/kg/day. Continuous i.v. 
infusion of Reparixin to the male and female rat at dose levels of up to 660.00 mg/kg/day did not have any 
significant adverse effects on mating performance and fertility. Reparixin poses no genotoxic hazard for humans. 
Reparixin lysine salt, at doses in excess of those intended to be used in humans, has a safe pharmacology profile 
in the renal, cardiovascular and respiratory systems of rats and dogs. The local tolerability of reparixin lysine salt 
was assayed in the rabbit ear lateral vein. The compound was well tolerated in concentrations up to 4.95 mg/mL 
(1 mL/kg) infused over a minute. In order to provide evidence of the safety of DF2243Y, the main metabolite of 
reparixin excreted in urine in humans, safety pharmacology and toxicity studies have been performed at doses 2 
to 3 times higher that those reached in man, as may occur during the treatment of patients receiving kidney 
transplantation. 
 
1.4 
Pharmacokinetics and product metabolism 
 
PK studies by i.v. injection revealed that Reparixin is very rapidly eliminated in rats and humans (t1/2 0.5-3 hrs 
and 1.0-1.5 hrs, respectively) whereas elimination is slower in dogs (12-28 hrs). 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 2.77 mg/kg/h for 48 hrs (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 rat, 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 21 consecutive days followed by 7 days of drug 
holyday 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 21, indicating the absence of accumulation over the dosing 
period. Also t1/2 did not change from day 1 to day 21, with a median value of about 2 hrs. Once absorbed, Reparixin 
is highly protein bound 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 21 within the observed intersubject variability. The t1/2 of all three metabolites 
appeared to remain about the same from day 1 to day 21. 
To investigate the PK/PD characteristics of Reparixin, we assessed the effect of the drug in inhibiting IL-8-
mediated hPMN NETs release in whole blood of healthy volunteers, 500 µL/sample of whole blood were pre-
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polylysine coated glass circular coverslips and incubated for 30 min at 37°C in a 5% CO2 atmosphere to allow for 
cell adherence.  Post-incubation, samples were stimulated with vehicle or IL-8 (100 ng/mL) for 4h (37°C, 5% 
CO2), after which the supernatant was removed and coverslips washed one time with HBSS. Next, samples were 
stained with 40 nM Sytox Green for 10 min. Finally, cells were fixed in 2% paraformaldehyde and NETs formation 
determined by confocal microscopy.  Reparixin blocked IL-8-induced NETs formation in a concentration 
dependent manner being the inhibition statistically significant at 5 µg/mL (40% of inhibition) and reaching the 
almost complete inhibition (about 90%) at 25 µg/mL thus confirming that the total blood concentration of 25 
µg/mL (corresponding to a free unbound concentration of 100 nM) that is reached at the steady state by iv infusion 
or by repeated oral administration (Css) 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. 
 
1.5 
Clinical development 
 
Reparixin is the first low molecular weight blocker of CXCL8 biological activity in clinical development.  
Reparixin was granted orphan drug designation for the “prevention of delayed graft function after (solid) organ 
transplantations” by the European Commission of Orphan Medicinal Products in September 2001 and by the Food 
and Drug Administration in January 2003. Recently orphan drug designation has been granted in the EU for 
“prevention of graft rejection in pancreatic islet transplantation”. In the 4th quarter of 2011, Dompé has received 
Scientific Advice from the European Medicines Agency (EMA) for the development of reparixin in pancreatic 
islet transplantation. 
 
REPARIXIN IMPROVED SURVIVAL AFTER LUNG TRANSPLANTATION. In a US-Canada phase 2 study 
, 101 
patients (46 on reparixin, 55 on placebo) undergoing single or bilateral lung transplant were trated with reparixin. 
The patients were randomized to receive 48h i.v. continuous infusion (loading: 4.488 mg/kg/h for 30 min, 
maintenance: 2.772 mg/kg/h for 47.5hrs) of either reparixin or placebo starting a few hours before the transplant. 
The study showed a statistically significant difference in patient survival at Month 12 post-transplant between the 
placebo (7 deaths) and reparixin (no deaths) groups (p-value = 0.0111 [Log-Rank]). 
 
IRCCS OSPEDALE SAN RAFFAELE COORDINATED A PHASE 3 INTERNATIONAL TRIAL WITH REPARIXIN IN 
PANCREATIC ISLET TRANSPLANTATION. A phase 3, multicenter, randomized, double-blind, parallel-assignment 
study (NCT01817959) was conducted and coordinated by Ospedale San Raffaele of Milan, Italy in recipients of 
islet allo-transplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Patients received 
either reparixin at a dose of 2.772 mg/kg body weight/h or matched (flow rate/length of infusion) placebo 
according to their randomization number. Study drugs were administered on top of immunosuppression by 
continuous infusion through a high-flow vein for 7 days starting 12 h before each islet infusion. No clear 
differences between treatment groups were observed for rates, severity, and distribution of AEs or SAEs. Analysis 
of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after 
a single islet infusion in patients receiving reparixin, as compared with patients receiving placebo (26.7% vs. 0%, 
P = 0.09) when antithymocyte globulin was used as induction immunosuppression (82). 
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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 10.6 mg/kg over 
30min or 133 mg/kg over 48h and, in pancreatic islet and liver transplantation studies, 2.772 mg/kg body 
weight/hour 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 (SAEs) or Adverse Event 
(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 2 
and 3 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 twice in several patients. Most frequent 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 judjed probable in relation to 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 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. 
Overall, the most frequent (>10%) ADRs observed in the phase 1 to phase 3 I.V. studies were: Gastrointestinal 
disorders (about 26% of the total number of reports), including abdominal pain lower, abdominal pain NOS, 
abdominal pain upper, constipation, diarrhea, dyspepsia, flatulence, gastroesophageal reflux disease, 
gastrointestinal haemorrhage, intra-abdominal haemorrhage, nausea and vomiting.  
Nervous system disorders (about 19%), including headache, dizziness, hypoaesthesia, 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 subjects receiving either single 
agent reparixin 
, operable breast cancer: 20 patients) or the combination of reparixin and weekly 
paclitaxel in metastatic breast cancer 
: 30 patients; 
 randomized 
 61 
patients). 
In the studies completed so far, 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 
 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 (Appendix 1) 
 
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1.7 
Phase 2 study  
An open-label, phase 2 study was conducted to assess the efficacy and tolerability of Reparixin in comparison with 
standard of care. The study included patients with severe COVID-19 requiring supplemental oxygen, or non-
invasive mechanical ventilation. 51 patients were randomized overall, 34 in the Reparixin group and 17 in the 
standard of care group (2:1 randomization ratio). The primary end-point was the first occurrence of a composite 
endpoint (supplemental oxygen requirement, invasive mechanical ventilation use, admission to ICU, use of a 
rescue medication for any reason). The treatment with reparixin was associated with a statistically significant 
improvement in the time to the composite endpoint (defined as the occurrence of at least one of the following: 
supplemental oxygen requirement, mechanical ventilation use, admission to ICU, use of a rescue medication for 
any reason), with fewer days of oxygen use and shorter duration of mechanical ventilation. The results of the study 
suggest that the treatment with reparixin may have prevented the progression to more severe respiratory disease. 
One death occurred in the Reparixin group and three in the control arm. No adverse events were related to 
Reparixin.  
The analysis of the phase 2 data has allowed establishing proof-of-concept, endpoint selection, and sample size 
planning along with review of Data Monitoring Committee (DMC) recommendations. 
1.8 
Phase 3 study  
This phase 3 study has been designed as a double-blind study comparing Reparixin vs placebo on top of the 
standard therapy in the same patient population as that enrolled in the phase 2. Hospitalized patient with severe 
COVID-19 pneumonia requiring supplemental oxygen will be randomized. The reference group with placebo is 
justified by the current unavailability of an effective therapy for COVID-19 after having various compounds been 
tested, e.g. remdesivir, hydroxychloroquine, protease inhibitors, tyrosine kinase inhibitors, convalescent plasma 
or intravenous immunoglobulins. The use of any of these treatments is allowed in the study provided that it is 
started as background treatment in all patients characterized by a similar level of disease severity, at a site level.  
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study objectives 
 
Efficacy and safety of Reparixin treatment as compared to placebo (both on top of standard treatment) in adult 
patients with severe COVID-19 pneumonia. 
2.2 
Primary Endpoint 
 
- 
 Proportion of patients alive and free of respiratory failure at Day 28, i.e. with no need of invasive 
mechanical ventilation or ECMO or admission to ICU linked to worsening of respiratory parameters 
compared to baseline.  
2.3 
Key Secondary Endpoints 
 
- 
Proportion of patients alive and free of respiratory failure (as described for the primary endpoint) at 
Day 60,  
- 
Mortality rates up to Day 28, 
- 
Incidence of ICU admission until Day 28, 

 
 
 
 
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5.2: Other treatments). Follow-up information on the patient’s clinical condition (new hospitalization, need of 
supplemental oxygen, adverse events) and survival will be collected until day90. 
An interim analysis for efficacy and futility is planned when half of the planned patients has reached the primary 
endpoint.   
 
3.2 
Study population 
Hospitalized adult patients with rt-PCR-confirmed severe COVID-19 pneumonia. Patients are considered to have 
severe disease in the presence of respiratory distress and requiring supplemental oxygen. 
No gender and/or ethnicity restrictions will apply. 
 
3.3 
Study duration 
The overall study duration is 90 days, including follow-up, but with a variable treatment period.  
The investigational treatment will last up to a maximum of 21 days (depending the Investigator’s decision based 
on the patient’s condition, or patient decision to withdraw), with a follow-up period lasting up to 90 days since 
baseline.  
The treatment is not foreseen to be continued at home.  
 
3.4 
Description of the study 
The study will consist of three study periods: screening, treatment period (up to a maximum of 21 days), follow-
up (up to 90 days).  
During the course of the study, visits and assessments will be performed as defined in the Schedule of Assessments. 
 
Screening period 
Patients are included in the study after a variable period at home with initial symptoms of the COVID-19 infection; 
during this period, the patient had supposedly been treated by the family doctor. In case of worsening of his/her 
general and pulmonary condition eventually requiring oxygen supplementation in a hospital environment, the 
patient will start the screening phase for the confirmation of the selection criteria.  
Before any study related procedures, at study entry all patients must have given a written informed consent for the 
study and will be assigned a screening number. 
Patient meeting all of the inclusion criteria and none of the exclusion criteria will be randomized (see section 4.2). 
No time limit has been posed for the time from the onset of symptoms and hospitalization. No time limit has been 
posed for the duration of the screening period until the treatment start as well. The time between onset of symptoms 
at home and the initiation of the investigational treatment, as well as the time between hospitalization and initiation 
of the investigational treatmentwill have to be recorded.  
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. 
 
Randomization and treatment  
In order to request randomization to the study, all the pre-treatment evaluations must be completed and all the 
inclusion and exclusion criteria satisfied. 
Consecutive randomisation 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 

 
 
 
 
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be randomized in a 2:1 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; sealed envelopes containing information on the actual study 
treatment to which the patient was randomized (active or placebo) will be provided for emergency use only. 
Information for unblinding is provided in section 5.1. 
 
Baseline is the day of randomization (study Day 1) and should possibly be coincident with the start of the 
investigational treatment. End of Treatment (EoT) is the last day of treatment administration.  
The treatment is allowed up to 21 days but it will be interrupted earlier for the following reasons:  
- 
Investigator’s decision based on clinical judgment of clinical improvement, even if the patient is still 
hospitalized but no longer requiring supplemental oxygen or significant medical care;  
- 
occurrence of adverse events;  
- 
patient’s withdrawal of consent to the treatment.  
During the treatment period assessment visits will be performed at study days 3 - 7 (±1) - 14 (±2) - 21 (±2), or 
until early treatment interruption for any reason.  
An additional visit will be performed on the day of discharge from hospital (or maximum at Day 28 ±2) for post-
treatment collection of clinical and laboratory data.  
 
Follow-up period 
After discharge from hospital, subjects will be contacted for a follow-up check on their health status at Day 60  
and Day 90 (preferably in person at the Center, or by interview via a telephone call), unless the patient also 
withdraws the consent to the follow-up.  
For subjects discharged home before the completion of the 21-day treatment period, follow-up visits will be held 
at days 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) - 60 (±2) and/or 90 (±2) depending on the discharge time point.   
End of Study (EoS) is defined as the last day the last patient completes the last study assessment (including the 
follow-up assessments), or withdraws the consent to participate in the study, including follow-up. Subjects with 
EoS before Day 28 should undergo a full evaluation (as required on Day 28). Subjects with EoS after Day 28 but 
earlier than Day  90 should undergo evaluation as required on Day90. 
 
 
 
4. STUDY POPULATION 
4.1 
Number of patients 
 
A total number of 312 subjects will be randomized with a 2:1 randomization ratio (208 in the reparixin group; 104 
in the placebo group).  No significant drop-out rate is foreseen which could impact on the number of the study 
population 
Enrollment can be interrupted at the interim analysys for futility or early efficacy (superiority) of Reparixin over 
placebo.  
 

 
 
 
 
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4.2 
Inclusion/exclusion criteria  
4.2.1 Inclusion Criteria: 
1. Age 18 to 90, male and female subject of any race 
2. Reverse transcriptase Polymerase Chain Reaction (rt-PCR)-confirmed COVID-19 infection based on a 
nasal / oropharyngeal swab within 10 days before randomization 
3. At least one of the following: 1) Respiratory distress with tachypnea (RR ≥ 24 breaths/min without 
oxygen); 2) Partial arterial oxygen pressure (PaO2) / Fraction of inspiration O2 (FiO2), P/F >100 and <300 
mmHg (1mmHg = 0.133kPa), 3) SpO2 ≤ 94% while breathing ambient air.  
Calculation through validated Sat/FiO2 scales is allowed. 
P/F value of reference if the last available before the signature of consent. 
4. Need of supplemental oxygen (i.e. new use of supplemental oxygen, or increased oxygen requirement if 
on chronic oxygen) requiring low- or high-flow oxygen or non-invasive mechanical ventilation (7-point 
WHO-OS category 4 or 5) 
5. Radiological chest imaging (X-rays, CT scan) confirms lung involvement and inflammation (presence of 
ground-glass opacities, and/or inter/intra lobular septal thickening, and/or consolidations in a patchy 
distribution).  
6. Inflammatory status as documented by at least one of the following: Lactate dehydrogenase (LDH) > 
normal range, C-reactive protein (CRP) ≥ 100 mg/L, IL-6 ≥ 40 pg/mL, serum ferritin ≥ 900 ng/mL, XDP 
> 20 mcg/mL.  
7  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:  
v) Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives for at least 
2 months before the screening visit until 30 days after final visit  
vi) 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 final visit  
vii) A male sexual partner who agrees to use a male condom with spermicide  
viii) 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. 
 
4.2.2 Exclusion Criteria: 
1. Cannot obtain informed consent. 
2. hepatic dysfunction with Child Pugh score B or C, or ALT or AST> 5 times the upper limit;  
3. renal dysfunction with estimated glomerular filtration rate (MDRD) < 50 mL/min/1.73 m2 or patient 
receiving continuous renal replacement therapy, hemodialysis, or peritoneal dialysis. 
4. Bacterial sepsis (besides COVID-19 sepsis) 
5. Positive test for influenza virus, if tested during the current illness (note: influenza testing is not required 
by protocol) 
6. Known congenital or acquired immune deficiency,  
7. Patients with hypersensitivity to ibuprofen or to more than one non-steroidal anti-inflammatory drug or 
to more than one medication belonging to the class of sulfonamides (e.g. sulfamethazine, 
sulfamethoxazole, sulfasalazine, nimesulide or celecoxib).  
Hypersensitivity to sulphanilamide antibiotics, e.g. sulfamethoxazole, does not qualify for exclusion.  

 
 
 
 
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Know allergy to any medication (either investigational or non-investigational) which is planned at study 
entry for use during the study. 
8. Patients receiving other not allowed medications (see Section: Not allowed medications) 
9. Severe, active bleeding such as hemoptysis, gastrointestinal bleeding, central nervous system bleeding, 
and nosebleeds within 1 month before enrollment. 
10. Evidence of COVID-19 disease progression during previously initiated treatment with remdesivir (alone 
on in any combination with other antiviral treatments), protease inhibitors (e.g. ritonavir, lopinavir, 
darunavir – atazanavir), tyrosine kinase inhibitors (e.g. baricitinib, imatinib, gefitinib), convalescent 
plasma or intravenous immunoglobulin for COVID-19, or investigational treatments 
11. More than three infusions of remdesivir, including the loading dose, prior to randomization 
12. Subject participating in other interventional clinical trials. Subject having received investigational therapy 
in the previous 3 days, or at least 5 half-lives.  
13. At the time of enrollment, patients not in a clinical condition compatible with the oral administration of 
the study drug.  
14. P/F < 100 mmHg 
15. Pregnancy:  
i) 
positive or missing pregnancy test before first drug intake or day 1;  
ii) 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.  
 
 
5. TREATMENTS 
5.1 
Investigational products 
5.1.1 Dose regimen and administration  
Patients who satisfy the predefined inclusion and exclusion criteria for this trial will be randomized at a 2:1 ratio 
to one of the following treatment groups: 
 
- 
Group 1: Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up 
to 21 days or until decision of discharge from the hospital, on top of standard supportive care.   
 
- 
Group 2 (control): placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until 
decision of discharge from the hospital, on top of standard supportive care.  
No dose modifications are allowed. In case of significant adverse events which are supposed to be possibly / 
probably related to Reparixin, the study drug may be temporarily interrupted (and eventually resumed at the 
standard dose / schedule, if considered safe for the patient), or definitively withdrawn.  
Because the blinded condition does not allow the Investigator to know the actual treatment in a given patient, any 
decision will be made assuming that the concerned treatment is Reparixin.  
 
For each administration, two tablets of Reparixin (600 mg each) or placebo will be taken, for the total of three 
daily administrations (6 tablets daily). It is advisable to take the tablets with a glass of water to facilitate 
swallowing. 
For patients who are unwilling or unable, in the opinion of the investigator, to comply with the oral tablet treatment, 
is possible to continue the regular administration of the study drug by administering the medicine through a naso-
gastric tube, following this procedure: for each administration, disperse two Reparixin 600 mg tablets in 25 mL of 

 
 
 
 
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drinking water in a suitable container (e.g. conical tubes for 50 mL Falcon centrifuge). Disgregate the tablets 
(shaking manually or with the aid of a planetary shaker or a rocker) until obtaining a homogeneous milky 
suspension (time required 7 - 10 minutes). Keep the prepared suspension at room temperature and protected from 
light for up to 24 hours. Immediately before administration, manually shake the suspension again until complete 
and homogeneous resuspension, withdraw using a 50 mL needle-free syringe and administer to the patient using 
a naso-gastric tube. After administration, run 25 ml of drinking water through the gastric tube. 
 
The use of the study drug not in accordance with this protocol could constitute a protocol violation.  
The use of the study drug outside this protocol is not allowed. 
 
5.1.2 Randomization 
Randomization will be performed through an Interactive Response System (IRS). Specific procedures for 
randomization through the IRT are contained in the study procedures manual. 
Each Patient’s treatment pak/Kit number will be randomly associated with a treatment group. The randomization 
list will be provided to the facility responsible for IMP packaging/labelling for the purpose of IMP preparation. 
Each randomized patient will be allocated with randomization number according to the stratified randomization 
list. Dropouts after randomization will not be replaced  
Randomization will be stratified by site, gender and age class (<65 yrs vs ≥ 65 yrs) to ensure balanced assignment 
across treatment groups. The stratified permuted block randomization list will be generated with a computer 
procedure by an independent statistician not involved in the conduct of the study. 
 
5.1.3 Unblinding   
For each randomized subject, individual code breaks will be accessible in the event of a medical emergency 
requiring knowledge of the treatment assigned to the subject. Only the responsible investigator, or authorized 
delegates, can break the code via the IRT or by opening the sealed envelopes with indication of the actual treatment. 
Describe unblinding procedure-to be modified based on study specific process. 
(Paper envelope unblinding) Individual treatment codes will be provided as a tamper-resistant system (either a 
sealed envelope or a scratch card) to:  
-     the Investigator for emergency procedures; 
-     the Dompé Drug Safety for safety procedures. 
Individual treatment codes must be kept in a secure location accessible only to designated staff in order to prevent 
dissemination of the treatment to personnel involved in study conduct who must remain blind.  
During the study the integrity of the envelopes will be regularly checked by [CRO] Monitor during the visits at 
site. At the end of the study all the individual envelopes must be returned to Dompé. A copy of the Individual 
envelopes identified with the subject assignment number will be also sent to the Dompé Pharmacovigilance 
Responsible. 
Any breaking of the treatment code by the investigational staff must be reported immediately to the Sponsor and 
must include an explanation for breaking the code. The sponsor should be contacted to discuss the case, if 
possible, prior to unblinding.  
A general rule is that breaking the code is only allowed if the knowledge of the actual treatment is necessary for 
an appropriate decision on actions / treatments for the safety of the patient.  
The DMC will have access to group-unblinded and/or fully unblinded DMC reports. 

 
 
 
 
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The sponsor’s personnel from the Pharmacovigilance Department of Dompè may break the treatment code for 
subjects who experience a Suspected Unexpected Serious Adverse Reaction (SUSAR), in order to determine if 
the individual case requires expedited regulatory reporting. 
Pharmacists will be provided with the ‘Instructions to the Pharmacy’. 
Investigators will be allowed to unblind study medication directly through the IRT system and must notify CRO’s 
medical monitor. Training is provided to investigators prior to authorization to use the IRT system and the 
unblinding function is outlined in the study specific user guide.  
The randomization code will be broken when the last enrolled patient has completed therapy, and once the database 
has been locked. 
 
Unblinding can only occur in case of emergency, when knowledge of the treatment identity is essential for treating 
the subject. 
If the treatment code needs to be broken in the interest of patient safety for a medical emergency, the Investigator 
is allowed to break the treatment code for the specific patient, even before informing the Sponsor. The Investigator 
must always notify the Sponsor, so that the reason for any premature unmasking can be documented, by means of 
a communication to CRO/Dompé Pharmacovigilance to the contact details in the section “Contact Information” 
and to Dompé Medical Expert. 
The Investigator will inform the Dompé representative (Dompé Medical Expert) if an emergency unmasking was 
performed without revealing the treatment identity, but only referring to the kit number involved in the unmasking 
in order to avoid a dissemination of unmasked information. 
Dompé Pharmacovigilance will unmask patient treatment only for safety reason and will document envelope 
opening or unblinding through the IRT system. 
Additionally, Dompé Pharmacovigilance may need to unmask the patient’s treatment if a reported SAE meets 
criteria of a Suspected Unexpected Serious Adverse Reaction (SUSAR) in order to fulfill expedited regulatory 
reporting requirements. Unmasked information shall not be disclosed to Investigators. 
The identity of the treatments will remain unknown to the subject, Investigator, site staff, CRO and Dompé’s 
Development personnel until the study completion and formal unmasking. 
 
5.1.4 Compliance to Treatment 
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 baseline and 
EoT. Discrepancies will have to be documented and justified.  
  
5.2 
Other treatments 
5.2.1 Additional therapy 
 
Any additional therapy must be considered as local standard of care treatment, and it must be able to be 
administered to all patients enrolled in the study. Investigators are allowed to provide any medications having 
received final or conditional approval for the treatment of the COVID-19 infection, or used off-label at the 
Investigator’s discretion and justified by scientific evidence of effectiveness against the COVID-19 infection 
without to stop study treatment. 
 

 
 
 
 
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5.2.3 Concomitant and not allowed medications  
No specific wash-out is required for treatments (symptomatic treatment for COVID-19, or any therapy for 
concomitant diseases) which are ongoing at screening, unless decided by the Investigator. 
During hospitalization, patient will receive the standard supportive care based on the patient’s clinical need, 
eventually including anticoagulants, corticosteroids, antibiotics, among others, as per local standard therapy and 
in line with international guidelines. Optimal oxygenation can be considered an SpO2 between 92% and 96%; 
however, no specific oxygen target is required by the protocol. 
The Investigator’s intention to adopt a supportive use of other specific COVID-19 treatments, available off-label 
or under conditional or final approval [for example: remdesivir (± baricitinib), hydroxychloroquine, protease 
inhibitors (e.g.  lopinavir / ritonavir, darunavir – atazanavir), tyrosine kinase inhibitors (e.g. baricitinib, imatinib, 
gefitinib), convalescent plasma or intravenous immunoglobulin] should be discussed with the Sponsor’s Clinical 
Operations. This preventive measure may be allowed only if that medication is routinely used at the site as a local 
standard of therapy, there is guarantee that it will be available during the whole duration of the study and it will be 
uniformly applied to all the study patients to be enrolled at that Center in this protocol characterized by a similar 
level of disease severity, at a site level.  
 
Any concomitant medication that the participant will be receiving during the participation in this study will be 
recorded in the CRF with annotation of whether the medication is considered a specific “standard of care” for the 
treatment of the COVID-19. Dose, schedule of administration, start and end date, and reason of use will be 
collected. In case of complex schedules of administrations or variable intraday dosing (as those possibly in use in 
the ICU) an estimated, consistent, average dose can be reported, if also recorded in the source documents. 
 
There is no contraindication to the use of concomitant supportive and prophylactic care medications as deemed 
necessary by the treating physicians, unless a significant drug-drug interaction leading to metabolic alterations and 
potential harm to the patient 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.  
A list of medications known to act as inhibitor or inducer of CYP2C9 is provided hereafter: 
- 
CYP2C9 Inducers: rifampin, carbamezapine, aprepitant, bosentan, phenobarbital, St. John’s Wort;  
- 
CYP2C9 Inhibitors: amiodarone, fluconazole, miconazole, oxandrolone, capecitabine, cotrimoxazole, 
etravirine, fluvastatin, fluvoxamine, metronidazole, sulfinpyrazone, tigecycline, voriconazole, 
zafirlukast. 
 
For remdesivir (recently receiving conditional approval for the treatment of COVID-19; June 2020) no clinical 
interaction studies have been performed and the overall potential of this drug for interactions is currently unknown. 
However, reparixin is not a substrate of the microsomal enzymes of which remdesivir is an in-vitro inhibitor 
(CYP3A4, OATP1B1, OATP1B3) or inducer (CYP1A2, CYP3A).  
Reparixin was found to slightly inhibit human CYP3A4 but only at very high unbound drug concentration of (IC50 
8 µM), concentration significantly higher than the concentration of unbound drug reachable with the proposed 
administration regimen.  
Furthermore, recent expert reports suggest remdesivir exposures unlikely to be substantially affected by CYP3A4, 
2C8, or 2D6 isoenzymes or by P-gp or OATP drug transporters and the drug may be administered with weak to 
moderate inducers or with strong inhibitors of these CYP isoenzymes or drug transporters. However, because 
strong inducers may modestly reduce remdesivir exposures and clinical relevance of lower exposures is unknown, 
experts state that concomitant use with drugs that are strong inducers (e.g., rifampin) not recommended (reference 
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keep a cumulative inventory and records of dispensing, use or loss of study drug. A reconciliation will be done 
between delivery and used / returned medication. Any discrepancies must be accounted for and documented. 
At the end of the study and after drug accountability has been conducted by the Sponsor or representative, partially 
used or unused study drug should be disposed for desctruction operated by the local inestigational site according 
to their procedures (documentation of destruction provided to Dompé farmaceutici), or returned to Dompé 
farmaceutici,  as agreed between the parts.  
Drug returns have to be performed before the drug’s expiry date.  
6. DISCONTINUATIONS
End of treatment (EOT) definition: EOT is defined as the last treatment day in a randomized patient. EOT occurs 
upon completion of the scheduled treatment period (up to 21 days) for clinical judgment of improvement, or at the 
time of discharge from hospital, or at any time the treatment is terminated early for any reason (e.g. for adverse 
events, ineffectiveness, withdrawal of consent for treatment). Patients randomized but with no actual treatment 
ever initiated, will have their EOT and EoS on the date of randomization. 
Patients who discontinue the treatment 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. 
End of study (EOS) definition: EOS is defined as the last day the last patient completes the last study assessment 
(including the follow-up assessments), or withdraws the consent to participate in the study including refusal to 
undergo follow-up, or is deceased or otherwise lost to follow-up.  
Discontinuation and withdrawal 
A patient has the right to withdraw from this clinical trial at any time and for any reason, without any repercussion. 
Investigators also have the right to withdraw a patient from the study at any time if in their opinion it is no longer 
in the best interest of the patient to remain in the study.  
The patient has no obligation to give a justification for his decision to withdraw from the study, however, the 
Investigator should investigate the reason, as far as possible, and record it in the CRF. The primary, actual, reason 
of withdrawal should be recorded, especially if there is supect of withdrawal due to adverse events (“withdrawal 
of consent” is a definition to be used if the patient does not give reasons). Notifications will be made to the 
regulatory authorities of study withdrawals for safety reasons and for any DMC decision to pause enrollment or 
terminate the study, according to the local country regulations.  
Participants who withdraw from the study cannot be re-randomized and are not replaced by another subject.  
All discontinuations must be recorded by the investigators; they should be promptly reported to the Sponsor if due 
to serious adverse events. In case of treatment discontinuation, an EoT visit should be conducted and data recorded; 
in case of withdrawal from the study, an EoT and/or EoS visit should be conducted. 
Patients will be followed-up according to the study procedures set forth in this clinical trial protocol and until the 
scheduled last day of follow-up (day90). The only exception will be the collection and reporting of AEs that have 
occurred during the clinical trial and have not resolved by the time of the end of follow-up: in this case AEs will 
be followed until resolution or stabilization. 
Stopping criteria for individual subjects  
Subjects should be prematurely discontinued from study treatment for any of the following reasons: 

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•
subject no longer consents to participate in the treatment phase of the study, yet consenting for the
continuation of the collection of information in the follow-up phase of the study (specific consent to be
signed).
Patient may eventually decide to withdraw the consent for the study continuation including the collection
of information in the follow-up phase,
•
physician decision that it is in the best interest of the subject to be discontinued from study treatment,
•
physician decision because of poor efficacy or poor tolerability of the investigational treatment,
•
the treatment will be interrupted in case of significant worsening of the renal function with eGFR
(MDRD) falling to below 30 ml/min/1.75m2 or an increase of serum creatinine by more than 50% since
randomization, either due to the study drug (or other concomitant drugs) or to the progression of the
underlying disease,
•
severe protocol deviations, e.g. in relation to the inclusion / exclusion criteria, major treatment
uncompliance (> 3 days of unjustified missed treatment), major procedural uncompliance (notably, the
missed collection of information for the determination of the study primary end-point).
All study subjects, including treatment discontinuations for any reason, will have to be followed up until the End 
of Study, unless the patient withdraws his/her consent to the study continuation including the follow-up.  
Stopping criteria for the clinical trial:   
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, for reasonable cause 
provided that written notice is submitted in advance of the intended termination. Advance notice is not required 
if the study is stopped due to safety concerns.  
The recommendations of the Data Monitoring Committee will be taken into consideration in this regard.  
If the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the investigator and 
subsequently provide written instructions for study termination.  
7. ASSESSMENTS AND PROCEDURES
7.1 
Procedures 
Potential study patients with confirmed COVID-19 diagnosis will be identified from those referring to the 
participating clinical sites for diagnosis and/or management. Screening will be performed and completed in 
consented patients and any suitable study patients will be treated. All subjects signing the informed consent form 
and screened for the present study will be coded with “unique subject identifiers” (see section 11.6).  
Each patient will be involved in the study for the entire duration of the hospital treatment and for a maximum of 
90 days since randomization and including the follow-up. 
Patient should not be screened if, for any reason, there is a high probability that he/she will be transferred during 
the treatment phase to another institution (administratively separated from the investigational site) not belonging 
to this study network. Should this occur, the patient will be withdrawn from the study. If the randomized patient 
is transferred to another already opened study center, the responsibility for the patient treatment and management 
will be assumed by the new Principal Investigator. Agreements will have to be made with the Sponsor for the 
provision of the study material for that patient.  
During the study, the results of all required clinical, laboratory, instrumental examination will have to be reported 
in the eCRF (date of the test, outcome, units). Original data have to be kept in the patient’s hospital files and made 
available to the clinical monitor of the study for quality checks. 
Clinical examinations will be performed by the Principal Investigator or authorized sub-Investigator or nurse.  

CCI CCI

 
 
 
 
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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 experience which is reasonably likely to have been 
caused by the drug.  Adverse events are to be considered unsuspected if the relationship to the study drug as 
described in the table in section 7.3.4 is none or unlikely; whereas any AE reported in the study having a possible, 
probable or highly probable relationship to study drug will be considered as an ADR. The definition covers also 
medication errors and uses outside what is foreseen in the protocol, including misuse and abuse of the product. 
Serious Adverse Event 
A Serious Adverse Event (SAE) 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, diarrhea, influenza, or accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions, but do not constitute a substantial disruption. 
• is a congenital anomaly/birth defect, 
• is 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. 
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. 
Death shall always be reported as SAE: anyway, death due to progression of disease would not have a causal 
relationship to the product, based on Investigator’s assessment. The investigator should report the event 
immediately to the sponsor, but the sponsor will not report the event as expedited to regulatory authority. Cause 
of death shall always be specified when known. 
Unexpected Adverse Events  
An AE or ADR is considered unexpected if it is not listed in the Investigator Brochure (Reference Safety 
Information section) or in the applicable authorised Summary of Product Characteristics. 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. 

 
 
 
 
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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. 
Suspected Serious Unexpected Adverse Reaction (SUSAR) 
A suspected serious unexpected adverse reaction 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  
During the study, the subject shall have the opportunity to spontaneously mention any problems and anyway the 
Investigator or appropriate designee should inquire about AEs by asking the standard questions:  
• “Have you had any health problems since your last study visit?”  
• “Have there been any changes in the medicines you take since your last study visit?”  
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 subject’s medical health, regardless of causality. Changes in 
any protocol-specific systemic parameter evaluated during the study are to be reviewed by the Investigator.  
8.3 Recording of adverse events 
AEs will be collected and recorded for any untoward event that occurs in a patient from the time he or she signs 
the Informed Consent for the trial until the end of the follow up period. Thus, any untoward medical occurrences 
or unfavorable and unintended signs, symptoms, or diseases that occur in the pretreatment, in treatment, or post 
treatment period are to be considered AEs and/or SAEs, and consequently recorded and reported as such. Should 
a non-serious AE become serious, the Investigator will then follow the same reporting procedures as for SAEs. 
Each AE will be described by:  
• 
Its duration (start and stop dates).  
• 
Its seriousness. 
• 
Its relationship to the study drug (suspected/unsuspected). 
• 
Action(s) taken. 
• 
Outcome. 
Medical conditions/diseases and related signs/symptoms present before starting study treatment shall be 
documented in the medical history section of the CRF; these conditions are considered AEs only if they increase 
either in frequency or severity once informed consent has been signed.  
 
8.4 
Relationship and severity of AEs to the Investigational product 
The Investigator will assess the possible relationship between the AE and the investigational medication, according 
to the criteria in Table below: 

 
 
 
 
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Relationship of the Adverse Event to the IMP 
None (Intercurrent 
Event) 
An event that is not and cannot be related to the Investigational Product, e.g. 
patient is a passenger in a road traffic accident.  
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 
 
The Investigator will grade the severity of any AE according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) toxicity grading scale, version 5.0, as per definitions in 
the Table below. For each episode, the highest severity grade attained should be reported.  
Grading scale of the Adverse Event 
 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
*Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
 
8.5 
Follow-up of patients with adverse events 
The Investigator is responsible for adequate and safe medical care of subjects during the trial and for ensuring that 
appropriate medical care and relevant follow-up procedures are maintained after the trial. All AEs should be 
followed-up to determine outcome of the reaction. The Investigator should follow up the event until resolution or 

 
 
 
 
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• 
 Abnormal 
 values or test results that do not induce clinical signs and/or symptoms and require 
intervention/therapy, i.e. are clinically significant. 
 
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. 
 
 
Reporting procedure of safety information  
SUSAR expedited reporting to Regulatory Authorities and ECs  
The Investigator shall report all serious adverse events immediately to Dompé Pharmacovigilance and Clinical 
Operations and to the CRO contact, as described in Section 7.3.6 . 
The Investigator shall notify SAE to his/her EC as applicable; in addition, for reported deaths of a subject, the 
Investigator shall supply Dompé Pharmacovigilance and Clinical Operations /CRO Monitorand the Ethics 
Committee with any additional information requested. Copies of all correspondence relating to reporting of any 
SAEs to the EC should be maintained in the Investigator’s Files. 
 
Dompé Pharmacovigilance shall submit any serious unexpected ADR (SUSAR) to the concerned EC and 
Regulatory Authority (via Eudravigilance Clinical Trial module) which approved the study, as soon as possible 
and in no event later than: 
• 
seven calendar days after becoming aware of the information if the event is fatal or life threatening; to be 
followed by any relevant information within eight days. 
• 
fifteen calendar days after becoming aware of the information if the serious event is neither fatal nor life 
threatening. 
 
Dompé Pharmacovigilance shall report any relevant updated follow-up safety information as soon as available. 
If the results of an investigation show that an ADR not initially determined to be reportable is reclassified as 
reportable, Dompé Pharmacovigilance shall report such reaction in a written safety report as soon as possible, 
within the timeframes defined by current law requirements. 
Treatment will be unblinded by Dompé Pharmacovigilance prior to regulatory submission of a SUSAR 
to Regulatory Authorities and ECs and only cases referred to active treatment will be considered 
expeditable for regulatory reporting, in line with law requirements. 
Periodical Reporting to Regulatory Authorities, ECs and Investigators  
Dompé shall be responsible to prepare and submit annual safety reports (Development Safety Update Report – 
DSUR) to relevant Regulatory Authorities, as applicable. In addition, Investigator will receive from Dompé 
Pharmacovigilance appropriate periodic safety updates, as per applicable local requirements and regulations.   
 
8.7 Exposure to investigational product during pregnancy  
 
Any pregnancy detected at screening leads to the immediate exclusion from the trial.  
 
CCI

 
 
 
 
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8.8 
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 
CRF, and the patient must be followed up until the resolution of the AE or as instructed by the medical monitor. 
 
8.9 
Overdose  
Cases of overdose (accidental or intentional) which may or may not result in serious adverse reactions are to be 
reported to Dompé Pharmacovigilance and Clinical Operations /CRO Monitor , following the same procedure for 
SAE, within 24 hours from the Investigator’s knowledge of its occurrence. The Medical Expert should be contacted 
to discuss corrective treatment, if necessary. 
An overdose of the study drug is defined as: 
- 
Tablets: The administration of 3 or more additional tablets on any given treatment day  
- 
IV formulation: The administration of more than 50% of the daily dose. 
Overdose includes reports related to drug intake through different routes (e.g. ingestion) or with suicidal intentions 
and consequent drug overdose. 
The Investigator shall provide in the SAE form information about symptoms, corrective treatment and outcome of 
overdose.  
 
 
 
9. DATA MONITORING  COMMITTEE  
 
An independent Data Monitoring Committee (DMC) will be appointed with the responsibility of safeguarding the 
interests of trial participants, assessing the safety and efficacy of the interventions during the trial, and monitoring 
the overall conduct of the clinical trial. These tasks will be accomplished on an ongoing basis throughout the trial. 
The DMC will provide recommendations about stopping or continuing the trial. In order to contribute to enhancing 
the 
integrity 
of 
the 
trial, 
the 
DMC 
may 
also 
formulate 
recommendations 
relating 
to 
the 
selection/recruitment/retention of participants, their management, improving adherence to protocol-specified 
regimens and retention of participants, and the procedures for data management and quality control.  
 
The DMC will be advisory to the clinical trial leadership group (the Scientific Committee of the study). The 
Scientific Committee will be comprised of the sponsor’s study team and lead study investigators, who jointly will 
have responsibility for the design, conduct and analysis of the clinical trial. The Scientific Committee 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. 
 
 
 

 
 
 
 
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10. STATISTICAL CONSIDERATIONS 
10.1 
Sample size 
The sample size of the study is calculated based on results from the phase II, open label REPAVID-19 study. 
Considering a randomization ratio 2:1 (Reparixin:placebo) and a one-sided alpha of 0.025, a total of 264 evaluable 
patients will allow to achieve an overall power of 90% to detect a group difference ≥20% in proportion of patients 
alive and free of respiratory failure at Day 28 in favor of reparixin, assuming that the proportion of patients alive 
and free of respiratory failure in the placebo group will be approximately 60%. 
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 10.4. 1. No additional multiplicity correction of alpha is required. 
Assuming that 15% of subjects will not be evaluable for primary analysis, a total of approximately 312 subjects is 
expected to be enrolled.  
10.2 
Overview of planned statistical analyses 
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 evaluable patients has reached the primary endpoints at Day 28 (details in section 10.4. 
1); 
• 
Key first efficacy analysis: this analysis will be conducted by an independent statistician when all enrolled 
patients are evaluable for the primary analysis at 28 days and the database has been interim locked (details 
in section 10.4.2);  
• 
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. 
 
10.3 
Analysis Population 
The following population will be defined: 
• 
The Safety (SAF) population will consist of all randomized patients who received at least one dose of the 
investigational product. Safety population will be analyzed according to the actual treatment received. 
The SAF population will be used to present results on safety data. 
• 
The Full Analysis Set (FAS) population will consist of all randomized patients who received at least one 
dose of the investigational product. FAS population will be analyzed according to ITT principle, i.e. by 
treatment allocation. The FAS population will be used for the primary analyses of the study and to present 
results on efficacy data. 
• 
The Per Protocol (PP) population will consist of all randomized patients who received at least one dose 
of the investigational product and do not have Major Protocol Deviations. The PP population will be used 
for sensitivity analyses. 

 
 
 
 
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10.5 
Statistical Methodology 
10.5.1 General Considerations 
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 not 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 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. Kaplan-Meier 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. 
Unless otherwise specified, the significance level used for 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 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.   
 
10.5.2 Analysis of efficacy variables 
10.5.2.1 
Primary analysis  
The following null hypothesis is defined:  the proportion of patients alive and free of respiratory failure at Day 28 
(see section 2.2 for details) in reparixin is lower or equal than control: 
 
H0: TREPARIXIN ≤ TCONTROL 
H1: TREPARIXIN > TCONTROL 
where TREPARIXIN and TCONTROL are the proportions of patients alive and free of respiratory failure at Day 28 for 
reparixin and control groups, respectively.The null hypothesis H0 will be rejected, and superiority of reparixin is 
declared if primary analysis p-value will be lower than pre-specified threshold, depending at which analysis 
(interim or final) the test is performed. Thresholds are calculated according to O’Brien-Fleming spending function 
boundaries and are reported in Table 2. 
 Primary endpoint will be analyzed by means of logistic regression adjusting by pre-defined baseline factors (site, 
gender, age class, and presence of concomitant disease) 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 will be addressed by modeling patients with missing 
data after retrieved drop-outs, assuming that missing data would have been like retrieved drop-outs if they were 
assessed. If there are no enough retrieved dropouts, a “wash-out” analysis instead of retrieved drop-out analysis 
will be performed: the missing primary endpoint at Day 28 will be imputed by wash-out the effect of treatment 
using placebo completers; this approach does not assume benefits for reparixin in case of discontinuation and 
limits a post-discontinuation clinical effect to that of placebo. 
 
10.5.2.2 
Sensitivity analyses 
The following sensitivity analyses are defined to assess the robustness of results on primary endpoint versus 
adherence to protocol and presence of missing data (details will be provided in the SAP): 
• 
The comparison between treatment and control will be performed in the PP population instead of FAS; 
• 
The comparison between treatment and control will be performed in the FAS population considering 
complete cases only (i.e. without considering patients with missing primary endpoints at Day 28) instead 
of MI under MNAR. This analysis will assess the robustness of results to the method of handling missing 
data.  
• 
The comparison between treatment and control will be performed in the FAS population by means of MI 
under missing at random (MAR) assumption instead of 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.  
Additional sensitivity analyses may be added in the SAP. 
 
10.5.2.3 
Secondary Analyses 
In case analysis of the primary endpoint leads to rejection of null hypothesis, the following key secondary 
endpoints will be tested in a conditional sequential manner to show superiority of reparixin versus control 
according to the following ranking: 
1. Proportion of patients alive and free of respiratory failure (as described for the primary endpoint) at Day 
60,  
2.  Mortality rates up to Day 28, 
3. Incidence of ICU admission up to Day 28, 
4. Time to recovery (category 1 - 2 - 3 of the 7-point WHO-OS of clinical improvement) up to Day 28. 
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 #3 will be analyzed by means of a logistic regression model; key secondary 
endpoint #4 will be analyzed as detailed in section 10.5.1. 
In case of futility at interim analysis or in case of not rejection of null hypothesis, the above test strategy will not 
be performed. Instead, independently of results on primary endpoint, descriptive in nature analyses will be 

 
 
 
 
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10.5.7 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 subject’s participation for the full duration of the trial. However, in order to 
minimize missing data, if a patient cannot refer to the site for a planned follow-up visit, the Investigator will try to 
obtain any relevant information from the patients, including documents/laboratory results available from local 
medical care. 
 
 
 
 
 

 
 
 
 
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11 STUDY ORGANIZATION  
11.1 
Study documentation and record keeping  
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor in the source documents and in all required reports.  
The investigator must keep source documents for each subject in the study.  
The investigator and the sponsor should maintain the study documents as specified in the “Essential Documents 
for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as required by the applicable regulatory 
requirement(s). 
These are documents which individually and collectively permit evaluation of a study and the quality of the data 
produced and include groups of documents, generated before the study commences, during the clinical study, and 
after termination of the study and include but are not limited to, study protocol, amendments, submission and 
approval of Ethics Committee (EC), raw data of subjects, insurance contracts, certificate of analysis of the IMP(s), 
drug accountability records, signed informed consent forms, confidential subjects identification code. 
The investigator and the sponsor should take measures to prevent accidental or premature destruction of these 
documents.  
Study documents must be retained by the investigator and the sponsor as long as needed to comply with ICH-
GCP, national and international regulations. By signing the protocol, the investigator and the sponsor agree to 
adhere to these requirements. 
 
11.2 
Ethical considerations, quality assurance and monitoring 
The procedures outlined in this clinical trial protocol are designed to ensure that the Sponsor and the Investigators 
from the Clinical Sites perform their activities throughout the set-up, conduct, evaluation, documentation and 
analysis of the study, in accordance to the principles of the Good Clinical Practice (GCP) guidelines of the 
International Conference on Harmonization (ICH) and the Declaration of Helsinki. The study will be carried out 
adhering to local legal requirements and the applicable national laws, whichever represents the greater protection 
for the individuals. 
Study protocol, patient information and informed consent will be submitted to the appropriate Ethics Committee 
(EC) / Institutional Review Board (IRB) for approval. The Sponsor will be responsible to inform in a timely manner 
the appropriate Ethics Committee about any changes in the study protocol which could interfere with the patient’s 
safety. 
Due to the constrains and risks of the ongoing COVID-19 pandemia, no on-site monitoring activities will be carried 
out. Remote monitoring will be available periodically or at the investigators’ request via web or phone 
communications with the adequate Sponsor personnel or their approved representatives. 
 
REGULATORY BODY APPROVAL  
Dompé or the CRO or other consultant appointed by Dompé will obtain the necessary approval from the Competent 
Authorities, as needed, prior to initiation of the study. 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. 
 
11.3 
Informed consent 
The investigators or sub-investigators involved in this clinical trial who are responsible for treating the hospitalized 
patient for COVID-19 are responsible for providing all necessary information about the participation in the study 
to their patients, and consequently to obtain the written Informed Consent. 

 
 
 
 
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The same procedure applies to the information of the patient and providing of consent to the processing of personal 
data according to the European Regulation n. 679/2016 on the Protection of Personal Data, the Personal Data 
Protection Code (Legislative Decree 196/03) and subsequent amendments and additions, and to the provisions, 
guidelines and general authorizations of the National Guarantor for personal Data Protection. 
Information to the study participant is provided with a study-specific Information Sheet. The patient will eventually 
sign the Informed Consent Form for consenting to the study. A sample Informed Consent Form is reported in 
Apppendix 5.  
 
11.4 Data collection 
The investigator must ensure that the clinical data required by the study protocol are carefully reported in the 
subject’s source documents detailing the unique identification number and the date and time of the study 
procedures performed. Any correction to the source data entries must be carried out by the investigator or a 
designated member of staff. Incorrect entries must not be covered with correcting fluid, or obliterated, or made 
illegible in any way. A single stroke must be drawn through the original entry. Corrections have to be dated and 
initialled. The investigator must provide a reasonable explanation for all missing data. The source documents will 
be completed, signed by the investigator, the sensitive data will be obscured (i.e. only randomization number will 
be clearly legible) and the source document will be made available to the Sponsor for data management procedures. 
Data Management will identify and implement the most effective data acquisition and management strategy for 
the clinical trial protocol and deliver datasets which support the protocol objectives.  Subject data will be entered 
into a defined CRFs and combined with data provided from other sources where applicable in a validated data 
system.  Subject initials will not be transmitted for inclusion in the datasets.  Clinical data management will be 
performed in accordance with applicable standards and data cleaning procedures with the objective of removing 
errors and inconsistencies in the data which would otherwise impact on the analysis and reporting objectives, or 
the credibility of the Clinical Study Report. Adverse events and concomitant medications terms will be coded 
using validated dictionaries.  
 
 
 
11.5 
Confidentiality and data protection  
By signing this protocol, the investigator agrees to keep all the information provided by the sponsor in strict 
confidentiality and to request the same confidentiality from his/her staff. Study documents provided by the sponsor 
(protocols, randomization list and other materials) will be stored appropriately to ensure confidentiality. The 
information provided by the sponsor to the investigator cannot be disclosed to others without direct written 
authorisation from the sponsor, except for the extent necessary to obtain the informed consent from the subjects 
wishing to participate in the study.  
  
Data on subjects collected in the source documents during the study will be transferred to the Sponsor in an 
anonymized way. If, as an exception, for safety or regulatory reasons identification of a subject becomes necessary, 
the sponsor and the investigator will be bound to keep this information confidential.  
   
11.6 
Unique subject identifier  
All the subjects who sign the informed consent form for the present study will be coded with “unique subject 
identifiers”. The unique subject identifier consists of the sponsor study code (i.e. REPAVID-19), the 3-digit site 

 
 
 
 
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number (i.e. 001), the 4-digit screening number (e.g. S001, S002, etc.) and, if applicable, the 3-digit subject 
randomisation number (e.g. 001, 002, etc.).  
Study code, site number, screening number and subject randomisation number are separated by slashes (“/”).  
  
11.7 
Database management  
This study will use an electronic CRF (eCRF).  It will be a web-based clinical trials data management system that 
provides investigational sites a standardised and validated, remote, electronic data capture system for the collection 
of clinical trial data.  Activities performed using the eCRF include data entry, modification, review and validation.  
Each activity performed carries a unique user identification code and a date-time stamp. 
 
An electronic audit trail of all changes made to the eCRF will be kept within the eCRF. This audit trail identified 
the user making the change by userid, and date and time of change. 
 
Pre-defined data validation checks will be run within the eCRF as the data were entered and submitted by 
authorised site staff.  The resulting data queries will then resolved.  Additional queries will generated within the 
eCRF by authorized staff as a result of data review (e.g., source document review, external data reconciliation etc).  
11.8 
Coding dictionaries 
Medical/surgical history and underlying diseases and AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA™). Previous and concomitant medications will be coded using the WHO Drug 
Dictionary Global, B3 format. The version of the coding dictionaries will be stated in the study report. 
 
11.9 
Publication policy  
Study results will be communicated in full to the competent Health Authorities by the submission of a complete 
clinical study report.  
The sponsor agrees that the study results may be published by the investigator, and the investigator agrees to 
submit any manuscript (abstract, publication, paper, etc.) to the sponsor before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, accurate and balanced 
manner. The sponsor reviews the proposed manuscripts, before submission, within a reasonable period of time 
(30-90 days in relation with the complexity of the work).  
The investigator will also be provided by the sponsor with the clinical study report and the results of any additional 
analysis, tables, figures, etc. undertaken for the purposes of the article, in order to take responsibility for the content 
of the publication(s). On an exceptional basis, the sponsor may temporarily delay registration of certain data 
elements (e.g. compound, name, outcome, measures, etc.) to seek necessary intellectual property protection. This 
is because early disclosure of such data could, in some circumstances, prevent or negatively impact patentability. 
11.10 Administrative aspects 
The investigational medicinal products required for the conduct of this study will be provided free of charge by 
the Sponsor to the participating clinical sites.  
Coverage for any damage resulting from the participation of the subjects in the clinical trial is warrented. In 
addition to the general insurance of the individual participating clinical centers, an insurance cover will be issued 
in favour of the subjects participating in this clinical study. The insurance is in compliance with the local regulation 
and with the requirements of the Health Authorities.  
 

 
 
 
 
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13 APPENDICES 
 
Appendix 1. Investigator’s Brochure (IB) 
Please refer to dedicated document 
 
 
 
Appendix 2. Investigational Drug Labels 
Please refer to dedicated document 
 
 
 
Appendix 3. Severe Adverse Event (SAE) reporting form and completion guideline 
Please refer to dedicated document 
 
 
 
Appendix 4. Pregnancy reporting form and completion guideline 
Please refer to dedicated document 
 
 
 
Appendix 5. Informed consent form 
Please refer to dedicated document