Conditions: Pneumonia, Viral
Keywords: Covid-19 SARS-CoV-2 Pneumonia Severe pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 287
Healthy volunteers: no

Brief summary:
The study objective is to assess Efficacy and safety of Reparixin treatment as compared to placebo (both on top of standard treatment) in adult patients with severe COVID-19 pneumonia.

Detailed description:
This is a phase 3 clinical trial designed as a randomized, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of Reparixin in hospitalized adult patients with severe COVID-19 pneumonia.

Patients will be screened for the participation in the study and eventually randomized based on an unbalanced randomization scheme (2:1) to Reparixin oral tablets (2 x 600 mg TID) for up to 21 days or to placebo.

An unequal randomization is justified by the need to gain experience and more safety data with the investigated treatment and by an expected better acceptability of the trial by patients.

The placebo control arm is justified by the unavailability of a well-defined standard of care for subjects with COVID-19 pneumonia who are candidates for this study.

All patient will receive the standard supportive care based on the patient's clinical need. Follow-up information on the patient's clinical condition will be collected until day 90.

Arms:
arm 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 arm 2: 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.

Interventions: intervention 1: Reparixin intervention 2: Placebo
Intervention descriptions: intervention 1: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). intervention 2: Matched placebo, i.e. 2 tablets for the total of three daily administrations (6 tablets daily).

Protocol document:
SAP_002.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
PROTOCOL: REP0220 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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·oocwnent Informatiori • 
Protocol Number: 
Version: 
Document Date: 
Prepared for: 
Title 
Statistical Anal sis Pian Tem late 
 
03 
28 Oct2019 
STATISTICAL 
ANALYSIS PLAN 
APPROVAL PAGE 
REP0220 
3.0 
23 November 2021 
Dompé farmaceutici s.p.a. [Dompé) 
Via Santa Lucia 6; 20122 Milan, Italy 
2 of68 
The Statistica! Analysis Pian has been completed and reviewed and the contents are approved for use 
for the analysis. 
Protocol Number: REP0220 
Version: 3. O 
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Table of Contents 
STATISTICAL ANALYSIS PLAN ................................................................................................... 2 
APPROVAL PAGE ............................................................................................................................ 2 
1. 
Abbreviations ........................................................................................................................... 6 
2. 
Revision History ...................................................................................................................... 8 
3. 
Introduction ............................................................................................................................. 9 
4. 
Study Objectives ...................................................................................................................... 9 
5. 
Study Design ............................................................................................................................ 9 
5.1 
General design and plan ................................................................................................... 9 
5.2 
Visit Schedule and Visit Windows ................................................................................. 10 
5.3 
Remapping visit .............................................................................................................. 12 
5.3.1 
Remapping Follow-up visits ....................................................................................... 13 
5.3.2 
Remapping of other visits ........................................................................................... 13 
5.3.3 
Additional notes for remapping .................................................................................. 14 
5.4 
Sample size justification ................................................................................................. 15 
5.5 
Randomization and blinding .......................................................................................... 15 
5.6 
Overview of planned statistical analyses ....................................................................... 16 
5.7 
Efficacy endpoints .......................................................................................................... 16 
5.7.1 
Primary endpoints ....................................................................................................... 16 
5.7.2 
Key secondary endpoints ............................................................................................ 16 
5.7.3 
Additional secondary endpoints ................................................................................. 17 
5.8 
Safety endpoints ............................................................................................................. 19 
6. 
Statistical Analysis ................................................................................................................ 19 
6.1 
General ........................................................................................................................... 19 
6.2 
Analysis sets ................................................................................................................... 20 
6.2.1 
Enrolled set ................................................................................................................. 20 
6.2.2 
Randomized set ........................................................................................................... 20 
6.2.3 
Safety set ..................................................................................................................... 20 
6.2.4 
Full Analysis set ......................................................................................................... 20 
6.2.5 
Per Protocol set ........................................................................................................... 20 
6.3 
Usage of analysis sets ..................................................................................................... 21 
6.4 
Sub-group analyses ........................................................................................................ 21 
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6.5 
Interim analysis .............................................................................................................. 22 
6.6 
Key first efficacy analysis .............................................................................................. 23 
6.7 
Data Monitoring Committee (DMC) .............................................................................. 23 
6.8 
Handling of missing and incomplete data ...................................................................... 24 
6.9 
Changes in the planned analysis ..................................................................................... 24 
6.10 
Blinded Data Review Meeting ....................................................................................... 24 
6.11 
Software ......................................................................................................................... 24 
7. 
Evaluation of Demographic and Baseline Characteristics .................................................... 25 
7.1 
Subject enrolment and disposition ................................................................................. 25 
7.2 
Protocol deviations ......................................................................................................... 25 
7.3 
Study discontinuations ................................................................................................... 25 
7.4 
Demographics and baseline characteristics .................................................................... 26 
7.5 
Medical or Surgical History and/or Concomitant Diseases ........................................... 26 
7.6 
Prior and concomitant medications ................................................................................ 28 
7.7 
Other baseline characteristics ......................................................................................... 28 
7.7.1 
Clinical severity score (7-point WHO-OS) ................................................................ 28 
7.7.2 
Dyspnea VAS Scale .................................................................................................... 28 
7.7.3 
Respiratory parameters ............................................................................................... 29 
7.7.4 
Chest imaging ............................................................................................................. 29 
8. 
Evaluation of Treatment Compliance and Exposure ............................................................. 29 
8.1 
Compliance to IMP ........................................................................................................ 29 
8.2 
Exposure to IMP ............................................................................................................. 29 
9. 
Evaluation of Efficacy ........................................................................................................... 30 
9.1 
Analysis of primary efficacy endpoint ........................................................................... 30 
9.1.1 
Testing strategy and multiplicity adjustment .............................................................. 30 
9.1.2 
Analysis details ........................................................................................................... 30 
9.1.3 
Sensitivity analysis ..................................................................................................... 31 
9.2 
Analysis of secondary efficacy endpoints ...................................................................... 34 
9.2.1 
Testing strategy and multiplicity adjustment .............................................................. 34 
9.2.2 
Analysis details ........................................................................................................... 34 
9.3 
 .................................................................... 39 
9.3.1 
Analysis details ........................................................................................................... 39 
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9.4 
 pre-planned per protocol) . 40 
10. 
Evaluation of Safety .............................................................................................................. 41 
10.1 
Adverse events ............................................................................................................... 41 
10.2 
 ........................................................................................ 44 
10.3 
 ....................................................................................................................... 44 
10.4 
.............................................................................................................................. 45 
10.5 
Child Pugh Score ............................................................................................................ 45 
11. 
Derivations and date conventions .......................................................................................... 46 
11.1 
Variable derivation ......................................................................................................... 46 
11.3 
Partial date conventions ................................................................................................. 53 
12. 
Tables, Figures and Listings .................................................................................................. 56 
12.1 
Output conventions ........................................................................................................ 56 
12.2 
Format requirements: ..................................................................................................... 56 
12.3 
Table Conventions .......................................................................................................... 57 
12.4 
Listing Conventions ....................................................................................................... 57 
13. 
Reference ............................................................................................................................... 58 
14. 
Appendices ............................................................................................................................ 59 
14.1 
TABLES ......................................................................................................................... 59 
14.2 
LISTINGS ...................................................................................................................... 64 
14.3 
FIGURES ....................................................................................................................... 66 
14.4 
SAS Code for the primary analysis ................................................................................ 66 
 
 
Index of Tables 
 
Table 1: Study Flow Chart ................................................................................................................ 11 
Table 2: Usage of analysis set .......................................................................................................... 21 
Table 3: O’Brien-Fleming spending functions boundaries for primary endpoints........................... 22 
Table 4: Variable derivation rules .................................................................................................... 46 
Table 5: Algorithm for Treatment Emergence of Adverse Events ................................................... 53 
Table 6: Algorithm for Prior/Concomitant medications ................................................................... 55 
 
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1.  Abbreviations 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BDRM 
Blind Data Review Meeting 
COVID-19 
Corona Virus Disease 2019 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
DMC 
Data Monitoring Committee 
eGFR 
Epidermal growth factor receptor 
ENR 
Enrolled set 
FAS 
Full Analysis set 
FiO2 
Fraction of inspired oxygen 
ICH 
International Council for Harmonization 
ICU 
Intensive Care Unit 
IMP 
Investigational Medicinal Product 
IMV 
Invasive Mechanical Ventilation 
IRS 
Interactive Response System 
ITT 
Intent to Treat 
KM 
Kaplan-Meier 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNAR 
Missing not at random 
NCI-CTCAE 
National Cancer Institute- Common Terminology 
Criteria for Adverse Events 
PaO2 
Partial arteriolar oxygen pressure 
PCR 
Polymerase chain reaction 
P/F 
Partial arteriolar oxygen pressure (PaO2) to 
fraction of inspiration O2 (FiO2) ratio 
PP 
Per Protocol set 
PT 
Preferred Term 
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RND 
Randomized set 
Rt-PCR 
Reverse transcriptase Polymerase Chain Reaction 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAF 
Safety set 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome CoronaVirus 
2 
SAS 
Statistical Analysis Systems 
SD 
Standard Deviation 
SE(M) 
Standard Error (of the Mean) 
SI 
Standard International 
SOC 
System Organ Class 
SPO2 
Peripheral arterial oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
TID 
Ter in die - three times a day 
TLF(s) 
Tables, Listings and Figures 
VAS 
Visual Analog Scale 
WHO DD 
World Health Organization Drug Dictionary 
WHO-OS 
7-point 
WHO 
Ordinal 
Scale 
of 
clinical 
improvement 
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2.  Revision History 
Document Version 
Changes Made 
Document Date 
Final 1.0 
Final version 
 
Final 2.0 
Primary endpoint sensitivity analysis added, 
(excluding patients who were already in the ICU 
at baseline)  
Analysis visit definition changed and, in 
particular, extended to cover End of Treatment, 
End of Study and Hospital Discharge 
Analyses of number of ICU admissions up to Day 
28, number of invasive mechanical ventilation 
use, or ECMO up to Day 28, and number of ICU 
admission, invasive mechanical ventilation use, 
or ECMO or death up to Day 28 added. 
 
 
Final 3.0 
The SAP version 2.0 has been reviewed after the 
Blind Data review Meeting. The previous version 
is confirmed except for the following items 
reported in Table 4: 
- 
Total number of tablets scheduled during 
the treatment period 
- 
PaO2/FiO2 ratio (when data is not 
available in the eCRF but PaO2 and FiO2 
are available separately.  
 
 
 
 
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3.  Introduction 
This document outlines the statistical methods to be implemented in the analysis of the data of 
REP0220 Clinical Trial. The purpose of this plan is to provide general guidelines from which the 
analysis will proceed, containing a more technical and detailed elaboration of the principal features 
of the analysis described in the protocol. Any changes to the protocol or Case Report Form (CRF) 
may necessitate updates to the Statistical Analysis Plan (SAP). In case of deviations from this updated 
SAP, explanations will be provided in the clinical study report. 
This SAP is based on study protocol Version 3.0 final – 09 April 20211, Case Report Form Version 
2.2 – 21 April 20212. 
4.  Study Objectives 
The objective of this clinical trial is to assess efficacy and safety of Reparixin treatment as compared 
to placebo (both on top of standard treatment) in adult patients with severe COVID-19 pneumonia. 
5.  Study Design 
5.1 
General design and plan  
This is a phase 3 clinical trial designed as a randomized, placebo-controlled, multicenter study to 
evaluate the efficacy and safety of Reparixin in hospitalized adult patients with severe COVID-19 
pneumonia.  
Patients will be screened for the participation in the study and eventually randomized based on an 
unbalanced randomization scheme (2:1) to Reparixin oral tablets (2 x 600 mg TID) for up to 21 days 
or to placebo. The investigational treatment is not foreseen to be continued at home after discharge 
from hospital. 
 
 
 The placebo control arm is justified by the unavailability of a well-defined “standard of 
care” for subjects with COVID-19 pneumonia who are candidates for this study. All patients will 
receive the standard supportive care based on the patient’s clinical need. Follow-up information on 
the patient’s clinical condition (new hospitalization, need of supplemental oxygen, adverse events) 
and survival will be collected until Day 90. 
An interim analysis for efficacy and futility is planned when half of the planned patients has reached 
the primary endpoint. 
DMC meetings will be performed during the trial, in order to monitor the safety of the patients and 
to protect study subjects from undue harm. 
 
 
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5.2 
Visit Schedule and Visit Windows 
Assessments and study visits will be performed as listed in Paragraph no. 7 “Assessments and 
procedures” of the Study Protocol containing additional details about scheduled visits and time 
windows. 
Baseline is defined as the last visit prior to and including date of the randomization visit. Unless 
otherwise specified, baseline values are defined as the measurements taken during this visit. 
In case of multiple measurements during baseline visit, the last assessment will be considered as 
baseline evaluation before start of treatment. 
In general, for efficacy and safety endpoints, data will be evaluated according to the Visit at which 
they have been collected, also if performed out-of-window (in case visit has been performed out of 
predefined window, available information at the actual effective day will be considered). 
For example, for the primary efficacy endpoint, the analysis will be performed using data collected 
in Day 28 visit (corresponding to 28±2 days); if assessment is out-of-window, the available 
information at 28 days post randomization will be used. In case the day of “Day 28” visit is after 30 
days, we can use that collected information. In case the day of “Day 28” visit is before 26 days, we 
have to evaluate the next assessment (i.e.: “Day 60” visit or an unscheduled visit). This approach will 
be implemented for primary and key-secondary efficacy endpoints with a defined “Day”. 
 
For convenience, Day 3, Day 7, Day 14, Day 21, Day 28, Day 60 and Day 90 will be used throughout 
the document. 
 
 
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Table 1: Study Flow Chart 
Study procedures 
Screening 
Baseline 
Day 1 
Day 3 
Day 7 
(±1) 
Day 14 
(±2) 
Day 21 
(±2) 
or EoT 1 
Day 28 
(±2) 
or 
discharge 
or EoS 1 
Day 60 
(±2) 
or 
discharge 
or EoS 1 
Day 90 
(±2) 
or EoS1 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Child Pugh score 
X 
X 
X 
X 
X 
X 
X 
 
 
Previous and concomitant 
medications 
<-------------------------------------------------------------------------  X 
Preventive off-label use of 
other anti-COVID-19 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Timing until start of 
investigational treatment 2 
 
X 
 
 
 
 
 
 
 
Clinical severity score 
(7-point WHO-OS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dyspnea Liker scale 
 
 
X 
X 
X 
X 
X 
 
 
Dyspnea VAS scale 
X 
X 
X 
X 
X 
X 
X 
 
 
Supplemental Oxygen 
X 
X 
<-------------------------------------------------  X 3 
 
Non-invasive mechanical 
ventilation 
X 
X 
<-------------------------------------------------  X 3 
 
Invasive mechanical 
ventilation / ECMO 
 
 
<-------------------------------------------------  X 3 
 
Total days of hospitalization 
 
 
<-------------------------------------------------  X 3 
 
ICU admission 
 
 
<-------------------------------------------------  X 3 
 
Chest imaging 
X 
X4 
X4 
X4 
X4 
X4 
X4 
X 
 
SpO2, PaO2, FiO2, P/F 
(PaO2/FiO2) 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
samples for Reparixin 
concentration 8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 virology (rt-
PCR) 
<----------  X 
 
 
 
 
X 
 
 
Study drug administration 
 
<-----------------------   X ------------> 
 
 
 
Record AEs / SAEs 
<-------------------------------------------   X ----------------------------------------------> 
1 EoT: End of Treatment.   EoS: End of Study  
EoT is the last day of treatment administration. The investigational treatment will last up to 21 days. Reasons for earlier treatment termination are: Investigator’s decision based on clinical judgment of 
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. After EoT, laboratory and clinical examinations shall be collected on the day of patient’s discharge from hospital, or on Day 28. The collection of follow-up information should be continued 
after EoT until EoS (Day 90), 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 (preferably 
in person at the Center, or via a telephone call) at days 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) - 60 (±2) and/or 90 (±2) depending on the discharge time point. 
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-wp. 
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 Day 90. 
2
 
3 to be recorded over the whole duration of the hospitalization (total number of days to be reported). For supplemental oxygen, please record daily (average) delivery as < 6 L/min, 6 - 10 L/min, >10 
L/min 
4 When deemed appropriate by the investigators 
 
 
 
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8 Samples for the determination of Reparixin concentrations collected immediately before and one hour (± 15 min) after first dosing at day 3 
 
5.3 
Remapping visit  
As specified in the section 0, in general, the following analysis timepoints will be presented: 
• Baseline Day 1 
• Day 3 
• Day 7 (+/- 1) 
• Day 14 (+/- 2) 
• Day 21 (+/- 2) 
• Day 28 (+/- 2) 
• Day 60 (+/- 2)  
• Day 90 (+/- 7) 
In addition, the following analysis time points will generally be presented: 
• End of Treatment (EoT) 
• Hospital discharge 
• End of Study (EoS) 
Data collected directly in the eCRF in the visits named “Baseline Day 1”, “Day 3”, “Day 7 (+/- 1)”, 
“Day 14 (+/- 2)”, “Day 21 (+/- 2) or EoT” (with visit type specified as “Visit as per study protocol 
schedule”), and “Day 28 (+/- 2) or discharge or EoS” (with visit type specified as “Visit as per study 
protocol schedule”),” will be used in the analysis, whenever present. In these cases, no visits 
remapping will be performed. 
The Day 60 (+/-2), Day 90 (+/-7), End of Treatment, Hospital discharge and End of Study analysis 
visits are defined as follows: 
Day 60 (+/-2): 
• 
Data collected at “Day 60 (+/-2) or discharge or EoS” with visit type specified as “Visit as 
per protocol schedule” or 
• 
Data collected at “Day 60 (+/2) or discharge or EoS” with missing information on visit type 
(only for patients who did not re-consent to protocol amendment v3.0 or had this visit 
performed prior to re-consent) and between day 58 and day 62 of study 
Day 90 (+/-7): 
• 
Data collected at “Day 90 (+/2) or EoS” and between day 83 and day 97 of study (somewhat 
extending the per-protocol window). 
 
 
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End of Treatment: 
• 
Data collected at “Day 21 (+/2) or End of Treatment” (irrespective of visit type) 
End of Study: 
• 
Data collected at “Day 90 (+/-2) or EoS” or data collected at “Day 28 (+/2) or discharge or 
EoS” with visit type specified as “End of study evaluation” or data collected at “Day 60 (+/2) 
or discharge or EoS” with visit type specified as “End of study evaluation” 
• 
Data collected at “Day 60 (+/2) or discharge or EoS” with missing information on visit type, 
in case that the patient either did not re-consent to protocol amendment v3.0 or in case that 
the patient is known to have completed/prematurely discontinued the study without a “Day 
90 (+/-2) or EoS” visit performed. 
Hospital discharge: 
• 
Data collected at “Day 28  (+/-2) or hospital discharge or EoS” with visit type specified as 
“Hospital discharge” or data collected at “Day 60  (+/-2) or hospital discharge or EoS”  with 
visit type specified as “Hospital discharge” 
 
5.3.1 Remapping Follow-up visits 
In case data was not collected at the above defined visits for Day 7 (+/-1), Day 14 (+/- 2), Day 21 
(+/-2), Day 28 (+/-2) or Day 60 (+/-2), data collected at the follow-up visits will be remapped and 
used in the analysis: 
• Follow-up Visit/Phone Call Day 7 (+/- 1) remapped as Day 7 (+/- 1) 
• Follow-up Visit/Phone Call Day 14 (+/- 2) remapped as Day 14 (+/- 2) 
• Follow-up Visit/Phone Call Day 21 (+/- 2) remapped as Day 21 (+/- 2) 
• Follow-up Visit/Phone Call Day 28 (+/- 2) remapped as Day 28 (+/- 2) 
• Follow-up Visit/Phone Call Day 60 (+/- 2) remapped as Day 60 (+/- 2) 
 
In case data was not collected at an analysis visit of “Hospital discharge” (see section 5.3 above), 
data collected at the visit “Follow-up Visit/Phone Call Discharge” will be remapped as “Hospital 
discharge” visit. 
5.3.2 Remapping of other visits 
Additionally, at the eCRF, data can be collected at the following study moments (that may or may 
not coincide with the analysis timepoints defined above): 
• End of Treatment (EoT) 
• Hospital Discharge 
• End of Study (EoS) 
After remapping of follow-up visits and in case data are still missing at a Day 3, Day 7 (+/-1), Day 
14 (+/- 2), Day 21 (+/-2), Day 28 (+/-2), Day 60 (+/-2) or Day 90 (+/-7) analysis visit , data collected 
in any of these additional moments will be remapped if the date of collection is within the analysis 
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timepoint window (“date of collection” defined as the specific assessment date, or the visit date in 
case the specific assessment date is not collected or is empty). 
Example: “End of Treatment” happens at day 13 of study and there is no data collected at visit “Day 
14 (+/- 2)” for that subject, then the data collected in the “End of Treatment” moment will be 
remapped to “Day 14 (+/- 2)” and it will be used in the analysis for that timepoint. 
All End of Treatment, Hospital Discharge and End of Study visits will also be analyzed “as such”, 
irrespective of whether they were also remapped to another study visit as per above (see section 5.3). 
5.3.3 Additional notes for remapping  
The following additional rules will be applied when performing visit remapping: 
• If more than one of additional visit (End of Treatment, Hospital Discharge, or End of Study) 
can be remapped to a specific analysis visit, then the one closer to the exact visit day of the 
“Day xx” visit will be used. If both are at the same time distance, then the latest one will be 
used. If there are two visits on the same day (e.g. End of treatment and Hospital Discharge 
performed at the same date but recorded twice in the CRF on the forms for “Day 21 (+/2) or 
EoT” and “Day 28 (+/2) or discharge or EoS”), then the information from the End of Study 
will be used, when available. Otherwise, the information from the Hospital Discharge will be 
used. 
• Visit remapping is done in each form independently of data collected in other forms. 
• Visit remapping performed at parameter-level (each parameter within the form will be 
considered independently): 
o Applies to: Clinical Severity Score, Dyspnea VAS Scale, Dyspnea Likert Scale, 
 
Chest Imaging, Lung Function, 
. 
▪ 
 
 
 
 
 
• Visit remapping performed at form-level (all data parameters must be remapped within the 
form or none is) for the following forms: 
o Child Pugh Score will be fully remapped if the “Total Score” is missing due to missing 
data in one or more parameters. 
▪ Example: “Ascites” is missing in the Child Pugh Score at “Day 14 (+/- 2)” 
and because of that the total score and class are also missing. The subject has 
an “End of Treatment” at study day 15 (within window) in which the “Child 
Pugh Score” was fully collected. In this case, the full “Child Pugh Score” 
collected in the “End of Treatment” will be remapped and that will be the score 
used in the analysis for “Day 14 (+/- 2)”. 
o “Additional Information” form will only be remapped if the form is fully missing at 
the analysis timepoint. 
▪ Example: “Does the patient need invasive mechanical ventilation / ECMO?” 
is missing in the form at “Day 14 (+/- 2)” but the subject has an “End of 
Treatment” at study day 15 (within window) in which the “Additional 
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Information” was fully collected. In this case, the full “Additional 
Information” form on “End of Treatment” will not be remapped. 
• Visits that cannot be mapped to any analysis visit will only be shown in subject data listings 
with the visit name as recorded in the CRF. 
 
• Forms that will not be remapped: 
o 
 will not be remapped as it is planned to be collected only at “Baseline Day 1” 
and “Day 21 or EoT”. 
o “SARS-CoV-2 virology (rt-PCR)” will not be remapped as it is planned to be 
collected only at “Baseline Day 1” and “Day 28 or Discharge or EoS”. 
o “Covid-19 Medication” will not be remapped as it is not needed for the analysis. 
5.4 
Sample size justification 
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%. 
The 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 6.5 of this document. No additional 
multiplicity correction of alpha is required. 
Assuming that 15% of subjects will not be evaluable for the primary analysis, a total of approximately 
312 subjects is expected to be enrolled. 
5.5 
Randomization and blinding 
Eligible Patient will be randomized in a 2:1 fashion to either Reparixin or placebo. 
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 pack/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. 
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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. 
The DMC will have access to fully unblinded DMC reports. 
The randomization code will be broken when the last enrolled patient has completed therapy, and 
once the database has been locked. 
5.6 
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 planned evaluable patients has reached the primary endpoints at 
Day 28 (details in section 6.5); 
• 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 (details in section 
6.6);  
• 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. 
5.7 
Efficacy endpoints 
5.7.1 Primary endpoints  
The primary efficacy endpoint is the 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. 
Admissions to ICU has to be considered only in presence of significant worsening of respiratory 
status. This condition will be objectively identified by means of a decrease of PaO2/FiO2 ratio of at 
least 40% from the baseline value or by a worsening of Investigator’s Interpretation. 
5.7.2 Key secondary endpoints  
The key secondary endpoints are the following: 
• 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, 
• Time to recovery (category 1 - 2 - 3 of the 7-point WHO Ordinal Scale of clinical 
improvement (WHO-OS) until Day 28. 
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5.7.3 Additional secondary endpoints 
The additional secondary efficacy endpoints are the following: 
• Proportion of patients 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),  
• Mean changes in clinical severity score based on the 7-point WHO-OS, 
• Time to clinical improvement 1 (decline of 1 category in the 7-point WHO-OS) up to Day 
28, 
• Time to clinical improvement 2 (decline of 2 categories in the 7-point WHO-OS) up to Day 
28, 
• Time to discharge from hospital (up to day 28), 
• 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, 
• Dyspnea severity (Likert scale and VAS scale) at days 3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) 
or until discharge, 
• Duration of supplemental oxygen treatment (days) up to Day 28, 
• Incidence of invasive mechanical ventilation use, or ECMO up to Day 60, 
• Duration of invasive mechanical ventilation, or ECMO (days) up to Day 60, 
• Duration of non-invasive mechanical ventilation (days) up to Day 60, 
• Duration of ICU admission (days) up to Day 60, 
• Duration of hospitalization since randomization (days) up to Day 60, 
• 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, 
• Pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2) at days 3 - 7 
(±1) - 14 (±2) - 21 (±2) - 28 (±2) or until discharge, 
• 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, 
• Hs-CRP: change from baseline to days 3 - 7 (±1) - 14 (±2) - 21 (±2) - 28 (±2) or until discharge 
(alternatively, CRP), 
• Mortality rates up to Day 60 and Day 90, 
• Freedom from (time to) death or respiratory failure (as described for the primary end-point). 
: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
 
 
 
 
 
 
 
 
 
 
 
 
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5.8 
Safety endpoints 
The safety endpoints are the following:  
• Incidence of Adverse Events (AEs), 
• Incidence of Serious Adverse Events (SAEs), 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
toxicity grading scale will be used to capture the severity of adverse events. 
6.  Statistical Analysis 
6.1 
General 
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, upper and 
lower quartiles, 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. 
For time-to-event variables, cumulative freedom from event will be evaluated using the Kaplan-
Meier method. The degree of uncertainty will be expressed with 95% confidence limits (calculated 
per the method proposed by Greenwood3). 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 will be censored at the study termination 
for the final analysis and will be censored at clinical cut-off date for the interim analysis. Reasons 
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for discontinuation will be incorporated into the analysis for determining censoring and failure status. 
Specifically, study discontinuation for Adverse Event, Death, Loss to follow-up or other negative 
outcomes (assessed during the Blinded Data Review Meeting (BDRM)) 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.  
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.   
All the data collected and derived in the study will be presented in subject data listings. All patient 
data collected on the CRF will be listed by patient and center.  
6.2 
Analysis sets 
6.2.1 Enrolled set 
The Enrolled set (ENR) will consist of all patients with signed written informed consent and 
undergoing to study evaluations/procedures. 
6.2.2 Randomized set 
The Randomized set (RND) will consist of all patients in the ENR set who are randomized to the 
study, regardless of whether they receive the Investigational Medicinal Product (IMP) or not. 
6.2.3 Safety set 
The Safety set (SAF) will consist of all randomized patients who receive at least one dose of the IMP. 
SAF population will be analyzed according to the actual treatment received and will be used to 
present results on safety data. 
6.2.4 Full Analysis set 
The Full Analysis Set (FAS) will consist of all randomized patients who receive at least one dose of 
the IMP (either Reparixin or placebo). FAS population will be analyzed according to ITT principle, 
i.e. by treatment allocation regardless of intercurrent events (treatment policy strategy). The FAS 
population will be used for the primary analyses of the study and to present results on efficacy data. 
6.2.5 Per Protocol set 
The Per Protocol set (PP) will consist of all patients from the FAS without any Major Protocol 
Deviations. The PP set will be used for sensitivity analyses. 
All the protocol deviations will be discussed case by case by the clinical team during the BDRM 
before the DB lock and described in the BDRM Report. 
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6.3 
Usage of analysis sets 
The usage of the analysis sets (see previous section) for the creation of tables and figures are 
illustrated in  
Table 2.  
Unless otherwise specified, all listings will be done for RND set. All listings will report: 
• planned and actual treatment names included,  
• the flag(s) of the analysis set(s) used to analyze the information of the listing (according to  
• Table 2).  
 
Table 2: Usage of analysis set 
Analysis 
ENR 
RND 
FAS 
SAF 
PP 
Subject enrolment and disposition 
☒ 
☐ 
☐ 
☐ 
☐ 
Protocol deviations 
☐ 
☒ 
☐ 
☐ 
☐ 
Study discontinuations 
☐ 
☒ 
☐ 
☐ 
☐ 
Demographics and baseline characteristics 
☐ 
☐ 
☒ 
☐ 
☐ 
Medical or surgical history and/or Concomitant 
Diseases 
☐ 
☐ 
☒ 
☒ 
☐ 
Prior and concomitant medications 
☐ 
☐ 
☒ 
☐ 
☐ 
Other baseline characteristics 
☐ 
☐ 
☒ 
☐ 
☐ 
Compliance to IMP 
☐ 
☐ 
☐ 
☒ 
☐ 
Exposure to IMP 
☐ 
☐ 
☐ 
☒ 
☐ 
Analysis of primary efficacy endpoints 
☐ 
☐ 
☒ 
☐ 
☐ 
Sensitivity analysis 
☐ 
☐ 
☒ 
☐ 
☒ 
Analysis of secondary efficacy endpoints 
☐ 
☐ 
☒ 
☐ 
☐ 
 
☐ 
☐ 
☒ 
☐ 
☐ 
Adverse events 
☐ 
☐ 
☐ 
☒ 
☐ 
 
☐ 
☐ 
☐ 
☒ 
☐ 
 
☐ 
☐ 
☐ 
☒ 
☐ 
 
☐ 
☐ 
☐ 
☒ 
☐ 
Child Pugh Score 
☐ 
☐ 
☐ 
☒ 
☐ 
6.4 
Sub-group analyses 
Statistical tests for interaction (between subgroup and treatment arm) will be performed to decide 
about the need to further investigate subgroups of the trial population. The consistency of the 
treatment effect will be assessed using a logistic regression model including treatment, subgroup 
variable and their interaction as covariate. 
The following subgroups will be defined based on demographic or baseline characteristics: 
• age group (<65 yrs vs ≥ 65 yrs ), 
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• Gender (Male, Female), 
• presence of concomitant disease (Yes, No). 
Subgroup analyses will be performed if interaction tests are statistically significant at 15% nominal 
level. In this case all primary and secondary efficacy endpoints will be analyzed in the same way as 
described in sections 9.1.2 and 9.2.2. 
Therefore, the steps to be performed are the following (for example age group): 
1. Perform logistic regression model including treatment, age group and their interaction as 
covariates, 
2. Evaluate interaction test “treatment*age group”, 
3. If this test is statistically significant at 15% nominal level (i.e., p-value < 0.15), then all 
primary and secondary efficacy endpoints will be analyzed in the same way as described in 
in sections 9.1.2 and 9.2.2 divided by age group, otherwise 
4. If the test is not statistically significant at 15% nominal level (i.e., p-value >= 0.15), all 
primary and secondary analyses will not be analyzed by age group. 
All points from 1 to 4 will be repeated for all subgroup variables. 
6.5 
Interim analysis 
An interim analysis is planned when half of the planned evaluable patients have reached the primary 
endpoints at Day 28 (i.e., first 132 patients, ordering by randomization date and afterwards by random 
number, who met the FAS definition; if the primary endpoint at Day 28 is missing, multiple 
imputation described in the section 9.1.2 will be used) for identification of early superiority of 
Reparixin (efficacy) or for early stopping of the trial for futility. 
O’Brien-Fleming spending functions will be used to control the type I and II errors for analyses of 
primary endpoints. P-values boundaries for efficacy and futility at interim and key first efficacy 
analyses are reported in Table 3. 
 
Table 3: O’Brien-Fleming spending functions boundaries for primary endpoints 
Analysis 
Sample Size 
(evaluable 
patients) 
Boundaries for primary endpoint 
Efficacy 
Futility 
Interim 
132 
p-value <0.00258 
p-value ≥0.32561 
Key first efficacy analysis 
264 
p-value <0.02400 
p-value ≥0.02400 
The interim analysis will be conducted by an independent statistician who will share the results on 
primary endpoint with the DMC. On the basis of the interim results, DMC will communicate to the 
Sponsor the decision on the continuation of the study. The following scenarios may emerge: 
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• Scenario 1: The communication will be “Not enough evidence for demonstrate superiority of 
Reparixin”. In this case, since results are not considered enough to draw conclusions on 
primary endpoints, the enrolment will continue up to the final analysis step, and treatments 
and follow-ups will proceed without modifications. Key first efficacy analysis and final 
analysis will be performed according to the rules described in section 5.6. 
• Scenario 2: The communication will be “Superiority of Reparixin is shown”. In this case, 
enrolment of subjects is stopped and considered completed. Already-enrolled subjects 
continue their residual treatment and follow-up as planned. Key first efficacy analysis and 
final analysis will be performed according to the rules described in section 5.6. 
• Scenario 3: The communication will be “Superiority of Reparixin is excluded”. In this case, 
the enrolment (if still ongoing) will be stopped and all subjects will discontinue the treatment 
and will be followed-up until the next scheduled visit where they will be notified of the 
termination of the study. When database is closed, final analysis will be performed and the 
clinical study report will be written and released. 
The level of data cleaning requested for the interim analysis is the following: 
• Primary efficacy endpoint and variables for the definition of FAS population: all data must 
be checked in term of missingness and inconsistencies, and all queries resolved up to the Day 
28, 
• The following forms will be cleaned: Eligibility, Inclusion Criteria, Exclusion Criteria, 
Randomization and IMP assignment (also for all visits post randomization), Additional 
Information on Invasive Mechanical Ventilation and ICU (it has to be aligned with the 
corresponding forms), Invasive Mechanical Ventilation / ECMO, ICU admission summary, 
Lung Function, Death report and Visit date, 
• Data not related to the interim analysis: no specific cleaning activities are required at this 
point. 
6.6 
Key first efficacy analysis 
The aim of this key first analysis is to provide efficacy results on primary endpoint to populate an 
intermediate clinical study report. It will be performed when all patients are evaluable for the primary 
analysis at Day 28. This analysis will be conducted by an independent statistician. 
To maintain the blinding, results will be disclosed to the Sponsor in an aggregate way. The entire 
study personnel will remain blinded to patient-level information.  
The level of data cleaning requested for the key first efficacy analysis is the same as described in the 
interim analysis section 6.5. 
6.7 
Data Monitoring Committee (DMC) 
DMC meetings will be performed during the trial, in order to monitor the safety of the patients and 
to protect study subjects from undue harm. 
The following information will be analyzed for safety reason at each meeting: 
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• Major protocol changes, 
• Information on subject screening,  
• Study accrual, 
• Eligibility violations, 
• Demographics, 
• Length of follow-up data available, 
• Analyses of adverse events, 
• 
, 
• 
lyses, 
• Discontinuation of medications. 
Further details will be provided in the DMC Charter, where all roles and responsibilities will be 
defined. 
Access to unblinded information on the efficacy analyses is allowed on DMC request in order to 
balance patient safety risk against a possible gain in efficacy. 
The DMC will give careful consideration to the appropriateness of trial continuation if there is 
emerging evidence that reparixin is harmful. Since the DMC does not monitor primary endpoints for 
early efficacy termination (except for the Interim Analysis), no Type I error adjustment is necessary. 
The DMC will be involved in the evaluation of the interim analysis results and in the consequent 
decision on the continuation of the study. 
6.8 
Handling of missing and incomplete data 
The number of patients with missing data will be presented under the “Missing” category, if present. 
Missing values will not be included in the denominator count when computing percentages. 
Similarly, only the non-missing values will be evaluated for computing summary statistics for 
continuous endpoint. Any exception will be clarified as a note. 
Critical missing data will be discussed prior to treatment unblinding, if any. Decisions will be taken 
during the BDRM and will be fully documented in the BDRM Report. 
6.9 
Changes in the planned analysis 
Duration of non-invasive mechanical ventilation and duration of hospitalization since randomization 
(additional secondary endpoints) will be analyzed up to Day 60, instead of Day 28 as specified in the 
Protocol Version 3.0. 
6.10 Blinded Data Review Meeting 
A BDRM will be held before the DB lock and the unblinding of the data. Any other details will be 
provided in the BDRM Report.  
6.11 Software 
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All statistical analyses and data processing will be performed using Statistical Analysis Systems 
(SAS®) Software (release 9.4 or later). 
7.  Evaluation of Demographic and Baseline Characteristics 
7.1 
Subject enrolment and disposition 
All presentations of subject disposition will be by treatment group, and overall.  
For describing the subject disposition, the following populations will be summarized:  
• Subjects enrolled (overall);  
• Subjects enrolled but not randomized and reasons for non-allocation (overall);  
• Subjects randomized;  
• Subjects randomized but not treated; 
• Subjects in each analysis set (FAS, SAF, PP) and reasons for exclusion; 
For the overall report, the percentage denominator will be the number of ENR subjects. For the “by 
treatment group” calculations, the percentage denominator will be the number of randomized 
subjects within each arm. 
Listings will be provided based on ENR set. 
7.2 
Protocol deviations 
All the protocol deviations will be discussed case by case before unblinding of the treatment code 
with the clinical team during the BDRM and described in the BDRM Report. Number of occurrences 
and of subjects with at least one major and minor protocol deviation will be summarized for each 
treatment. 
7.3 
Study discontinuations 
The following information will be summarized for the randomized patients by treatment and overall: 
• Trial completers; 
• Subjects who discontinued the trial prematurely (and reasons); 
• Number of subjects who completed each planned visit; 
• Subjects who discontinued the IMP (and reasons): Subjects who discontinued the IMP are 
defined as subjects without clinical judgement of improvement (as noted on the end of 
treatment page) and with a primary reason for end of treatment different from “reached Day 
21”. Correspondingly, subjects with clinical judgement of improvement or the primary reason 
for end of treatment given as “reached Day 21” are evaluated as having completed the 
treatment; 
• Primary reason for ending the treatment: overall and in subjects with clinical judgment of  
improvement 
• Subjects who discontinued the IMP but completed the study; 
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• Subjects who discontinued the IMP and discontinued the trial prematurely; 
• Broken randomization code (and reasons). 
If more than 30% of randomized subjects discontinue the study prematurely, the distribution of the 
time from randomization to discontinuation will be summarized using time-to-event method. 
Subjects who have not prematurely discontinued the trial will be censored at study termination for 
final analysis and will be censored at clinical cut-off date for interim analysis and key first results. 
7.4 
Demographics and baseline characteristics 
The baseline demographic characteristics will be summarized by treatment and overall, by means of 
descriptive statistics. No statistical testing will be carried out for demographic or other baseline 
characteristics. 
The following demographic and baseline characteristics will be reported for this study: 
• 
Geographic region of the site (Italy, US, Other)  
• Demographics: 
o Age (years); 
o Age group (<65 years, ≥65 years); 
o Gender (Male, Female); 
▪ If female, potential childbearing (Yes, No); 
o Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander , Other); 
o Ethnicity (Hispanic or Latino, Not Hispanic or Latino); 
• Pregnancy test result (Positive or Negative), if appropriate; 
• Reasons for no pregnancy test; 
• Height (cm), weight (Kg) and BMI (BMI≤25kg/m2 vs 25kg/m2<BMI≤30kg/m2 vs 
BMI>30kg/m2); 
• Has the patient ever consumed alcohol? (Never, Former or Current) ; 
o If former or current, Amount of alcohol consumed daily (<1 Liter of wine (or 
equivalent) or (≥1 Liter of wine (or equivalent)); 
• Has the patient ever consumed tobacco? (Never, Former or Current) ; 
o If former or current, Amount of cigarettes consumed daily (<10 cigarettes or ≥10 
cigarettes); 
• Influenza test result (Positive or Negative); 
• SARS-CoV-2 RT-PCR test result (Positive, Negative or Not evaluable); 
• RT-PCR output. 
7.5 
Medical or Surgical History and/or Concomitant Diseases 
A disease is considered as medical/surgical history if it has ended before screening visit date. 
A disease is considered as concomitant disease if it is ongoing at screening visit. 
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Medical history and concomitant diseases will be coded using the Medical Dictionary for regulatory 
activities (MedDRA) dictionary and frequency distributions and percentages will be summarized by 
treatment, by System Organ Class (SOC), and Preferred Term (PT). 
Medical history and concomitant diseases will be analyzed separately. Frequency distributions and 
percentages by treatment will be given for both SOC and PT by subject. Subjects experiencing more 
than one past/concomitant disease event will be counted only once within each SOC and PT. 
 
 
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7.6 
Prior and concomitant medications 
Medications will be coded using World Health Organization Drug Dictionary (WHO DD). 
Prior medications are those which stopped prior to the date of informed consent. Concomitant 
medications are those which: 
• start prior to, on or after the date of informed consent and start no later than date of study 
completion or discontinuation, and 
• end on or after the date of informed consent or are ongoing at the study completion or 
discontinuation. 
In case of missing or incomplete dates/times not directly allowing allocation to either of the two 
categories of medications, a worst-case allocation will be done according to the available parts of the 
start and the end dates (see Table 6). The medication will be allocated to the first category allowed 
by the available data, according to the following order: 
• concomitant medication; 
• prior medication. 
Prior and concomitant medications will be summarized separately. Frequency distributions and 
percentages by treatment will be given by Anatomical Main Group (1st level of the Anatomical 
Therapeutic Chemical (ATC) classification), Chemical Subgroup (4th level of the ATC 
classification) and Preferred Name.  
Subjects taking more than one medication classified in the same category (prior medications or 
concomitant medications) within the same anatomical main group, chemical subgroup and preferred 
name will be counted only once. 
Preventive off-label use of anti-COVID-19 medication and Standard care for COVID-19 medications 
(
 and Error! Reference source not found.) will 
be evaluated separately in the same way as described in this section. These medications will be 
collected in the CRF in the same form of the prior and concomitant medications and will be clearly 
identifiable via a corresponding tick-box. 
7.7 
Other baseline characteristics 
7.7.1 Clinical severity score (7-point WHO-OS) 
Frequency distributions and percentages by treatment of Clinical severity score (7-point WHO-OS) 
at baseline will be provided. 
7.7.2 Dyspnea VAS Scale 
Dyspnea VAS Scale (from 0 to 100, where number "0" equals the worst breathing the patient has 
ever felt and the number "100" equals the best the patient has ever felt) results will be descriptively 
summarized by treatment. 
 
 
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7.7.3 Respiratory parameters 
Summary statistics by treatment of respiratory parameters at baseline will be provided. 
The following information will be summarized: 
• FiO2 (0.21 to 1) 
• SpO2 (%) 
• PaO2 (mmHg) 
• PaO2/FiO2 (Ratio) 
• Investigator’s interpretation (Normal, Abnormal NCS, Abnormal CS, No Result) for each 
parameter. 
7.7.4 Chest imaging 
Frequency distributions and percentages by treatment of clinical evaluation of Chest imaging at 
baseline will be provided. 
8.  Evaluation of Treatment Compliance and Exposure 
8.1 
Compliance to IMP 
Descriptive analyses of the following parameters will be presented by treatment group at each 
available time point and during the entire treatment period: 
• Total number of tablets administered 
• Volume administered 
• Total number of treatment days 
On a per patient basis, the evaluation of the compliance by visit and during the overall treatment 
period will be done using the following formula: 
 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = 
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑡𝑎𝑘𝑒𝑛 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑠𝑐ℎ𝑒𝑑𝑢𝑙𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 ×  100 
 
where “total number of tablets taken during the treatment period” is the sum of number of tables 
taken during each day, while the “total number of tablets scheduled during the treatment period” is 
given by the number of total scheduled tablets, considering that each patient takes 2 tablets three 
times daily (6 tablets daily) for up to 21 days or until decision of premature interruption (for 
improvement or, in any case, for the physician’s decision). 
Further details are reported in Table 4. 
Compliance will be summarized by treatment by means of summary statistics. In addition, 
compliance to IMP will also be presented for the following categories: <80%, ≥80%. 
8.2 
Exposure to IMP 
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The extent of exposure to IMP in days will be summarized overall with descriptive statistics by 
treatment group. The extent of exposure (days) will be calculated using the formula reported in Table 
4. 
9.  Evaluation of Efficacy 
9.1 
Analysis of primary efficacy endpoint 
9.1.1 Testing strategy and multiplicity adjustment 
The following null hypothesis is defined: the proportion of patients alive and free of respiratory 
failure at Day 28 (See section 5.7.1 for details) in Reparixin (TREPARIXIN) is lower or equal control 
(TCONTROL): 
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 key first efficacy) the test is performed. Thresholds 
are calculated according to O’Brien-Fleming spending function boundaries and are reported in Table 
3. 
9.1.2 Analysis details 
Primary endpoint will be analyzed by means of logistic regression adjusting by pre-defined baseline 
factors (treatment, gender, age class and presence of concomitant disease as fixed effect and site as 
random effect) and a one-sided test will be used to test for differences between treatment groups. 
Missing data on the primary endpoint will be handled by means of Multiple Imputation using retrieve 
dropouts (MI-RD) under MNAR assumption. Specifically, MI will be performed based on the 
subjects’ allocated treatment arm and observed values as covariates in a regression model using data 
from subjects that discontinued the treatment but have the primary endpoint measurement with 
gender, age class and presence of concomitant disease as covariates. Please see section 7.3 for 
definition of treatment discontinuation. 
If there are no enough retrieved dropouts for convergence of MI regression model, MI will be 
performed using data from completers from the placebo arm (i.e., subjects in the placebo arm with 
assessment of primary endpoint). The final decision will be done at the time of the analysis and 
reported in the CSR. Measurements for patients on the placebo arm with missing primary endpoint 
will be imputed using a monotone regression model based on observed data of placebo completers 
with gender, age class and presence of concomitant disease as covariates. For patients on the 
reparixin arm who had missing primary endpoint data, the imputation model with subject’s gender, 
age class and presence of concomitant disease as covariates will be used based on data from 
completers from the placebo arm. 
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One thousand data sets will be generated. The random seed number will be 200582. Each of 1000 
imputed dataset will be analyzed by means of the logistic regression model specified above. Rubin’s 
rule will be used for combining results to draw inference. The adjusted estimated treatment odds ratio 
between reparixin and placebo at Day 28 will be displayed together with the corresponding 95% 
confidence interval and p-value. This p-value will be compared to the thresholds in Table 3 in order 
to demonstrate the superiority of reparixin. 
9.1.3 Sensitivity analysis 
The primary analyses will be assessed in sensitivity analyses using different assumptions and 
populations, as detailed below. 
• The analysis of the primary endpoint will be repeated on the PP set instead of FAS, as well 
as on the FAS excluding patients who were already in the ICU at baseline, using the same 
methodology described in section 9.1.2. These analyses will assess the robustness of results 
to protocol deviations. 
• 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. Comparison between treatment will be 
performed according to the logistic regression model described in section 9.1.2. 
• 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. MI will be 
implemented in this way:  
o Imputation assuming MAR will be carried out to impute missing data based on 
logistic regressions. A separate imputation model will be used for each treatment arm. 
The imputation models will include the gender, age class and presence of concomitant 
disease. In case of non-convergence or non-estimability issues, a single model will be 
considered with treatment arm added as an explanatory variable in the model. 
o Rounding restrictions will be applied to imputed binary values due to type of primary 
endpoint variable (endpoint = 0 if value <0.5, endpoint = 1 if value ≥0.5).  
o Imputed data will consist of 200 imputed datasets. The random seed number for 
imputation with the MCMC method will be 40110.  
o Each of the 200 imputed datasets will be analyzed using observed and imputed data 
using regression logistic models as described in section 9.1.2. Rubin’s rule will be 
used for combining results to draw inference. The adjusted estimated treatment odds 
ratio between Reparixin and placebo at Day 28 will be displayed together with the 
corresponding 95% confidence intervals and p-value. 
• A tipping point strategy will be used as a sensitivity analysis for missing data for assessment 
of superiority (if shown) of Reparixin. Tipping point analysis 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. In the first 
iteration, MI-RD method is assumed as described in section 9.1.2. In successive iterations, 
the imputed values for the Reparixin arm are shifted by a constant to represent a worse effect 
in each iteration. This can be achieved by using the N completed data-sets obtained under 
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MI-RD and shift the imputed values. The tipping point is the shift at which the p-value 
becomes non-significant. Outline of tipping point: 
o Use MI-RD to impute missing values; 
o Assuming that the tipping point is between -3 and 3, the following actions will be 
performed for Δ = 3, 2.9, 2.8, …,0, -0.1, -0.2, -0.3, …, -3: 
▪ Add Δ to the imputed values at the Reparixin arm; 
▪ Analyze the completed data sets using the same method outlined in section 
9.1.2; 
o the plot of all p-values for Δ between -3 and 3 will be created; 
o based on the plot, the approximate value of the tipping point Tpapprox is identified 
considering a threshold for the p-values of 0.02400; 
o after identification of Tpapprox, a finest research of the tipping point will be performed 
in the range Tpapprox ± 1 by incrementing Δ of 0.01 and following the usual steps: 
▪ Add Δ to the imputed values at the Reparixin arm; 
▪ Analyze the completed data sets using the same method outlined in section 
9.1.2; 
o The tipping point is the smallest Δ at which p-value ≥ 0.02400. 
• The comparison between treatment and control will be performed in the FAS population 
using the Win Ratio (RWIN) calculated by Pocock et al method4 with the unmatched approach. 
The outcomes used in calculating the win ratio ordered by their clinical importance (from 
high to low) will be: 
o death, 
o Invasive Mechanical Ventilation or ECMO, and  
o admission to ICU linked to worsening of respiratory parameters compared to baseline 
within Day 28. 
The steps needed to follow for the calculation of RWIN: 
1. Let NR= total patients on Reparixin, and let NP= total patients on Placebo; 
2. Compare the timing of death, IMV and ICU for each patient on Reparixin to each 
patient on Placebo (NR x NP comparisons) for the shortest time duration that exists 
between each pair of patients (this determination would happen if event dates are 
available for both patients, or if one patient was censored at a later time than the event 
time for the other);  
3. Classify each patient into one of 7 exclusive categories: 
a. Reparixin patient died prior to Placebo patient, 
b. Placebo patient died prior to Reparixin patient, 
c. Reparixin patient had IMV prior to Placebo patient, 
d. Placebo patient had IMV prior to Reparixin patient, 
e. Reparixin patient had ICU admission prior to Placebo patient, 
f. Placebo patient had ICU admission prior to Reparixin patient, 
g. None of the above; 
4. Calculate RWIN: 
▪ Since groups b, d and f are in favor of Reparixin, Nb + Nd + Nf = NWIN, 
▪ Since groups a, c and e are not in favor of Placebo, Na + Nc + Ne = NLOSS, 
▪ 
RWIN =Nwin/NLOSS. 
 
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The significance test and the method for determining the p-value for the unmatched approach 
is based on the Finkelstein and Schoenfeld5 approach: 
1. If patient i is known to have a better condition than patient j (point b., d., and f. 
according to the above criteria), then 𝑢𝑖𝑗 = 1; else, if patient j is known to have a better 
condition than patient i, then 𝑢𝑖𝑗 = -1, otherwise 𝑢𝑖𝑗 = 0. In all cases, 𝑢𝑖𝑗= −𝑢𝑗𝑖. 
2. The final test statistic is based on the sum of the scores for patients in the Reparixin 
group: 
𝑇= ∑𝑈𝑖𝐷𝑖
𝑁
𝑖=1
 
 
where: 
▪ N is the total of patients (NR + NP), 
▪ 𝑈𝑖= ∑
𝑢𝑖𝑗
𝑖≠𝑗
, and  
▪ 
Di = 1 for patients in the Reparixin group and let Di = 0 for patients in the 
Placebo group. 
Values for T greater than zero indicate superiority of the Reparixin arm as the mean of the 
test statistic is 0 under the null hypothesis of no difference between treatment and control. 
Finkelstein and Schoenfeld5 derive the variance for this statistic according to the following 
rule:  
𝑉= 𝑁𝑅∗𝑁𝑃
𝑁(𝑁−1) ∑𝑈𝑖
2
𝑁
𝑖=1
 
 
Superiority of the Reparixin group will be tested by comparing T / V1/2 to the percentiles of 
the standard normal distribution. 
 
Finally, the confidence interval of RWIN will be calculated by the bootstrap method: data will 
be sampled with replacement 1000 times and from each bootstrap sample the win ratio will 
be calculated in order to determine the empirical distribution of the win ratio. The random 
seed number will be 31598. The 95% confidence interval will be created by calculating the 
2.5th and 97.5th percentiles of the empirical distribution. The bootstrap method will proceed 
as follows: 
1. a random sample SP of size NP is drawn from the original Placebo group; 
2. The unmatched analysis is performed on the samples SR and SP, and the win ratio is 
calculated; 
3. Steps 1 and 2 are repeated M times (M=1000); 
4. the empirical bootstrap distribution of the win ratio is determined from the M 
bootstrap values; 
5. the 2.5th and 97.5th percentiles of the bootstrap distribution are obtained: these are the 
estimated limits of the 95% confidence interval for the win ratio. 
 
 
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9.2 
Analysis of secondary efficacy endpoints 
9.2.1 Testing strategy and multiplicity adjustment 
In case the analysis of the primary endpoints leads to rejection of null hypothesis (section 9.1.1), 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 until Day 28, 
4. Time to recovery (category 1 – 2 – 3 of the 7-point WHO-OS of clinical improvement) until 
Day 28. 
This hierarchical test strategy protects the family-wise false positive error rate at the overall one-
sided 0.025 level. In case of futility at interim analysis (scenario 3, see section 6.5) or in case of not 
rejection of null hypothesis, the above test strategy will not be performed.  
9.2.2 Analysis details 
Analysis of key secondary endpoints are detailed below in sections 9.2.2.1, 9.2.2.2, 9.2.2.3, and 
9.2.2.4, and p-values to be evaluated for comparison between treatments in a sequential order are the 
following: 
1. P-value of treatment variable from logistic regression model, 
2. P-value of treatment variable from logistic regression model, 
3. P-value of treatment variable from logistic regression model, 
4. P-value from Gray’s test. 
Independently of results on primary and key secondary endpoints, descriptive in nature analyses will 
be performed on all secondary endpoints (section 5.7.2 and 5.7.3) at each available timepoints by 
means of descriptive statistics (section 6.1). In case of continuous measures, analyses will be 
provided for: 
• baseline visit,  
• each post-baseline visit, and  
• the change from baseline measurements to each visit.  
In case of categorical variables, shift tables showing difference as to the respective classifications at 
baseline will be provided. 
In addition to the above summary statistics, comparisons between treatments will be performed as 
detailed in the next sub-sections. Parametric tests (i.e. two-sample t-test (assuming unequal 
variances) for continuous variables, Chi-square test for categorical) will be adopted as a first choice. 
In case the required assumptions are not met, the corresponding non-parametric counterparts will be 
used (i.e. the two-sample Mann–Whitney U test for continuous variables (using the normal 
approximation with continuity correction), and the Fisher’s Exact test for the categorical variables). 
Assumption of normal distribution of endpoints for continuous data will be assessed by a visual 
inspection of distribution. If required, data transformation will be applied and specified in the notes. 
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Comparison will be performed at each available time point, where applicable. Any exception will be 
declared. 
9.2.2.1 Proportion of patients alive and free of respiratory failure at Day 60 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of 
patients alive and free of respiratory failure will be calculated. 
Proportion of patients alive and free of respiratory failure at Day 60 will be compared between 
treatments group using the same logistic regression model used for primary endpoint and detailed in 
section 9.1.2.  
9.2.2.2 Mortality rates up to Day 28 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of 
subjects who die will be calculated up to Day 28. 
Mortality rates up to Day 28 will be compared between treatments group using a logistic regression 
model, with treatment group, age group, gender and presence of concomitant disease at baseline as 
covariates.  
9.2.2.3 Incidence of ICU admission until Day 28 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of 
subjects requiring post-randomization ICU admission will be calculated up to Day 28. All deaths 
until Day 28 will be counted as failures. 
Similarly, number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of 
patients requiring post-randomization ICU admission up to Day 28 which has been followed by 
invasive mechanical ventilation (or ECMO) or death will be calculated by treatment group.  
In both cases, incidences of ICU admission until Day 28 will be compared between treatments group 
using a logistic regression model, with treatment group, age group, gender and presence of 
concomitant disease at baseline as covariates.  
9.2.2.4 Time to recovery (category 1 - 2 - 3 of the 7-point WHO-OS of clinical improvement) 
Time to recovery up to Day 28 will be analyzed according to survival analysis methodology detailed 
in section 9.1.2 with the following modifications: 
• the common representation of survival curves using the Kaplan-Meier estimator will be 
replaced by the cumulative incidence function,  
• death, discontinuation for Adverse Events and patient transferred to another institution will 
be considered as competing risks. 
• the comparison between treatment and control will be performed by means of a Gray's test6 
instead of the standard log-rank test. 
An event (recovery) will be considered as such, if patient has scored category 1, 2 or 3 from the 7-
point WHO Ordinal Scale of clinical improvement (WHO-OS), otherwise it will be considered free 
of event.  
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9.2.2.5 Proportion of patients alive and free of respiratory failure at fixed time-points 
Number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of patients 
alive and free of respiratory failure (as described for the primary endpoint – Section 5.7.1) will be 
calculated for each time point. The comparison between the two study treatment arms will be 
performed by means of a Chi-square test or, if more appropriate, a Fisher’s Exact test at each time 
point. 
9.2.2.6 Mean changes in clinical severity score based on the 7-point WHO-OS 
Changes from baseline in clinical severity score based on the 7-point WHO-OS will be analyzed at 
each available time points by means of descriptive statistics (Section 6.1). Comparison between 
treatments will be performed by means of two-sample Mann-Whitney U test. 
Along with this analysis, absolute values at baseline and post-baseline will be analyzed at each 
available time points by means of descriptive statistics (Section 6.1). 
9.2.2.7 Time to clinical improvement 1 (decline of 1 category in the 7-point WHO-OS)  
Time to clinical improvement 1 up to Day 28 will be analyzed as described in section 9.2.2.4. 
An event will be considered as such, if patient declines of at least 1 category in the 7-point WHO 
Ordinal Scale of clinical improvement (WHO-OS) respect to the baseline, otherwise it will be 
considered free of event.  
9.2.2.8 Time to clinical improvement 2 (decline of 2 categories in the 7-point WHO-OS) 
Time to clinical improvement 2 up to Day 28 will be analyzed as described in section 9.2.2.4. 
An event will be considered as such, if patient declines of at least 2 categories in the 7-point WHO 
Ordinal Scale of clinical improvement (WHO-OS) respect to the baseline, otherwise it will be 
considered free of event.  
9.2.2.9 Time to discharge from hospital (up to Day 28) 
Time to discharge from hospital up to Day 28 will be analyzed as described in section 9.2.2.4. 
9.2.2.10 Clinical status (7-point WHO-OS)  
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of 
patients with clinical status (7-point WHO-OS) by category and treatment group will be calculated 
for each time point. The comparison between the two study treatment arms will be performed by 
means of a Chi-square test or, if more appropriate, a Fisher’s Exact test at each time point. 
When patient is at home, his/her clinical status can be assessed by phone. 
9.2.2.11 Dyspnea severity (Likert scale and VAS scale)  
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of 
patients with Dyspnea severity Likert scale by score and treatment group will be calculated for each 
time point. The comparison of the Liker scale between the two study treatment arms will be 
performed by means of a Chi-square test or, if more appropriate, a Fisher’s Exact test at each time 
point. 
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VAS scale will be analyzed at each available time points by means of descriptive statistics (Section 
6.1). Specifically, analyses will be provided for baseline visit, each post-baseline visit and the change 
from baseline measurements to each visit. Comparison between treatments for change from baseline 
will be performed by means of two-sample t-test or, if assumptions of normality is not confirmed (by 
a visual inspection of distribution), two-sample Mann-Whitney U test. 
9.2.2.12 Duration of supplemental oxygen treatment (days) up to Day 28 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of 
patients using supplemental oxygen treatment by treatment group will be calculated. 
Cumulative duration of supplemental oxygen treatment (days) will be analyzed by means of 
descriptive statistics (Section 6.1) by treatment and overall. Comparison between treatments will be 
performed by means of two-sample t-test or, if assumptions of normality is not confirmed (by a visual 
inspection of distribution), two-sample Mann-Whitney U test. 
9.2.2.13 Incidence of invasive mechanical ventilation use, or ECMO up to Day 60 
Number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of patients 
requiring invasive mechanical ventilation or ECMO up to Day 60 by treatment group will be 
calculated.  
Similarly, number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of 
patients requiring invasive mechanical ventilation or ECMO up to Day 60 which has been followed 
by death will be calculated by treatment group.  
In both cases, the comparison between the two study treatment arms will be performed by means of 
a Chi-square test or, if more appropriate, a Fisher’s Exact test. 
9.2.2.14 Duration of invasive mechanical ventilation, or ECMO (days) up to Day 60 
Cumulative duration of invasive mechanical ventilation or ECMO (days) up to Day 60 will be 
analyzed by means of descriptive statistics (Section 6.1) by treatment and overall. Comparison 
between treatments will be performed by means of two-sample t-test or, if assumptions of normality 
is not confirmed (by a visual inspection of distribution), two-sample Mann-Whitney U test. 
9.2.2.15 Duration of non-invasive mechanical ventilation (days) up to Day 60 
Cumulative duration of non-invasive mechanical ventilation (days) up to Day 60 will be analyzed by 
means of descriptive statistics (Section 6.1) by treatment and overall. Comparison between 
treatments will be performed by means of two-sample t-test or, if assumptions of normality is not 
confirmed (by a visual inspection of distribution), two-sample Mann-Whitney U test. 
9.2.2.16 Duration of ICU admission (days) up to Day 60 
Cumulative duration of ICU admission (days) up to Day 60 will be analyzed by means of descriptive 
statistics (Section 6.1) by treatment and overall. Comparison between treatments will be performed 
by means of two-sample t-test or, if assumptions of normality is not confirmed (by a visual inspection 
of distribution), two-sample Mann-Whitney U test. 
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9.2.2.17 Duration of hospitalization since randomization (days) up to Day 60 
Duration of hospitalization (days) up to Day 60 will be analyzed by means of descriptive statistics 
(Section 6.1) by treatment and overall. Comparison between treatments will be performed by means 
of two-sample t-test or, if assumptions of normality is not confirmed (by a visual inspection of 
distribution), two-sample Mann-Whitney U test. 
9.2.2.18 Partial pressure of oxygen (PaO2): change from baseline to the firstly available daily value  
Partial pressure of oxygen (PaO2) will be analyzed at each available time points by means of 
descriptive statistics (Section 6.1). Specifically, analyses will be provided for baseline visit, each 
post-baseline visit and the change from baseline measurements to each visit. Comparison between 
treatments will be performed by means of two-sample t-test or, if assumptions of normality is not 
confirmed (by a visual inspection of distribution), two-sample Mann-Whitney U test. 
Summary statistics of Investigator’s interpretation (Normal, Abnormal NCS, Abnormal CS) will be 
provided by treatment arm at each timepoint. The comparison between the two study treatment arms 
will be performed by means of a Chi-square test or, if more appropriate, a Fisher’s Exact test at each 
time point. 
9.2.2.19 Pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2) 
Pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2) will be analyzed at 
each available time points by means of descriptive statistics (Section 6.1). Specifically, analyses will 
be provided for baseline visit, each post-baseline visit and the change from baseline measurements 
to each visit. Comparison between treatments will be performed by means of two-sample t-test or, if 
assumptions of normality is not confirmed (by a visual inspection of distribution), two-sample Mann-
Whitney U test. 
Summary statistics of Investigator’s interpretation (Normal, Abnormal NCS, Abnormal CS) will be 
provided by treatment arm at each timepoint. The comparison between the two study treatment arms 
will be performed by means of a Chi-square test or, if more appropriate, a Fisher’s Exact test at each 
time point. 
9.2.2.20 P/F ratio [partial arteriolar oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) 
ratio] from baseline 
PaO2/FiO2 ratio will be analyzed at each available time points by means of descriptive statistics 
(Section 6.1). Specifically, analyses will be provided for baseline visit, each post-baseline visit and 
the change from baseline measurements to each visit. Comparison between treatments will be 
performed by means of two-sample t-test or, if assumptions of normality is not confirmed (by a visual 
inspection of distribution), two-sample Mann-Whitney U test. 
In addition, number and proportion of patients with a decrease of PaO2/FiO2 ratio of at least 40% or 
a worsening of Investigator’s Interpretation (from “Normal” to “Abnormal” or from “Abnormal, not 
clinically significant” to “Abnormal, clinically significant”) from the baseline value will be provided 
to each visit. 
The number and proportion of patients with a decrease of PaO2/FiO2 ratio of at least 40% or a 
worsening of Investigator’s Interpretation from the baseline value which has been followed by: 
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• an ICU admission, and/or  
• IMV or ECMO, and/or  
• death  
will be provided to each visit by treatment group. 
Summary statistics of Investigator’s interpretation (Normal, Abnormal NCS, Abnormal CS) will be 
provided by treatment arm at each timepoint. The comparison between the two study treatment arms 
will be performed by means of a Chi-square test or, if more appropriate, a Fisher’s Exact test at each 
time point. 
9.2.2.21 Hs-CRP: change from baseline 
Hs-CRP (alternatively CRP) will be analyzed at each available time points by means of descriptive 
statistics (Section 6.1). Specifically, analyses will be provided for baseline visit, each post-baseline 
visit and the change from baseline measurements to each visit. Comparison between treatments will 
be performed by means of two-sample t-test or, if assumptions of normality is not confirmed (by a 
visual inspection of distribution), two-sample Mann-Whitney U test. 
Summary statistics of Investigator’s interpretation (Normal, Abnormal NCS, Abnormal CS, No 
Result) will be provided by treatment arm at each timepoint. The comparison between the two study 
treatment arms will be performed by means of a Chi-square test or, if more appropriate, a Fisher’s 
Exact test at each time point. 
9.2.2.22 Mortality rates up to Day 60 and Day 90 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of 
subjects who die will be calculated up to Day 60 and Day 90. 
Mortality rates up to Day 60 and Day 90 will be compared between treatments group using a logistic 
regression model, with treatment group, age group, gender and presence of concomitant disease at 
baseline as covariates.  
9.2.2.23 Freedom from (time to) death or respiratory failure  
Freedom from (time to) death or respiratory failure (need of invasive mechanical ventilation or 
ECMO or admission to ICU linked to worsening of respiratory parameters compared to baseline) up 
to Day 90 will be performed using the same Kaplan-Meier analysis and the one-sided log-rank test 
will be used to test for differences between treatment groups. 
 
 
9.3.1 Analysis details 
 
 
 
 
 
 
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10.  
Evaluation of Safety 
10.1 Adverse events 
Any AE which starts at or after the first administration of study treatment will be considered a 
Treatment Emergent Adverse Event (TEAE). Pre-treatment AEs and TEAEs will be presented 
separately. Pre-treatment AEs will be presented in the listings only. In case of missing or incomplete 
dates not allowing a direct allocation to any of the two categories of AEs, a worst-case allocation 
will be done according to the available parts of the onset and the end dates (see Table 5). The AE 
will be allocated to the first category allowed by the available data, according to the following order: 
• TEAE; 
• Pre-treatment AE. 
In case of TEAE, the event can be classified as:  
• On Treatment Period, or  
• On Follow-up period  
according to the available parts of the onset and the end dates (see Table 5). 
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All AEs will be assigned to a Preferred Term (PT) and will be classified by primary System Organ 
Class (SOC) according to the MedDRA thesaurus. In addition, each AE will be graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
toxicity grading scale (version 5.0) to capture the severity, as per definition in the table below: 
 
 
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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. 
 
TEAEs will be reported on a per-patient basis, i.e. if a patient reported the same event repeatedly (i.e. 
events mapped to the preferred term) the event will be counted only once. 
For summaries, the drug-event relationship will be assessed as “None”, “Unlikely”, “Possible” 
“Probable” or “Highly probable” by the investigator. Any TEAE reported in the study having a 
possible, probable or highly probable relationship to IMP will be defined as “Adverse Drug 
Reaction” (ADR). 
The following tables and listings will be presented by treatment group: 
• An overview of TEAEs including the number of patients who exhibited at least one TEAE, 
at least one severe TEAE, at least one serious TEAE, at least one non-serious TEAE, at least 
one ADR, at least one serious ADR, at least one TEAE leading to discontinuation of IMP, at 
least one TEAE leading to discontinuation of study, at least one TEAE leading to death, 
number of TEAEs, number of non-serious TEAEs, number of TESAEs, number of ADRs, 
number of serious ADRs, number of severe TEAEs, number of TEAEs leading to 
discontinuation of IMP, number of TEAEs leading to discontinuation of study, number of 
TEAEs leading to deaths.; 
• Summary of TEAEs by primary System Organ Class and Preferred Term and by study period 
(on treatment/follow-up and overall); 
• Summary of TEAEs by primary System Organ Class, Preferred Term and Severity; 
• Summary of Serious TEAEs by Primary System Organ Class and Preferred Term and by 
study period (on treatment/follow-up and overall); 
• Summary of ADRs by Primary System Organ Class and Preferred Term and by study period 
(on treatment/follow-up and overall); 
• Summary of ADRs by Primary System Organ Class and Preferred Term and Severity; 
• Summary of TEAEs leading to IMP Discontinuation by Primary System Organ Class and 
Preferred Term and by study period (on treatment/follow-up and overall); 
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• Summary of TEAEs leading to study Discontinuation by Primary System Organ Class and 
Preferred Term and by study period (on treatment/follow-up and overall); 
• Summary of TEAEs leading to Death by Primary System Organ Class and Preferred Term; 
• Listing of all AEs by Patient; 
• Listing of all AEs leading to IMP discontinuation; 
• Listing of all AEs leading to study discontinuation; 
• Listing of SAEs by Patient; 
• Listing of ADR by Patient; 
• Listing of Deaths. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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• 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
10.5 Child Pugh Score 
Summary statistics by treatment of the Child Pugh Score will be provided along with summary of 
the change from baseline at each available timepoint. Comparison between treatments for change 
from baseline will be performed by means of two-sample t-test or, if assumptions of normality is not 
confirmed (by a visual inspection of distribution), two-sample Mann-Whitney U test. In addition, 
summary statistics of the number and frequency of patients for all other categorical parameters will 
be provided by treatment arm and overall at each available timepoint. 
 
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11.  
Derivations and date conventions 
11.1 Variable derivation 
Table 4: Variable derivation rules 
Parameter 
Calculation 
Need of invasive mechanical 
ventilation or ECMO at Day 28 (or 
Day 60) 
From INVASIVE MECHANICAL VENTILATION / ECMO form or ADDITIONAL INFORMATION form:  
Event derivation: 
The subject will be considered as having an "IMV/ECMO" event (“Yes”) at Day 28 (or Day 60), if one of the following criteria is met: 
• 
At least one observation in the "INVASIVE MECHANICAL VENTILATION / ECMO" form with start date after randomization date and up 
to Day 28 (or Day 60);  
• 
At least one observation in the "ADDITIONAL INFORMATION" form performed in a visit after "Baseline Day 1" and up to Day 28 (or Day 
60) with answer to question "Does the patient need invasive mechanical ventilation / ECMO?" = "Yes". 
The subject will be considered as not having an "IMV/ECMO" event (“No”) at Day 28 (or Day 60) if the following criteria are met: 
• 
He/she has completed the Day 28 (or Day 60) assessment, or subsequent; 
• 
He/she has no observations in “INVASIVE MECHANICAL VENTILATION / ECMO” form up to Day 28 (or Day 60). 
Event date derivation: 
If the subject has the event ("Yes") then the event date will be the minimum date among the following: 
• 
Start date of IMV/ECMO in the "INVASIVE MECHANICAL VENTILATION / ECMO" form (after randomization date) 
• 
Date of the visit in which the "ADDITIONAL INFORMATION" form performed after "Baseline Day 1" visit has the answer to the question 
"Does the patient need invasive mechanical ventilation / ECMO?" = "Yes". 
 
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Parameter 
Calculation 
Admission to ICU at Day 28 (or 
Day 60) 
From ICU ADMISSION SUMMARY form or ADDITIONAL INFORMATION form:  
Event derivation: 
The subject will be considered as having an "ICU" event (“Yes”) at Day 28 (or Day 60) if one of the following criteria is met: 
• 
At least one observation in the "ICU ADMISSION SUMMARY" form with start date after randomization date and up to Day 28 (or Day 60); 
• 
At least one observation in the "ADDITIONAL INFORMATION" form performed in a visit after "Baseline Day 1" and up to Day 28 (or Day 
60) with answer to question "Does the patient need to be admitted to the ICU?" = "Yes". 
The subject will be considered as not having an "ICU" event (“No”) at Day 28 (or Day 60) if the following criteria is met: 
• 
He/she has completed the Day 28 (or Day 60) assessment, or subsequent; 
• 
He/she has no observations in “ICU ADMISSION SUMMARY” form up to Day 28 (or Day 60). 
Event date derivation: 
If the subject has the event ("Yes") then the event date will be the minimum date among the following: 
• 
Start date of ICU in the "ICU ADMISSION SUMMARY" form (after randomization date) 
• 
Date of the first visit in which the "ADDITIONAL INFORMATION" form performed after "Baseline Day 1" visit has the answer to the question 
"Does the patient need to be admitted to the ICU?" = "Yes". 
 
PaO2/FiO2 ratio 
When the PaO2/FiO2 ratio is not reported in the eCRF (i.e. the value is missing) but the two values for PaO2 and FiO2 are available separately, the 
PaO2/FiO2 ratio will be derived as ratio between the two values. 
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Parameter 
Calculation 
Worsening of respiratory 
parameters (decrease of 
PaO2/FiO2 ratio of at least 40% or 
a worsening of Investigator’s 
Interpretation from the baseline 
value) at Day 28 (or Day 60) 
From LUNG FUNCTION form: 
Event derivation: 
The subject will be considered as having a "Respiratory worsening" event (“Yes”) at Day 28 (or Day 60) in case of: 
• 
a decrease of PaO2/FiO2 ratio of at least 40% from the baseline value and up to Day 28 (or Day 60), or 
• 
a worsening of Investigator’s Interpretation (from “Normal” to “Abnormal” or from “Abnormal, not clinically significant” to “Abnormal, 
clinically significant”) from the baseline value and up to Day 28 (or Day 60). 
The subject will be considered as not having a "Respiratory worsening" event (“No”) at Day 28 (or Day 60) if the following criteria are met: 
• 
He/she has completed the Day 28 (or Day 60) assessment, or subsequent; 
• 
He/she has no decrease of PaO2/FiO2 ratio (or case of a decrease lower than 40%) and no worsening of Investigator’s Interpretation from 
baseline and up to Day 28 (or Day 60) . 
Event date derivation: 
If the subject has the event ("Yes") then the event date will be the date of assessment or PaO2/FiO2 ratio 
If baseline PaO2/FiO2 ratio is missing, the change from baseline cannot be computed and it will be set as missing. 
 
Need of admission to ICU related 
to a worsening of the respiratory 
parameters at Day 28 (or Day 60) 
From Admission to ICU (see above derivation rule) and Worsening of respiratory parameters (see above derivation rule): 
Event derivation: 
The subject will be considered as having a "Need of an admission to ICU related to a worsening of respiratory parameters" event (“Yes”) at Day 28 (or 
Day 60) if the following criteria are met: 
• 
Admission to ICU at Day 28 (or Day 60) =”Yes” with an non-missing event date 
• 
Respiratory worsening at Day 28 (or Day 60)  =”Yes” with an non-missing event date 
• 
The Admission to ICU has happened within 7 days after Respiratory worsening. 
The subject will be considered as not having an " Need of an admission to ICU related to a worsening of respiratory parameters " event (“No”) at Day 
28 (or Day 60) if the following criteria is met: 
• 
He/she has no Admission to ICU happening within 7 days after Respiratory worsening up to Day 28 (or Day 60). 
In case of admission to ICU and missing change from baseline of PaO2/FiO2 ratio, information from queries might be used in order to determine if 
ICU is linked to worsening of respiratory parameters. 
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Parameter 
Calculation 
Primary endpoint (patients alive 
and free of respiratory failure at 
Day 28) 
The primary endpoint is equal to “No” if at least one of the following criteria is met before Day 28: 
• 
The patient died within Day 28 date; 
• 
The patient had need of invasive mechanical ventilation or ECMO at Day 28 (see derivation rule);  
• 
The patient had need of admission to ICU related to a worsening of the respiratory parameters at Day 28 (see derivation rule); 
Otherwise, the primary endpoint is equal to “Yes” if all the following criteria are met up to Day 28 (i.e. there are no missing assessment for “Need of 
Invasive Mechanical Ventilation or ECMO” and for “Admission to ICU related to a worsening of the respiratory parameters” up to Day 28): 
• 
The patient is alive at Day 28; 
• 
The patient had no need of invasive mechanical ventilation or ECMO at Day 28 (see derivation rule);  
• 
The patient had no need of admission to ICU related to a worsening of the respiratory parameters at Day 28 (see derivation rule). 
In case of the last available assessment of endpoint is before Day 28, the primary endpoint at Day 28 will be set as missing. 
 
Secondary endpoint (patients alive 
and free of respiratory failure at 
Day 60) 
The primary endpoint is equal to “No” if at least one of the following criteria is met before Day 60: 
• 
The patient died within Day 60 date; 
• 
The patient had need of invasive mechanical ventilation or ECMO at Day 60 (see derivation rule);  
• 
The patient had need of admission to ICU related to a worsening of the respiratory parameters at Day 60 (see derivation rule); 
Otherwise, the primary endpoint is equal to “Yes” if all the following criteria are met up to Day 60 (i.e. there are no missing assessment for “Need of 
Invasive Mechanical Ventilation or ECMO” and for “Admission to ICU related to a worsening of the respiratory parameters” up to Day 60): 
• 
The patient is alive at Day 60; 
• 
The patient had no need of invasive mechanical ventilation or ECMO at Day 60 (see derivation rule);  
• 
The patient had no need of admission to ICU related to a worsening of the respiratory parameters at Day 60 (see derivation rule). 
In case of the last available assessment of endpoint is before Day 60, the primary endpoint at Day 60 will be set as missing. 
Time to death (days) 
Time to death (days) = Date of death - Date of randomization + 1 
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Parameter 
Calculation 
Time to recovery (days) 
Recovery = any of these answers from 7-point WHO Ordinal Scale: 
• 
1 = not hospitalized, with resumption of normal activities 
• 
2 = not hospitalized, but unable to resume normal activities 
• 
3 = hospitalized, not requiring supplemental oxygen 
Time to recovery (days) = First recovery date – Date of randomization + 1 
Subjects who are free from event will be censored at the study termination for the final analysis and will be censored at clinical cut-off date for interim 
analysis. Subjects who have discontinued without an event will be censored at the date of discontinuation. 
 
Time to clinical improvement 1 
(days) 
Improvement 1 = decline of at least 1 category in the 7-point WHO Ordinal Scale respect to the baseline 
Time to improvement 1 (days) = Date of visit when there is an improvement – Date of randomization + 1 
Time to clinical improvement 2 
(days) 
Improvement 2 = decline of at least 2 categories in the 7-point WHO Ordinal Scale respect to the baseline 
Time to improvement 2 (days) = Date of visit when there is an improvement – Date of randomization + 1 
Time to discharge from hospital 
(days) 
Time to discharge from hospital (days) = Date of discharge - Date of randomization + 1 
Cumulative duration (days) of 
supplemental oxygen treatment 
Cumulative duration of supplemental oxygen treatment (days) = 
Sum of duration of supplemental oxygen administration (days) in DAILY SUPPLEMENTAL OXYGEN form, from randomization up to Day 28. 
Duration of supplemental oxygen administration (days) = count how many time patients require any supplement oxygen administration, counting 
number of rows from DAILY SUPPLEMENTAL OXYGEN form. 
Cumulative duration (days) of 
invasive mechanical ventilation or 
ECMO 
Cumulative duration of invasive mechanical ventilation or ECMO (days) = 
Sum of duration of invasive mechanical ventilation or ECMO (days) in INVASIVE MECHANICAL VENTILATION / ECMO form, from 
randomization to Day 28. 
Duration of invasive mechanical ventilation or ECMO (days) = End date – Start date + 1. 
Only post-randomization events will be considered. 
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Parameter 
Calculation 
Cumulative duration (days) of non-
invasive mechanical ventilation 
Cumulative duration of non-invasive mechanical ventilation (days) = 
Sum of duration of non-invasive mechanical ventilation (days) in NON-INVASIVE MECHANICAL VENTILATION form, from randomization to 
Day 28. 
Duration of non-invasive mechanical ventilation (days) = End date – Start date + 1 
Only post-randomization events will be considered. 
Duration (days) of ICU admission 
Duration of ICU admission (days) = Discharge date – Admission date + 1 
Only post-randomization events will be considered. 
Duration (days) of hospitalization 
since randomization up to Day 28 
Duration of hospitalization (days) = Discharge date – Hospital admission date + 1 
Only post-randomization events will be considered. 
Number of ICU admissions up to 
Day 28 
Number of non-adjacent entries (defined as number of entries with ≥ 2 days of difference between end date of previous entry and start date of next 
entry, when soring all entries by start date) of ICU admission in the ICU admission summary form, from randomization to Day 28. Only post-
randomization events will be considered. 
Number of use of invasive 
mechanical ventilation or ECMO 
up to Day 28 
Number of non-adjacent entries (defined as number of entries with ≥ 2 days of difference between end date of previous entry and start date of next 
entry, when soring all entries by start date) of invasive mechanical ventilation or ECMO in INVASIVE MECHANICAL VENTILATION / ECMO 
form, from randomization to Day 28. Only post-randomization events will be considered. 
Number of ICU admissions use of 
invasive mechanical ventilation or 
ECMO and death up to Day 28 
For patients who died up to Day 28: Sum of number of ICU admissions and number of use of invasive mechanical ventilation or ECMO up to Day 28 
+1 
Otherwise: Sum of number of ICU admissions and number of use of invasive mechanical ventilation or ECMO up to Day 28 
Follow-up time until Day 28 (in 4 
weeks) 
For patients who discontinued the study prior to Day 28: (date of discontinuation – date of randomization +1)/28 
Otherwise: 1 
 
 
 
 
 
 
 
 
 
 
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Parameter 
Calculation 
Total number of tablets taken 
during the treatment period 
The total number of tablets taken will be calculated considering the period from the first date and time of IMP intake at Day 1 and the date and time of 
the next day of the interested visit.  
For example: if a subject takes the first dose (Day 1) at 01JAN2021 08:00 we will consider all doses up to 02JAN2021 07:59 as being part of "Day 1" 
of administration. If for example the subject takes the first dose (Day 1) at 01JAN2021 22:00, to derive the number of tablets taken up to "Day 7 (+/- 
1)" all the tablets up to 08JAN2021 21:59 will be considered. 
Total number of tablets scheduled 
during the treatment period 
Total number of tablets scheduled = 6* Extent of exposure 
where extent of exposure is expressed in days. 
Extent of exposure (days) 
Extent of exposure (days) = Date / time of last IMP intake – Date / time of first IMP intake + 1 day. 
Time from randomization to study 
discontinuation (days) 
Time from randomization to study discontinuation (days) =  
Date of study discontinuation - Date of randomization +1. 
Change from baseline 
For changes from baseline the baseline value will constitute the subtrahend and the later value the minuend.  
Conversion of Time Intervals  
 
If a time interval was calculated in minutes, hours or days and needs to be converted into months or year the following conversion factors will be used:  
• 
1 hour = 60 minutes 
• 
1 day = 24 hours 
• 
1 week = 7 days 
• 
1 month = 30.4375 days  
• 
1 year = 365.25 days  
 
General rule 
For calculation of difference between dates, in case time is available, it is considered in the formula. 
 
 
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11.3 Partial date conventions 
Table 5: Algorithm for Treatment Emergence of Adverse Events 
AE START DATE 
AE STOP DATE 
RULE for TEAE definition 
RULE for “Treatment”/”Follow-up” study period 
definition for TEAE summaries  
Known 
Known, 
Partial 
or 
Missing 
If AE start date < IMP start date, then not TEAE 
If AE start date >= IMP start date, then TEAE 
In case of Treatment Discontinuation (for definition, see 
section 7.3):  
If start date > Date of last IMP intake, then Follow-up study 
period for TEAE occurrence. 
Otherwise, Treatment study period for TEAE occurrence. 
 
In case of NO Treatment Discontinuation:  
If start date ≥ Date of “Day 21” visit, then Follow-up study 
period for TEAE occurrence. 
Otherwise, Treatment study period for TEAE occurrence. 
 
 
 
 
Partial, but known components show 
that it cannot be on or after IMP start 
date 
Known, 
Partial 
or 
Missing 
Not TEAE 
Not applicable 
 
 
 
 
Partial, could be on or after IMP start 
date 
Known 
If AE stop date < IMP start date, then not TEAE 
If AE stop date >= IMP start date, then TEAE 
If TEAE, then Treatment study period for TEAE 
occurrence. 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If AE stop date < IMP start date, then not TEAE 
If AE stop date >= IMP start date, then TEAE 
 
Missing 
Assumed TEAE 
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AE START DATE 
AE STOP DATE 
RULE for TEAE definition 
RULE for “Treatment”/”Follow-up” study period 
definition for TEAE summaries  
 
 
 
 
Missing 
Known 
If AE stop date < IMP start date, then not TEAE 
If AE stop date >= IMP start date, then TEAE 
If TEAE, then Treatment study period for TEAE 
occurrence. 
 
Partial 
Impute AE stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If AE stop date < IMP start date, then not TEAE 
If AE stop date >= IMP start date, then TEAE 
 
Missing 
Assumed TEAE 
NOTE: Assignment to “Treatment” or “Follow-up” study period is applicable only for TEAEs.  
 
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Table 6: Algorithm for Prior/Concomitant medications 
MEDICATION START DATE 
MEDICATION STOP DATE 
RULE for prior or concomitant categorization 
Known 
Known 
If medication stop date < date of informed consent, assign as prior  
If medication stop date >= date of informed consent, assign as concomitant  
 
Partial 
Impute medication stop date as latest possible date (i.e. last day of month if day unknown or 31st December if day 
and month are unknown), then: 
If medication stop date < date of informed consent, assign as prior 
If medication stop date >= date of informed consent, assign as concomitant 
 
Missing 
Assign as concomitant 
 
 
 
Partial or Missing 
Known 
If medication stop date < date of informed consent, assign as prior 
If medication stop date >= date of informed consent, assign as concomitant 
 
Partial 
Impute medication stop date as latest possible date (i.e. last day of month if day unknown or 31st December if day 
and month are unknown), then: 
If medication stop date < date of informed consent, assign as prior 
If medication stop date >= date of informed consent, assign as concomitant 
 
Missing 
Assign as concomitant 
 
 
 
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12.  
Tables, Figures and Listings 
12.1 Output conventions 
• Each Table, Listing and Figure (TLF) should be numbered, following the ICH E3 Guideline. 
• All titles have to be sufficiently explanatory, i.e. the content of the outputs should be clear 
even when consulted independently from the SAP. 
• For numeric variables, units will be presented enclosed in square brackets ([ ])., when 
appropriate. 
• Each table and each figure should provide reference to the listing where the data on which 
the table/figure is based are shown. 
• Listings should include raw data, i.e. data collected in CRF or other data collection tool, as 
well as derived data, i.e. data of variables that have been generated for statistical analysis. 
The derived data must be clearly identified. 
• Every TLF should report the following information on the upper side of the output: 
o Left aligned: 
▪ Protocol number 
o Centered aligned: 
▪ “Confidential” 
o Right aligned: 
▪ Dompé Farmaceutici SpA 
▪ Draft/Final Run <date> 
• Every TLF should report the following information on the bottom side of the output: 
o Left aligned: 
▪ the name of the SAS program which will generate the output 
o Centered aligned: 
▪ Draft/Final Version - Date <date> 
o Right aligned: 
▪ “Page n of N”, where n is the page number and N is the total number of pages 
of the document. 
12.2 Format requirements: 
• All TLFs will be produced in landscape format on A4 paper size, unless otherwise specified.  
• The titles are centered. The analysis sets are identified on the line following the title.  
• it is preferable to use “Courier New” with minimal font size of 8, which is the smallest 
acceptable point size for the Regulatory Authorities. 
• Output files will be delivered in Rich Text Format (RTF) that can be manipulated in Word. 
 
 
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12.3 Table Conventions 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table even in case of frequency equal to 0.  
• If the categories are not ordered (e.g., Medical History), then only those categories for which 
there is at least 1 subject represented in 1 or more groups are included. 
• Unless otherwise specified, the estimated mean and median for a set of values are printed out 
to 1 more significant digit than the original values, and SDs. 
• Missing descriptive statistics or p-values which cannot be estimated are reported as “-”. 
12.4 Listing Conventions 
• Listings will be sorted for presentation in order of treatment groups, subject number, and 
visit. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of 
dates are represented on subject listings as dashes (--JUL2000). 
• In case listings will not fit the page, it will be splitted in two different parts. 
 
 
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13.  
Reference 
1. 
Study protocol, 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, Protocol Version - Date: 
Version 3.0 final – 09 April 2021. 
2. Case Report Form, Version 2.2 final – 21 April 2021. 
3. Kalbfleisch, J. D., and Prentice, R. L. (1980). The Statistical Analysis of Failure Time Data. New York: John Wiley 
& Sons. 
4. Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of composite endpoints in 
clinical trials based on clinical priorities. Eur Heart J. 2012 Jan;33(2):176-82. doi: 10.1093/eurheartj/ehr352. Epub 
2011 Sep 6. PMID: 21900289. 
5. Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical trials. Stat Med. 1999 
Jun 15;18(11):1341-54. doi: 10.1002/(sici)1097-0258(19990615)18:11<1341::aid-sim129>3.0.co;2-7. PMID: 
10399200. 
6. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-
1154, 1988 
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14.  
Appendices 
14.1 TABLES 
Number 
Title 
Population 
DMC 
Interim 
Key 
First 
Efficacy 
Results 
Final 
Table 14.1.1 
Subject enrolment and disposition 
Enrolled Set 
X 
X 
X 
X 
Table 14.1.2 
Analysis Sets 
Randomized Set 
 
 
 
X 
Table 14.1.3.1 
Study discontinuations 
Randomized Set 
X 
X 
X 
X 
Table 14.1.3.2 
Time to discontinuation 
Randomized Set 
 
 
 
X 
Table 14.1.4.1 
Major protocol violations 
Randomized Set 
 
 
 
X 
Table 14.1.4.2 
Minor protocol violations 
Randomized Set 
 
 
 
X 
Table 14.1.5.1 
Demographics and baseline characteristics – part 1 
Full Analysis Set 
X 
X 
X 
X 
Table 14.1.5.2 
Demographics and baseline characteristics – part 2 
Full Analysis Set 
X 
X 
X 
X 
Table 14.1.6.1 
Medical or surgical history 
Full Analysis Set 
X 
 
 
X 
Table 14.1.6.2 
Concomitant Diseases 
Full Analysis Set 
X 
 
 
X 
Table 14.1.7.1 
Prior medications 
Full Analysis Set 
 
 
 
X 
Table 14.1.7.2 
Concomitant medications 
Full Analysis Set 
X 
 
 
X 
Table 14.1.7.3 
Standard care for COVID-19 medications 
Full Analysis Set 
 
 
 
X 
Table 14.1.8 
Other baseline characteristics 
Full Analysis Set 
X 
X 
X 
X 
Table 14.2.1.1 
Compliance to IMP – by visit 
Safety Set 
 
 
 
X 
Table 14.2.1.2 
Compliance to IMP - overall treatment period 
Safety Set 
X 
X 
X 
X 
Table 14.2.2.1 
Proportion of patients alive and free of respiratory failure at Day 28 – Logistic regression 
model with Multiple Imputation under missing not at random  
Full Analysis Set 
 
X 
X 
X 
Table 14.2.2.2.1 
Sensitivity Analysis: Proportion of patients alive and free of respiratory failure at Day 28 – 
Logistic regression model with Multiple Imputation under missing not at random 
Per Protocol Set 
 
 
 
X 
Table 14.2.2.2.2 
Sensitivity Analysis: Proportion of patients alive and free of respiratory failure at Day 28 – 
Logistic regression model with Multiple Imputation under missing not at random 
Full Analysis Set, 
excluding pts in 
the ICU at 
baseline 
 
 
 
X 
Table 14.2.2.3 
Sensitivity Analysis: Proportion of patients alive and free of respiratory failure at Day 28 – 
Logistic regression model considering complete cases only 
Full Analysis Set 
 
 
 
X 
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Number 
Title 
Population 
DMC 
Interim 
Key 
First 
Efficacy 
Results 
Final 
Table 14.2.2.4 
Sensitivity Analysis: Proportion of patients alive and free of respiratory failure at Day 28 – 
Logistic regression model with Multiple Imputation under missing at random 
Full Analysis Set 
 
 
 
X 
Table 14.2.2.5 
Sensitivity Analysis: Proportion of patients alive and free of respiratory failure at Day 28 – 
Tipping point analysis 
Full Analysis Set 
 
 
 
X 
Table 14.2.2.6 
Sensitivity Analysis: Win-ratio analysis 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.1.1 
Proportion of patients alive and free of respiratory failure at Day 60 – Logistic regression 
model 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.1.2 
Mortality rates up to Day 28 – Logistic regression model 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.1.3 
Incidence of ICU admission until Day 28 – logistic regression model 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.1.4.1 
Time to recovery until Day 28 – Cumulative incidence function 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.2 
Proportion of patients alive and free of respiratory failures at fixed time points 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.3 
Mortality rates up to fixed time points 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.4.1 
Proportion of incidence of ICU admission until Day 28 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.4.2 
Proportion of incidence of ICU admission until Day 28 followed by invasive mechanical 
ventilation (or ECMO) or death 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.4.3 
Incidence of ICU admission until Day 28 followed by invasive mechanical ventilation (or 
ECMO) or death – logistic regression model 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.5 
Summary of clinical severity score based on the 7-point WHO-OS as measured at fixed time 
points and change from baseline 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.6.1 
Time to clinical improvement 1 up to Day 28 – Kaplan-Meier methodology 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.7.1 
Time to clinical improvement 2 up to Day 28 – Kaplan-Meier methodology 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.8.1 
Time to discharge from hospital up to Day 28 – Kaplan-Meier methodology 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.9 
Clinical status at fixed time points either in hospital or at home 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.10.1 
Dyspnea severity (Likert scale) at fixed time points 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.10.2 
Summary of Dyspnea severity (VAS scale) at fixed time points and change from baseline 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.11 
Duration of supplemental oxygen treatment (Days) up to Day 28 
Full Analysis Set 
 
 
 
X 
Table 14.2.3.12.1 
Incidence of invasive mechanical ventilation use, or ECMO up to Day 60 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.12.2 
Incidence of invasive mechanical ventilation use, or ECMO up to Day 60 followed by death 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.13 
Duration of invasive mechanical ventilation, or ECMO (days) up to Day 60 
Full Analysis Set 
 
 
 
X 
Table 14.2.3.14 
Duration of non-invasive mechanical ventilation (days) up to Day 60 
Full Analysis Set 
 
 
 
X 
Table 14.2.3.15 
Duration of ICU admission (days) up to Day 60 
Full Analysis Set 
 
 
 
X 
Table 14.2.3.16 
Duration of hospitalization since randomization (days) up to Day 60 
Full Analysis Set 
 
 
 
X 
Table 14.2.3.17.1 
Summary of partial pressure of oxygen (PaO2) and change from baseline 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.17.2 
Summary of partial pressure of oxygen (PaO2) – Investigator’s interpretation 
Full Analysis Set 
 
 
X 
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Number 
Title 
Population 
DMC 
Interim 
Key 
First 
Efficacy 
Results 
Final 
Table 14.2.3.18.1 
Summary of pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2) 
and change from baseline 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.18.2 
Summary of pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2) – 
Investigator’s interpretation 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.19.1 
Summary of PaO2/FiO2 ratio and change from baseline 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.19.2.1 
Proportion of patients with a decrease of PaO2/FiO2 ratio from the baseline value 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.19.2.2 
Proportion of patients with a decrease of PaO2/FiO2 ratio from the baseline value followed by 
ICU admission or IMV or ECMO or death 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.19.3 
Summary of PaO2/FiO2 ratio – Investigator’s interpretation 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.3.20.1 
Summary of Hs-CRP and change from baseline 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.20.2 
Summary of Hs-CRP – Investigator’s interpretation 
Full Analysis Set 
 
 
X 
X 
Table 14.2.3.21 
Mortality rates up to Day 60 and Day 90 – Logistic regression model 
Full Analysis Set 
 
 
 
X 
Table 14.2.3.22.1 
Freedom from (time to) death or respiratory failure – Kaplan Meier methodology 
Full Analysis Set 
 
X 
X 
X 
Table 14.2.4.1 
 
 
Full Analysis Set 
 
 
 
X 
Table 14.2.4.2 
 
Full Analysis Set 
 
 
 
X 
Table 14.2.4.3 
nts 
Full Analysis Set 
X 
 
X 
X 
Table 14.2.4.4 
 
Full Analysis Set 
 
 
 
X 
Table 14.2.4.5 
Summary of concentration of Reparixin in serum measured immediately before and one hour 
(± 15 min) after first dosing at Day 3 
Full Analysis Set 
 
 
 
X 
Table 14.2.4.6.1 
Summary of SARS-CoV-2 viral burden (quantitative rt-PCR) 
Full Analysis Set 
 
 
 
X 
Table 14.2.4.6.2 
Summary of SARS-CoV-2 viral burden – categorical result 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.1 
Subgroups evaluation: Proportion of patients alive and free of respiratory failure at Day 28 – 
Logistic regression model 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.1 
Proportion of patients alive and free of respiratory failure at Day 28 by Age group – Logistic 
regression model 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.2 
Proportion of patients alive and free of respiratory failure at Day 60 by Age group – Logistic 
regression model 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.3 
Mortality rates up to Day 28 by Age group – Logistic regression model 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.4 
Incidence of ICU admission until Day 28 by Age group – Logistic regression model 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.5 
Time to recovery up to Day 28 by Age group – Cumulative incidence function 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.6 
Proportion of patients alive and free of respiratory failure at fixed timepoints by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.7 
Mortality rates up to fixed timepoints 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.8 
Proportion of incidence of ICU admission until Day 28 by Age group 
Full Analysis Set 
 
 
 
X 
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Number 
Title 
Population 
DMC 
Interim 
Key 
First 
Efficacy 
Results 
Final 
Table 14.2.5.2.9 
Summary of clinical severity score based on the 7-point WHO-OS as measured fixed time 
points and change from baseline by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.10 
Time to clinical improvement 1 up to Day 28 by Age group – Cumulative incidence function 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.11 
Time to clinical improvement 2 up to Day 28 by Age group – Cumulative incidence function 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.12 
Time to discharge from hospital up to Day 28 by Age group – Cumulative incidence function 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.13 
Clinical status at fixed time points either in hospital or at home by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.14 
Dyspnea severity (Likert scale) at fixed time points by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.15 
Summary of Dyspnea severity (VAS scale) at fixed time points and change from baseline by 
Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.16 
Duration of supplemental oxygen treatment (Days) up to Day 28 by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.17 
Incidence of invasive mechanical ventilation use, or ECMO up to Day 60 by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.18 
Duration of invasive mechanical ventilation, or ECMO (days) up to Day 60 by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.19 
Duration of non-invasive mechanical ventilation (days) up to Day 60 by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.20 
Duration of ICU admission (days) up to Day 60 by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.21 
Duration of hospitalization since randomization (days) up to Day 60 by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.22 
Summary of partial pressure of oxygen (PaO2) and change from baseline by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.23 
Summary of pulse oximetry by measurement of peripheral arterial oxygen saturation (SpO2) 
and change from baseline by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.24 
Summary of PaO2/FiO2 ratio and change from baseline by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.25 
Proportion of patients with a decrease of PaO2/FiO2 ratio from the baseline value by Age 
group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.26 
Summary of Hs-CRP and change from baseline by Age group 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.27 
Mortality rates up to Day 60 and Day 90 by Age group – Logistic regression model 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.2.28 
Freedom from (time to) death or respiratory failure by Age group – Kaplan Meier 
methodology 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.X.1-28 
(X can vary from 3 
to 4, based on how 
many subgroups 
will be used) 
Repeat set of tables from 14.2.5.2.1 to 14.2.5.2.28 for all subgroups defined in the SAP 
(section 6.4), in case the interaction is statistically significant in the logistic regression model 
specified before (i.e. 14.2.5.1) 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.29 
Number of ICU admissions until Day 28 – Poisson regression model 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.30 
Number of invasive mechanical ventilation or ECMO until Day 28 – Poisson regression model 
Full Analysis Set 
 
 
 
X 
Table 14.2.5.31 
Number of IC admission, invasive mechanical ventilation or ECMO or Death until Day 28 – 
Poisson regression model 
Full Analysis Set 
 
 
 
X 
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Number 
Title 
Population 
DMC 
Interim 
Key 
First 
Efficacy 
Results 
Final 
Table 14.3.1 
Exposure to IMP 
Safety Set 
 
 
 
X 
Table 14.3.2.1 
Overview of Treatment Emergent Adverse Events 
Safety Set 
X 
X 
X 
X 
Table 14.3.2.2 
Summary of Treatment Emergent Adverse Events by primary System Organ Class and 
Preferred Term and by study period 
Safety Set 
X 
X 
X 
X 
Table 14.3.2.3 
Summary of Treatment Emergent Adverse Events by primary System Organ Class, Preferred 
Term and Severity 
Safety Set 
 
 
 
X 
Table 14.3.2.4 
Summary of Serious Treatment Emergent Adverse Events by primary System Organ Class and 
Preferred Term and by study period 
Safety Set 
X 
 
X 
X 
Table 14.3.2.5 
Summary of ADRs by primary System Organ Class and Preferred Term and by study period 
Safety Set 
X 
 
X 
X 
Table 14.3.2.6 
Summary of ADRs by Primary System Organ Class and Preferred Term and Severity 
Safety Set 
 
 
 
X 
Table 14.3.2.7 
Summary of TEAEs leading to IMP Discontinuation by Primary System Organ Class and 
Preferred Term and by study period 
Safety Set 
X 
 
X 
X 
Table 14.3.2.8 
Summary of TEAEs leading to study Discontinuation by Primary System Organ Class and 
Preferred Term and by study period 
Safety Set 
X 
 
 
X 
Table 14.3.2.9 
Summary of TEAEs leading to Death by Primary System Organ Class and Preferred Term 
Safety Set 
 
 
 
X 
Listing 14.3.3 
Deaths 
Safety Set 
X 
X 
X 
X 
Table 14.3.5.1.1.1 
 
Safety Set 
X 
 
X 
X 
Table 14.3.5.1.2 
 
Safety Set 
 
 
 
X 
Table 14.3.5.1.3 
 
 
Safety Set 
 
 
 
X 
Table 14.3.5.2.1.1 
 
Safety Set 
X 
 
X 
X 
Table 14.3.5.2.2 
 
Safety Set 
 
 
 
X 
Table 14.3.5.2.3 
 
 
Safety Set 
 
 
 
X 
Table 14.3.6.1.1 
 
Safety Set 
X 
 
X 
X 
Table 14.3.6.2.1.1 
 
Safety Set 
X 
 
X 
X 
Table 14.3.6.2.2 
 
Safety Set 
 
 
 
X 
Table 14.3.6.2.3 
 
Safety Set 
 
 
 
X 
Table 14.3.6.3.1 
Summary of Child Pugh Score and change from baseline 
Safety Set 
 
 
 
X 
Table 14.3.6.3.2 
Child Pugh Score: proportion of patients for all categorical parameters 
Safety Set 
 
 
 
X 
 
 
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14.2 LISTINGS 
Number 
Title 
Population 
DMC 
Interim 
Key First 
Efficacy 
Results 
Final 
Listing 16.1.7 
Randomization schedule 
Randomized Set 
 
 
 
X 
Listing 16.2.1.1 
Disposition of subjects 
Enrolled Set 
X 
 
 
X 
Listing 16.2.1.2.1 
Subjects enrolled but not randomized 
Enrolled Set 
 
 
 
X 
Listing 16.2.1.2.2 
Study termination 
Randomized Set 
 
 
 
X 
Listing 16.2.1.2.3 
Treatment termination 
Randomized Set 
 
 
 
X 
Listing 16.2.2.1 
Inclusion criteria 
Randomized Set 
 
 
 
X 
Listing 16.2.2.2 
Exclusion criteria 
Randomized Set 
 
 
 
X 
Listing 16.2.2.3.1 
Major protocol deviations 
Randomized Set 
X* 
 
 
X 
Listing 16.2.2.3.2 
Minor protocol deviations 
Randomized Set 
 
 
 
X 
Listing 16.2.3.1 
Analysis Sets 
Enrolled Set 
 
 
 
X 
Listing 16.2.3.2 
Subjects excluded from Full Analysis Set 
Enrolled Set 
 
 
 
X 
Listing 16.2.4.1.1 
Demographic and baseline characteristics – part 1 
Randomized Set 
 
 
 
X 
Listing 16.2.4.1.2 
Demographic and baseline characteristics – part 2 
Randomized Set 
 
 
 
X 
Listing 16.2.4.2 
Medical or Surgical History 
Randomized Set 
 
 
 
X 
Listing 16.2.4.3 
Concomitant Diseases 
Randomized Set 
X 
 
 
X 
Listing 16.2.4.4 
Prior Medications 
Randomized Set 
 
 
 
X 
Listing 16.2.4.5 
Concomitant Medications 
Randomized Set 
X 
 
 
X 
Listing 16.2.4.6 
Other baseline characteristics 
Randomized Set 
 
 
 
X 
Listing 16.2.5.1 
Compliance to study medication 
Randomized Set 
 
 
 
X 
Listing 16.2.6.1.1 
Primary endpoint and mortality rates 
Randomized Set 
 
 
 
X 
Listing 16.2.6.1.2 
ICU admission 
Randomized Set 
 
 
 
X 
Listing 16.2.6.1.3 
Clinical severity score based on the 7-point WHO-OS 
Randomized Set 
 
 
 
X 
Listing 16.2.6.1.4 
Dyspnea severity (Likert scale and VAS scale) 
Randomized Set 
 
 
 
X 
Listing 16.2.6.1.5 
Daily Supplemental Oxygen 
Randomized Set 
 
 
 
X 
Listing 16.2.6.1.6 
Invasive mechanical ventilation / ECMO 
Randomized Set 
 
 
 
X 
Listing 16.2.6.1.7 
Non-Invasive mechanical ventilation 
Randomized Set 
 
 
 
X 
Listing 16.2.6.1.8 
Lung function 
Randomized Set 
 
 
 
X 
Listing 16.2.6.1.9 
 
Randomized Set 
 
 
 
X 
Listing 16.2.6.2 
Exposure to study medication 
Randomized Set 
 
 
 
X 
Listing 16.2.7.1 
Pre-treatment Adverse Events 
Randomized Set 
 
 
 
X 
Listing 16.2.7.2 
Treatment emergent adverse events 
Randomized Set 
X 
 
 
X 
Listing 16.2.7.3 
Serious treatment emergent adverse events 
Randomized Set 
 
 
 
X 
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Number 
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Interim 
Key First 
Efficacy 
Results 
Final 
Listing 16.2.7.4 
Treatment emergent adverse drug reactions 
Randomized Set 
 
 
 
X 
Listing 16.2.7.5 
Serious treatment emergent adverse drug reactions 
Randomized Set 
 
 
 
X 
Listing 16.2.7.6 
Severe treatment emergent adverse events 
Randomized Set 
 
 
 
X 
Listing 16.2.7.7 
Treatment emergent adverse events leading to IMP discontinuation 
Randomized Set 
 
 
 
X 
Listing 16.2.7.8 
Treatment emergent adverse events leading to study discontinuation 
Randomized Set 
 
 
 
X 
Listing 16.2.7.9 
Treatment emergent adverse events leading to death 
Randomized Set 
 
 
 
X 
Listing 16.2.8.1 
 
Randomized Set 
X 
 
 
X 
Listing 16.2.8.2 
 
Randomized Set 
X 
 
 
X 
Listing 16.2.8.3 
 
Randomized Set 
 
 
 
X 
Listing 16.2.8.4 
 
Randomized Set 
 
 
 
X 
Listing 16.2.8.5 
Child Pugh Score 
Randomized Set 
 
 
 
X 
*All deviations will be reported for DMC meetings 
 
 
 
 
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14.3 FIGURES 
Number 
Title 
Population 
DMC 
Interim 
Key First 
Efficacy 
Results 
Final 
Figure 14.1.3.3 
Time from randomization to discontinuation (Kaplan-Meier) 
Randomized Set 
 
 
 
X 
Figure 14.2.2.5.2 
Tipping point analysis 
Full Analysis Set 
 
 
 
X 
Figure 14.2.3.1.4.2 
Time to recovery (Cumulative Incidence Function) 
Full Analysis Set 
 
X 
X 
X 
Figure 14.2.3.6.2 
Time to clinical improvement 1 (Cumulative Incidence Function) 
Full Analysis Set 
 
 
 
X 
Figure 14.2.3.7.2 
Time to clinical improvement 2 (Cumulative Incidence Function) 
Full Analysis Set 
 
 
 
X 
Figure 14.2.3.8.2 
Time to discharge from hospital (Cumulative Incidence Function) 
Full Analysis Set 
 
 
 
X 
Figure 14.2.3.22.2 
Time to death or respiratory failure up to Day 90 (Kaplan Meier) 
Full Analysis Set 
 
 
 
X 
Figure 14.3.5.1.1.2 
 
Full Analysis Set 
X 
 
 
X 
Figure 14.3.5.1.1.3 
 
Full Analysis Set 
X 
 
 
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Figure 14.3.5.1.1.4 
 
Full Analysis Set 
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Figure 14.3.5.1.1.5 
 
Full Analysis Set 
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Figure 14.3.5.2.1.2 
 
Full Analysis Set 
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Figure 14.3.5.2.1.3 
 
Full Analysis Set 
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Figure 14.3.5.2.1.4 
 
Full Analysis Set 
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Figure 14.3.5.2.1.5 
 
Full Analysis Set 
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Figure 14.3.6.1.2 
 
Full Analysis Set 
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Figure 14.3.6.1.3 
 
Full Analysis Set 
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Figure 14.3.6.1.4 
 
Full Analysis Set 
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Figure 14.3.6.1.5 
 
Full Analysis Set 
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Figure 14.3.6.2.1.2 
 
Full Analysis Set 
X 
 
 
X 
14.4 SAS Code for the primary analysis 
First Step: Multiple imputation MNAR, using data from subjects that discontinued treatment (EOTSTT=”NOT COMPLETED”) but have the 
primary endpoint measurement (i.e. whether the patient was alive and free of respiratory failure at Day 28 or not (AVALC = “Y” or “N”)), to 
impute missing information on the primary endpoint  with the following covariates: planned treatment group (TRT01P), sex (SEX),  presence of 
concomitant disease (CONDISBL), and age class (AGEGR1). 
 
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Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
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Protocol Number: REP0220 
Version: 3.0 
   
 
   
 
   
 
   
 
 
Second Step: Fit the primary analysis logistic regression model with the same fixed effects as above and site (SITEID) as random effect in each 
of the imputed datasets. 
 
 
 
 
 
 
  
  
 
 
Third Step: Combine the results across the imputed datasets using Rubin’s rule. 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
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Protocol Number: REP0220 
 
Version: 3.0 
 
  
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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Prot_000.pdf: 
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 
EudraCT number 2020-005919-51 
 
 
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 
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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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REP0220_Final Version No. 3.0_09/APR/2021 
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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). 
CCI




 
 
 
 
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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) 
 
CCI
CCI
CCI
CCI
CCI
CCI


 
 
 
 
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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 
attached. 




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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.  










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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.  
 
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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 
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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 
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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