Conditions: Severe Pneumonia
Keywords: COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 56
Healthy volunteers: no

Brief summary:
* Phase 2 Study Objectives: efficacy and safety of of Reparixin treatment as compared to the control arm in adult patients with severe COVID-19 pneumonia
* Phase 3 Study Objectives: efficacy and safety of Reparixin treatment as compared to the control arm in adult patients with moderate or severe COVID-19 pneumonia

Detailed description:
This clinical trial is an adaptive phase 2/3, randomized, controlled multicenter study on the efficacy and safety of Reparixin in the treatment of hospitalized patients with COVID-19 pneumonia. 48 patients are planned to be enrolled in Phase 2 and an estimated total of 111 patients are planned to be enrolled up to the end of Phase 3, with a randomization 2:1 Reparixin vs Control (Standard of care).

In the phase 2 segment of this study, patients are randomized 2:1 to Reparixin oral tablets 1200 mg (Group 1, active treatment) or standard of care (Group 2, control arm). In case of worsening (e.g. need of ICU and/or mechanical ventilation) after the first 24hrs, patients are offered a rescue medication with no restriction from the sponsor and fully based on their physicians' judgement.

In the phase 3 segment of this study, it is planned that patients are randomized 2:1 to Reparixin or standard of care. The Phase 3 design will be reassessed and decided based on the results of the Phase 2.

Arms:
arm 1: Reparixin oral tablets 1200 mg TID for 7 days arm 2: Standard of care

Interventions: intervention 1: Reparixin intervention 2: Standard of care
Intervention descriptions: intervention 1: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first. intervention 2: Standard of care

Protocol document:
Prot_000.pdf: 
REPAVID-19 
 
 
 
 
 
 
Version n. 1.5 April 23, 2020 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
EudraCT Number: 2020-001645-40 
IND Number: _____________________ 
 
Protocol Title: Adaptive phase 2/3, randomized, controlled multicenter study on the efficacy and 
safety of Reparixin in the treatment of hospitalized patients with COVID-19 pneumonia 
Short Tile: Reparixin in COVID-19 pneumonia 
Acronym: REPAVID-19 
 
Protcol Number: 1.5  
Amendment Number: 4 
 
Investigational compound: Reparixin  
 
Study period   
Projected starting date (first-patient-in):  
 
April 2020 
Projected study end date (last-patient-last-visit):  
June 2020 
 
Promoter Name and Legal Registered Address: Ospedale San Raffaele. Via Olgettina 60, 20132, 
Milan. Italy. 
 
SPONSOR: Dompé farmaceutici Spa. Via Santa Lucia 6, 20122, Milan, Italy. 
 
COORDINATING INVESTIGATORS: Prof. Lorenzo Piemonti, Prof. Alberto Zangrillo. Ospedale 
San Raffaele. Milan, Italy. 
 
INVESTIGATIONAL SITES:  
- 
Ospedale San Raffaele. Milan, Italy. Principal Investigator Prof. Giovanni Landoni, Sub-
Investigator Prof. Stefano Franchini 
- 
Ospedale San Paolo. Milan, Italy. Principal Investigator Prof. Antonella D’Arminio 
Monforte, Sub-Investigator Dr.ssa Camilla Tincati 
- 
Ospedale di Varese. Varese, Italy. Principal Investigator Prof. Paolo Antonio Grossi, Sub-
Investigator Prof. Luca Cabrini 
 
Scientific committee:  
- 
Prof. Giovanni Landoni. Ospedale San Raffaele  
- 
Prof. Lorenzo Piemonti. Ospedale San Raffaele 
- 
Marcello Allegretti, PhD. Chief Scientific Officer, Dompé Farmaceutici Spa 
- 
Flavio Mantelli, MD, PhD. Chief Medical Officer, Dompé Farmaceutici Spa 
 
 
 


STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or confidential information that is 
the property of Dompé farmaceutici s.p.a. It is understood that the information will not be used, divulged, or 
published without prior written consent of Dompé farmaceutici s.p.a., except to the extent such disclosure is 
required by applicable laws and regulations. 


CONTACT INFORMATION 
 
SPONSOR 
Dompé farmaceutici S.p.A., Via S. Martino 12, 20122 Milan, Italy 
Phone: +39.02.583831 
Fax: +39.02.58383324 
 
 
 
Research & Development  
Director  
Marcello Allegretti – Chief Scientific Officer 
 
Email to: marcello.allegretti@dompe.com 
 
or Fax: +39.02.58383324 
 
 
Medical Expert 
Flavio Mantelli – Chief Medical Officer 
Email to: flavio.mantelli@dompe.com 
or Fax: +39.02.58383324 
 
 
Clinical Development  
Manager  
Pier Adelchi Ruffini – Global Head Clinical Development 
 
Email to: pieradelchi.ruffini@dompe.com 
 
or Fax: +39.02.58383324 
 
Clinical Operations  
Manager  
Maria De Pizzol – Global Head Clinical Operations 
 
Email to: maria.depizzol@dompe.com 
 
or Fax: +39.02.58383324 
 
 
 
SAE Reporting  
Laura Boga, Senior Safety Manager  
Email to: farmacovigilanza@dompe.com 
or Fax: +39.02.36026913 
 
 
 
 
 
 
 
CLINICAL RESEARCH 
ORGANIZATION 
                 n/a 
 
 


 
TABLE OF CONTENTS 
 
1. 
PROTOCOL SUMMARY 
2. 
INTRODUCTION  
2.1 Background 
2.2 Drug mechanism of action and study rationale 
3. 
OBJECTIVES AND ENDPOINTS 
4. 
STUDY DESIGN AND METHODOLOGY 
4.1 Phase 2 Study design 
4.2 Phase 3 Study design 
5. 
POPULATION 
5.1 Number of patients 
5.2 Inclusion/exclusion criteria 
6. 
INTERVENTIONS 
6.1 Interventional treatments 
6.2 Control treatment 
6.3 Preparation, Handling, Storage and Accountability of the study drug 
6.4 Compliance to treatment 
7. 
ASSESSMENTS AND PROCEDURES 
7.1 Procedures 
7.2 Efficacy assessments 
7.3 Evaluation of adverse events and safety information 
7.4 Study procedures and randomization 
 
8. 
END OF STUDY, DISCONTINUATION AND WITHDRAWAL 
8.1 End of Study 
8.2 Discontinuation and Withdrawal 
9. 
STATISTICAL CONSIDERATIONS 
9.1 Sample size 
9.2 Overview of planned statistical analyses 
9.3 Analysis population 
9.4 Statistical methodology 


10. 
SUPPORTING DOCUMENTATION  
10.1 Clinical and non-clinical pharmacology 
10.2 Study documentation and record keeping 
10.3 Ethical considerations, quality assurance and monitoring 
10.4 Informed consent 
10.5 Data collection 
10.6 Confidentiality and data protection 
10.7 Unique subject identifier 
10.8 Database management 
10.9 Coding dictionaries 
10.10 
Publication policy 
10.11 
Administrative aspects 
11. 
TABLES AND FIGURES 
11.1 Study outline 
11.2 Schedule of evaluations 
12. 
REFERENCES 
 
APPENDICES 
 
 
 
 


1. PROTOCOL SUMMARY 
 
Protocol Title: Adaptive phase 2/3, randomized, controlled, multicenter study on the efficacy and 
safety of Reparixin in the treatment of hospitalized patients with COVID-19 pneumonia  
 
Short Title: Reparixin in COVID-19 pneumonia. 
 
Investigational medicinal products: Reparixin oral tablets. 
Rescue medication: At discretion of investigators in phase 2; Reparixin oral tablets or intravenous 
(IV) infusion in Phase 3. 
 
Background and Rationale: see section 2.1 and 2.2 
 
Phase of development: 2 and 3 
 
Patient population: 48 patients will be enrolled in Phase 2 and an estimated total of 111 patients will 
be enrolled up to the end of Phase 3, with a randomization 2:1 Reparixin vs Control (Standard of care) 
 
Study Objectives and Endpoints 
- Phase 2 Study Objectives: efficacy and safety of Reparixin as compared to the control arm in adult 
patients with severe COVID-19 pneumonia 
- Phase 3 Study Objectives: efficacy and safety of Reparixin treatment as compared to the control arm 
in adult patients with severe COVID-19 pneumonia 
- Phase 2 Primary Endpoint: Composite endpoint of clinical events (the patient requires at least one 
of the following: supplemental oxygen requirement, mechanical ventilation use, admission to Intensive 
Care Unit (ICU), and use of a rescue medication for any reason) 
- Phase 3 Primary Endpoint: Composite endpoint of death and of severe clinical events (the patient 
dies or requires mechanical ventilation use and/or admission to ICU) 
 
- Other Phase 2/3 Study Endpoints: 
- 
Secondary Endpoints: 
o Changes in clinical severity score (as recommended by the World Health 
Organization –WHO– for COVID studies)  
o Dyspnea severity (Liker scale and VAS scale) 
o Changes in body temperature 
o Changes in hematology test values 
o Duration and quantity of supplemental oxygen treatment 
o Incidence and duration of mechanical ventilation use 
o Incidence of intensive care unit (ICU) admission need 
o Lung damage extension changes from baseline (assessed by Chest CT or Rx) 
o Change from baseline in lung exudation degree (assessed by Chest CT or Rx) 
o PaO2 
o SpO2 
o Partial arterioral oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) ratio 
o CRP 
o Hs-CRP 
- 
Exploratory Endpoints (not mandatory): 
o Cytokine profile 


o Concentration of Reparixin in serum over time 
o SARS-CoV-2 virologic counts 
- 
Safety Endpoints: 
o Adverse events 
o Serious adverse events 
 
 
Procedures and Assessments: Efficacy and Safety procedures and assessments for this study will 
include all the listed enpoints as well as the recording of concomitant medications’ use. 
 
Overall Study Design:  this clinical trial is designed as an adaptive, randomized, controlled, 
multicentre study to evaluate efficacy and safety of Reparixin in hospitalized adult patients with severe 
COVID-19 pneumonia. In the phase 2 segment of this study, patients will be randomized 2:1 to 
Reparixin oral tablets 1200 mg (Group 1, active treatment) or standard of care (Group 2, control arm). 
In case of worsening (e.g. need of ICU and/or mechanical ventilation) after the first 24hrs, patients will 
be offered a rescue medication based on their physicians’ judgement, without any constrain from the 
sponsor. The administration of rescue medications is allowed, without constituting a protocol deviation. 
In the phase 3 segment of this study, it is planned that patients will be randomized 2:1 to Reparixin or 
standard of care. In case of worsening after the first 24hrs, patients under the control arm will be 
offered a rescue medication with the active treatment (Reparixin 1200 mg oral tablets TID) or 
Reparixin 2.772 mg/kg body weight/hour IV infusion, if the oral route is unfeasible for the clinical 
condition. The Phase 3 design will be reassessed and decided based on the results of the Phase 2. 
 
Population: Hospitalized adult (≥18 <90 years old) patients with severe COVID-19 pneumonia. No 
gender and/or ethnicity restrictions will apply. 
 
Inclusion/exclusion criteria  
- Phase 2 Inclusion Criteria: 
1. Age 18 to 90. 
2. Confirmed COVID-19 diagnosis 
3. At least one of the following: ① Respiratory distress, RR ≥ 30 breaths/min without oxygen; ② 
Partial arterial oxygen pressure (PaO2) / Fraction of inspiration O2 (FiO2) >100 <300mmHg 
(1mmHg = 0.133kPa). 
4. Chest imaging confirms lung involvement and inflammation. 
5. Inflammatory status as documented by at least one of the following: Lactate dehydrogenase 
(LDH) > normal range, C-reactive protein (CRP) ≥ 100mg/L or IL-6 ≥ 40pg/mL, serum ferritin 
≥ 900ng/mL, XDP >20mcg/mL. 
 
- Phase 3 Inclusion Criteria: Same as above; other criteria TBD based on Phase 2 outcomes. 
 
- Phase 2/3 Exclusion Criteria: 
1. Cannot obtain informed consent. 
2. Severe hepatic dysfunction (Child Pugh score ≥ C, or AST> 5 times the upper limit); Severe 
renal dysfunction (estimated glomerular filtration rate ≤ 30mL / min / 1.73 m2) or receive 
continuous renal replacement therapy, hemodialysis, or peritoneal dialysis. 
3. 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 alone, e.g. sulfamethoxazole, does not qualify for exclusion)  
4. Severe, active bleeding such as hemoptysis, gastrointestinal bleeding, central nervous system 
bleeding, and nosebleeds within 1 month before enrollment. 
5. Pregnant and lactating women and those planning to get pregnant. 
6. Participated in other interventional clinical trials with investigational medicinal products, not 
considered suitable for this study by the researchers. 
7. At the time of enrollment, patients not in a clinical condition compatible with the oral 
administration of the study drug. 
Number of patients enrolled: It is planned that 48 patients will be enrolled in Phase 2 and a total of 
111 patients will be enrolled up to completion of the Phase 3. However, the sample size for the Phase 3 
segment of this study may be re-estimated based on the Phase 2 results. In the current sample size 
scenario, 32 patients will receive Reparixin in Phase 2. 
 
Study duration: treatment duration will be up to a maximum of 21 days. Overall Phase 2 study 
duration will be maximum 1 month (including 21 days of treatment and up to 7±3 days of follow-up). 
 
End of study (EOS) definition: EOS is defined as the last day the last patient completes the last study 
assessment in the hospital, or retracts the consent to participate in the study, or withdraws from the 
study, or is deceased or otherwise lost to follow-up.  
 
Interventions: Patients who satisfy the predefined inclusion and exclusion criteria for this trial will be 
randomized 2:1 to one of the following treatment groups: 
 
• GROUP 1: Reparixin oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be 
prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live 
discharge from the hospital, whichever comes first. 
• GROUP 2 (CONTROL): Standard of care.  
 
RESCUE MEDICATION: In case of worsening (e.g. need of ICU and/or mechanical ventilation), 
patients will be offered after the first 24hrs, patients will be offered a rescue medication based on their 
physicians’ judgement, without any constrain from the sponsor. In the phase 3 segment of this study, it 
is planned that patients will be randomized 2:1 to Reparixin or standard of care. In case of worsening 
after the first 24hrs, patients under the control arm will be offered a rescue medication with the active 
treatment (Reparixin 1200 mg oral tablets TID) or Reparixin 2.772 mg/kg body weight/hour IV 
infusion, if the oral route is unfeasible for the clinical condition. The Phase 3 design will be reassessed 
and decided based on the results of the Phase 2. 
 
Statistical plan: The sample size for this trial will be adaptively determined through a phase 2/3 
design. Enrollement is planned to last approximately 2 months. Each patient will be randomly allocated 
to Raparixin or Control according to a randomization ratio of 2:1 and he/she will be followed for the 
subsequent 21 days for collectioning the efficacy endpoints of each study phase. 
For the Phase 2 portion of the study, the primary analysis will compare Reparixin versus Control in 
terms of time to a composite endpoint including the following events: supplemental oxygen 
requirement, mechanical ventilation use, admission to ICU, and any use of rescue medication. 
Expecting an 1.5 fold improvement of the median time freedom from composite event and assuming an 


exponential distribution, a total sample size of 48 patients will allow to provide 80% power to show 
superiority of Reparixin compared to control using a log-rank test at a one-sided significance level of 
0.025. 
 
The sample size for the phase 3 is based on assessment of superiority of Reparixin compared to control 
arm in terms of freedom from a composite endpoint of severe events including: death, admission to the 
ICU, and mechanical ventilation. 
Based on same assumptions of phase 2 and expecting a double median time freedom from severe 
composite endpoint for Reparixin compared to control (2-4 days), a total sample size of 111 patients 
will allow to achieve a power of 90% to show superiority of Reparixin over control using a log-rank 
test at a one-sided significance level of 0.025. No drop-out are expected to happen. The number of 
patients to be included may be revised based on considerations from Phase 2 data analysis. 
Primary endpoint of phase 3 will be tested only if superiority of reparixin is shown in phase 2. Thus, 
the overall type I error of the study will be controlled at 0.025 via the hierarchical testing procedure. 
 
Additional Statistical considerations: This trial’s design will allow for adaptations based but not 
limited to the following: 
- 
Interruption of an experimental treatment route of administration in favour of the other due 
to safety reasons; 
- 
Confirmation or modification of the primary, secondary and exploratory endpoints; 
- 
Confirmation or modification of the sample size for the Phase 3 segment; 
- 
Early closure of the study for efficacy, futility or safety reasons. 
 
Due to the open-label nature of this trial, an Indipendent Data Monitoring Committee (DMC) is 
foreseen to provide timely recommendations about the above mentioned early closures or 
modifications. This monitoring committee will include 2 to 4 indipendent physicians, supported by a 
statistician. 
 
 


 
2. INTRODUCTION 
 
2.1 BACKGROUND:  
IN DECEMBER 2019, A NEW IDENTIFIED CORONAVIRUS (SARS-COV-2) OUTBREAK IN WUHAN, CAUSES PUBLIC 
HEALTH CRISIS IN CHINA AND SPREADS WORLDWIDE. On February 11, 2020, the World Health 
Organization officially named the disease caused by the new coronavirus "COVID-19". The Chinese 
Government takes stronger and harsher measures to control the progression of its outbreak. Meanwhile, 
five editions of "Diagnosis and Treatment for Novel Coronavirus-Infected Pneumonia" has been timely 
and continuously issued, which play extremely important roles in guiding the clinical management of 
COVID-19 nationwide in China.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 severe and critical type, among which acute lung injury (ALI) and acute respiratory 
distress syndrome (ARDS) are the most common complications, resulting in a large number of 
pneumonia hospitalized patients requiring supplemental oxygen, mechanical ventilation, or even 
ECMO.Pulmonary edema is a detrimental feature as well as a key causal factor of ALI/ARDS. 
 
LUNG EDEMA, ENDOTHELIAL AND EPITHELIAL INJURY ARE ACCOMPANIED BY AN INFLUX OF NEUTROPHILS 
INTO THE INTERSTITIUM AND BRONCHEOALVEOLAR SPACE. Neutrophils are considered to play a key role 
in the progression of ALI and ARDS (1), as activation and transmigration of neutrophils is a hallmark 
event in the progression of ALI and ARDS. 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 (ROS).  
 
2.2 DRUG MECHANISM OF ACTION AND STUDY RATIONALE: 
 
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 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).  
 
REPARIXIN IS A POTENTIAL DRUG FOR THE TREATMENT OF SEVERE OR CRITICAL PATIENTS WITH COVID-
19 PNEUMONIA. 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. 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.  
 
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 RPX (15 mg/kg) suppressed neutrophil recruitment into the lungs. In the CDE Multiple 
Challenge Model, RPX 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 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, belong 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.  
[Moriconi et.al ACS Med Chem Lett. 2011 Aug 7;2(10):768-73.; Moriconi et al. J Med Chem. 2007 Aug 
23;50(17):3984-4002.; Allegretti M et al J Med Chem. 2005 Jun 30;48(13):4312-31.; Bertini R et al; 
Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11791-6.]. 
The different pharmacokinetic profile of the two molecules account for a bid (15mg/Kg) oral 
administration of DF2162 as compared 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 the 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. 
 
 
REPARIXIN IMPROVED SURVIVAL AFTER LUNG TRANSPLANTATION. In a US-Canada phase 2 study 
[REP0104], 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 OSR 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). 
 
IRCCS OSPEDALE SAN RAFFAELE IS A REFERENCE CENTER IN THE MANAGEMENT OF THE COVID-19 
PANDEMIC EMERGENCY, AND HAS RECENTLY TREATED WITH REPARIXIN (UNDER A COMPASSIONATE USE 
APPLICATION) FOUR PATIENTS WITH SEVERE COVID-19 PNEUMONIA. THE SPONSOR PROVIDES HERE THE 
OUTCOMES OF SUCH TREATMENTS AS PROVIDED BY THE SAN RAFFAELE HOSPITAL PHYSICIANS: Four 
patients with ARDS caused by COVID-19 pneumonia with the clinical indication for intubation and 
mechanical ventilation were treated with Reparixin IV infusion (2.772 mg/kg body weight/hour) into a 
high-flow central vein for 5 days at the San Raffaele Hospital of Milan, Italy. The first patient started 
treatment on 24 March 2020 and the last patient on 31 March 2020. As of the date of preparation of the 
this Protocol (Version 1.3 dated 9 April 2020), all patients are still alive. Specifically, two of the four 
patients were never intubated, and two of them are currently intubated: from the report of their ICU 
physician one is currently in stable conditions, and one is improving. Therefore, looking at this 
preliminary results on a limited number of patients who had an indication for intubation and mechanical 
ventilation in ICU care (both events being in the proposed primary endpoint of this study) before starting 
treatment, the improvement observed on the expected clinical outcome in 2 out of 4 patients is aligned 
with the assumptions we used for sample size calculations of this trial.  
From a hematochemical standpoint, during treatment with Reparixin an improvement or at least 
stabilization of the inflammatory markers (C-reactive protein, procalcitonin, ferritin) and of the tissue 
damage markers (LDH, AST, ALT) was also observed during this compassionate use experience. A list 


of the patients’ characteristics is provided below in tabular format as provided by the San Raffaele 
Hospital physicians 
 
As of today no other compassionate use cases for the use of Reparixin in patients with Covid-19 
pneumonia have been activated at the San Raffaele Hospital or in other sites. 
 


3 OBJECTIVES AND ENDPOINTS 
 
- Phase 2 Study Objectives: efficacy and safety of of Reparixin treatment as compared to the control 
arm in adult patients with severe COVID-19 pneumonia 
 
- Phase 3 Study Objectives: efficacy and safety of Reparixin treatment as compared to the control arm 
in adult patients with moderate or severe COVID-19 pneumonia 
 
- Phase 2/3 Study Endpoints: 
- 
Primary Endpoint for Phase 2: Composite endpoint of clinical events (the patient requires 
at least one of the following: supplemental oxygen requirement, mechanical ventilation use, 
admission to ICU, and use of a rescue medication for any reason)  
- 
Primary Endpoint for Phase 3: Composite endpoint of death and clinical severe events 
(the patient dies or requires mechanical ventilation use and/or admission to ICU) 
- 
Secondary Endpoints: 
o Changes in clinical severity score (as recommended by WHO for COVID studies), 
defined as the time to clinical improvement of two points from the time of 
randomization on a seven-category ordinal scale or live discharge from the hospital, 
whichever comes first. The seven-category ordinal scale consists of the following: 1) 
not hospitalized, with resumption of normal activities; 2) not hospitalized, but unable 
to resume normal activities; 3) hospitalized, not requiring supplemental oxygen; 4) 
hospitalized, requiring supplemental oxygen; 5) hospitalized, requiring high-flow 
oxygen therapy, noninvasive mechanical ventilation, or both; 6) hospitalized, 
requiring ECMO, invasive mechanical ventilation, or both; and 7) death. 
o Dyspnea severity (Liker scale and VAS scale) 
o Changes in body temperature 
o Changes hematology test values 
o Duration and quantity of supplemental oxygen treatment 
o Incidence and duration of mechanical ventilation use 
o Incidence of intensive care unit (ICU) admission need 
o Lung damage extension changes from baseline (assessed by Chest CT or Rx) 
o Change from baseline in lung exudation degree (assessed by Chest CT or Rx) 
o PaO2 
o SpO2 
o Partial arterioral oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) ratio 
o CRP 
o Hs-CRP 
- 
Exploratory Endpoints (not mandatory): 
o Cytokine profile 
o Concentration of Reparixin in serum over time 
o SARS-CoV-2 virologic counts 
- 
Safety Endpoints: 
o Serious adverse events 
o Adverse events (AEs) coded by System Organ Class (SOC) and preferred Term 
(PT), using the Medical Dictionary for Regulatory Activities (MedDRA). 
o The number and percentage of patients with any AE and the number of TEAEs, 
tabulated by SOC and PT, seriousness, relationship to treatment and severity. 
 
 


 
4 STUDY DESIGN AND METHODOLOGY 
 
 
4.1 Phase 2 Study design 
The study is designed for the investigational use of a CXCR1 and CXCR2 allosteric antagonist named 
Reparixin. It will involve 48 adult patients with severe COVID-19 pneumonia in accord with any of the 
following:  
1. 
Age 18 to 90. 
2. 
Confirmed COVID-19 diagnosis 
3. 
At least one of the following: ① Respiratory distress, RR ≥ 30 breaths/min without oxygen; ② 
Partial arterial oxygen pressure (PaO2) / Fraction of inspiration O2 (FiO2) >100 <300mmHg (1mmHg 
= 0.133kPa). 
4. 
Chest imaging confirms lung involvement and inflammation. 
5. 
Inflammatory status as documented by at least one of the following: Lactate dehydrogenase 
(LDH) > normal range, C-reactive protein (CRP) ≥ 100mg/L or IL-6 ≥ 40pg/mL, serum ferritin ≥ 
900ng/mL, XDP >20mcg/mL. 
Patients randomized to the active treatment will receive an oral dose of reparixin (1200 mg tablets TID) 
for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a 
total of 21 days of treatment. Patients randomized to the both arms will be offered, in case of worsening 
(e.g. need of ICU and/or mechanical ventilation), a rescue medication based on their physicians’ 
judgement, without any constrain from the sponsor.   
 
  
4.2 Phase 3 Study design 
In the phase 3 segment of this study, it is planned that patients will be randomized 2:1 to Reparixin or 
standard of care. Patients randomized to the control arm will be offered a rescue medication with the 
active treatment (Reparixin 1200 mg oral tablets TID) or Reparixin 2.772 mg/kg body weight/hour IV 
infusion, if the oral route is unfeasible for the clinical condition. The Phase 3 design will be reassessed 
and pending re-evaluation based on Phase 2 study results. 
 
 
Phase 2 Study Design and Methodology:  Randomized 2:1, controlled, multicentre clinical trial in 48 
adult patients with severe COVID-19 pneumonia 
 
Phase 3 Study Design and Methodology: Randomized 2:1, controlled, multicentre clinical trial in 111 
adult patients with severe COVID-19 pneumonia, to be re-assessed based on Phase 2 results. 
 
 
 


 
5 POPULATION 
 
5.1 Number of patients 
A maximum of 48 patients with moderate-to-severe COVID-19 pneumonia will be enrolled in the Phase 
2 study. Enrollment can be interrupted at any given time for futility or clear superiority reasons of the 
oral tablet vs IV infusion, or both vs standard of care, to proceed into Phase 3 or interrupt the clinical 
study.  
The estimated number of 111 patients to be enrolled until the end of Phase 3 will be re-estimated based 
on the Phase 2 results.  
 
 
5.2 Inclusion/exclusion criteria  
Phase 2 Inclusion Criteria: 
1. Age 18 to 90. 
2. Confirmed COVID-19 diagnosis 
3. At least one of the following: ① Respiratory distress, RR ≥ 30 breaths/min without oxygen; ② 
Partial arterial oxygen pressure (PaO2) / Fraction of inspiration O2 (FiO2) >100 <300mmHg 
(1mmHg = 0.133kPa). 
4. Chest imaging confirms lung involvement and inflammation. 
5. Inflammatory status as documented by at least one of the following: Lactate dehydrogenase 
(LDH) > normal range, C-reactive protein (CRP) ≥ 100mg/L or IL-6 ≥ 40pg/mL, serum ferritin 
≥ 900ng/mL, XDP >20mcg/mL. 
Phase 3 Inclusion Criteria: same as above; other criteria TBD based on Phase 2 outcomes. 
Phase 2/3 Exclusion Criteria: 
1. Cannot obtain informed consent. 
2. Severe hepatic dysfunction (Child Pugh score ≥ C, or AST> 5 times the upper limit); Severe 
renal dysfunction (estimated glomerular filtration rate ≤ 30mL / min / 1.73 m2) or receive 
continuous renal replacement therapy, hemodialysis, or peritoneal dialysis. Serum albumin <2.5 
g/dL. 
3. 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 alone, e.g. sulfamethoxazole, does not qualify for exclusion)  
4. Severe, active bleeding such as hemoptysis, gastrointestinal bleeding, central nervous system 
bleeding, and nosebleeds within 1 month before enrollment. 
5. Pregnant and lactating women and those planning to get pregnant. 
6. Participated in other interventional clinical trials with investigational medicinal products, not 
considered suitable for this study by the researchers. 
7. At the time of enrollment, patients not in a clinical condition compatible with the oral 
administration of the study drug. 
 


 
 


 
6 INTERVENTIONS 
 
6.1 Interventional treatments 
 
Phase 2 Investigational treatment 
Reparixin in oral pharmaceutical form (1200 mg tablets TID), as follows: 
GROUP 1: Reparixin oral tablets 1200 mg TID for 7 days.  
- 
In case of improvement, treatment can be prolonged at discretion of the investigator up to a -
maximum of 21 days of treatment in total. 
 
Phase 3 Investigational treatment 
Reparixin in oral pharmaceutical form (1200 mg tablets TID). Treatment duration to be decided based 
on Phase 2 study results.  
 
6.2 Control treatment 
 
Phase 2/3 Control treatment 
Control group in both the phase 2 and 3 segments will be standard of care, which due to the nature of 
the COVID-19 pandemic is expected to evolve over time and, thus, cannot be prespecified. This group 
will be populated in a prospective manner and offered a rescue medication in case of worsening (e.g. 
need of ICU and/or mechanical ventilation). Due to the evolving understanding of novel treatments 
being currently tested during the COVID-19 pandemic, the Sponsor will not put any restriction on the 
selection of the rescue medication during phase 2. In the phase 3, Reparixin will be offered as rescue 
medication, as oral tablets or as IV infusion in case of unfeasibility of the oral administration due to the 
clinical conditions (e.g. intubated patients in the ICU). 
 
 
6.3 Preparation, Handling, Storage and Accountability of the study drug 
 
Study Drug (REPARIXIN tablets) 
FORMULATION  
The investigational product is in the form of oral immediate release 600 mg tablets containing the 
active ingredient reparixin. Reparixin 600 mg immediate release tablets are white oblong tablets.  
Refer to the following table for Reparixin tablets Description and Composition.  
NAMES OF INGREDIENTS 
AMOUNT PER 
TABLET 
FUNCTION OF 
INGREDIENT 
REFERENCE  TO QUALITY  
STANDARDS 
Reparixin 
(DF 1681Y) 
600.0 mg 
Drug substance 
Internal monograph 
Cellulose 
Microcrystalline 
141.48 mg 
Diluent/ 
Disintegrant 
Eur. Ph. 
Lactose monohydrate 
94.77 mg 
Diluent 
Eur. Ph. 
Croscaramellose 
Sodium 
36.00 mg 
Disintegrant 
Eur. Ph. 
Hydroxypropyl 
cellulose  
20.07 mg 
Binder 
Eur. Ph. 


Silica, 
colloidal 
anhydrous 
3.15 mg 
Glidant 
Eur. Ph. 
Magnesium stearate 
4.50 mg 
Lubricant 
Eur. Ph. 
Total 
900 mg 
- 
- 
 
 
  
Manufacturing, Packaging and Labelling of Investigational Product  
Reparixin tablets will be packaged in white PVDC/PE/PVC/Aluminum blister packages and should be 
stored at temperatures not higher than 30°C.  
The drug is manufactured by Monteresearch according to current Good Manufacturing Practice 
requirements.  
Medication labels will comply with the Competent Authority requirements and will be printed in a 
Multilanguage format where needed. Refer to the Appendix 4 for reparixin packaging and labeling 
details.  
Reparixin tablets are packaged in white PVDC/PE//PVC/Aluminum blisters in the form of patient kits, 
numbered to maintain blinding and should be stored at temperature not higher than 30°C. 
The Investigator (or pharmacist in those countries where it is required that shipment is made directly to 
the hospital pharmacy) is responsible for receipt, proper storage and usage of study drug. Partially used 
or unused study drug boxes should be destroyed on site (and documentation of destruction provided to 
Dompé farmaceutici s.p.a.) or returned to Dompé farmaceutici s.p.a., at the end of the study. The 
Investigator, who will keep a cumulative inventory and dispensing records, will maintain all supplies 
under adequate security. Adequate record of receipt, use or loss of drug will be retained.  
Pharmacists will be provided with the ‘Instructions to the Pharmacy’. 
 
  
Dose and Route of Administration  
 
- 
Oral tablets:  For patients able to comply with the oral treatment, it is recommended to take for 
each administration two Reparixin 600 mg tablets, for the total of three daily administrations. 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 tablets treatment, is possible to administer the medicine through a naso-gastric tube, 
following this procedure: for each administration, disperse two Reparixin 600 mg tablets in 25 
mL of drinking water in a suitable container (e.g. conical tubes for 50 mL Falcon centrifuge). 
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. 
 


Study Drug (REPARIXIN iv) 
FORMULATION  
The investigational product is in the form of concentrate for solution for i.v. infusion packaged into 250 mL 
clear Glass Vials with the following composition per single (250 mL) unit. 
 
Refer to the following table for Reparixin i.v.  33mg/mL Description and Composition 
NAME OF INGREDIENT 
PER-UNIT 
FORMULA 
FUNCTION OF 
INGREDIENT 
REFERENCE  TO QUALITY  STANDARDS 
Reparixin (DF1681Y) 
8.25 g 
Drug substance 
Internal monograph 
Sodium Dihydrogen 
Phosphate Dihydrate 
1.96 g 
Buffer 
Eur. Ph.  
L-lysine monohydrate 
4.78 g 
Solubilizer 
German Pharmacopoeia - current edition 
Sodium hydroxide 
qs to pH 8.0  
Buffer 
Eur. Ph. 
Water for injections 
qs to 250 mL 
Solvent 
Eur. Ph. 
 
Manufacturing, Packaging and Labelling of Investigational Product 
Reparixin will be manufactured by Patheon (Italy) according to current Good Manufacturing Practice 
requirements.  
The Reparixin iv is packaged into 250 mL clear Glass Vials.  
The Investigational Product must be kept at a temperature not exceeding 30°C and must not be frozen 
Medication labels will comply with the Competent Authority requirements and will be printed in a 
Multilanguage format where needed. Refer to the Appendix 4 for reparixin packaging and labeling 
details.  
The Investigator (or pharmacist in those countries where it is required that shipment is made directly to 
the hospital pharmacy) is responsible for receipt, proper storage and usage of study drug. Partially used 
or unused study drug boxes should be destroyed on site (and documentation of destruction provided to 
Dompé farmaceutici s.p.a.) or returned to Dompé farmaceutici s.p.a., at the end of the study. The 
Investigator, who will keep a cumulative inventory and dispensing records, will maintain all supplies 
under adequate security. Adequate record of receipt, use or loss of drug will be retained.  
Pharmacists will be provided with the ‘Instructions to the Pharmacy’. 
 
 
 
 
Dose and Route of Administration  
 
IV infusion: In the Phase 3, for patients randomized to the control arm who have worsened after 24hrs 
and within 14 days from randomization, Reparixin will be offered as rescue medication also as a 
continuous i.v. infusion into a central vein or dedicated peripherally inserted central catheter at a dose of 
2.772 mg/kg body weight/hour for up to 7 days (120hrs).  


The Reparixin solution for IV infusion will be provided by the Sponsor. 
The dosing solution for infusion will be prepared at the designated Pharmacy or authorized location 
within each centre according to local guidelines for sterile re-consitution of i.v. injectable solutions. 
For each 750 mL dosing solution volume, the content of a Vial (250 mL) will be diluted with 500 mL of 
0.9% sterile saline to dispense reparixin as 11.00 mg/mL solution.  The dosing solution will be placed in 
a 1000 mL sterile empty Infusion Bag.  Dosing solutions will be prepared and used within 72 hours from 
preparation, unless the site has more restrictive rules 
 
 
 
6.4 Compliance to Treatment 
The effective doses of study drugs received by each patient during the trial will be recorded. 
Treatments received by the patients in the control (standard of care) group will be recorded. 
Any concomitant medication that the participant receives during the participation in this study will also 
be recorded. Specifically, dose, posology, frequency of administration, start and end date and reason of 
use will be required and collected. 
There is no contraindication to the use of concomitant supportive and prophylactic care medications as 
deemed necessary by the treating physicians, unless incompatible with the study drug. Since Reparixin 
is metabolized by CYP2C9 there could be a theoretic effect on drug availability by any medication that 
is a known inhibitor or inducer of CYP2C9. These medications are not considered incompatible with 
Reparixin, however, a list of such medications is provided below for the consideration of the 
investigators: 
 
- 
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. 
 
 


 
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 potential study patients will be treated. Each patient will be 
involved in the study for the entire duration of the hospital treatment and for a maximum of 31 days 
(one month) including the follow-up. 
 
7.2 Efficacy assessments 
Clinical parameters to assess the efficacy of the experimental treatment will be assessed according to 
the Statistical Analysis Plan (SAP) and the Schedule of Evaluations.  
All the laboratory and clinical parameters, including radiography imaging assessments, will be 
collected based on the local procedures of the participating clinical sites.  
The degree of dyspnea will be collected using the “Liker” and Visual Analogues (VAS) scales. 
The Liker scale is used as follows: the patient grades his current breathing compared to when he first 
started the drug (from -3 to 3). "0" = no change, "1" =minimally better, "2" =moderately better, "3" 
=markedly better, "-1" =minimally worse, "-2" =moderately worse, "-3" =markedly worse. 
The VAS scale is used as follows: the patient draws a horizontal line on an axial graph (from 0 to 100) 
to show the degree of how he feels about breathing. The number "0" equals the worst breathing the 
patient has ever felt and the number "100" equals the best he has ever felt. 
All the clinical endpoints are listed in Section 3 of this protocol but may be implemented considering 
the adaptive nature of this clinical trial, at the end of phase 2 of at any given time following the advice 
of the Data Monitoring Committee (DMC). The SAP will be modified accordingly.  
 
7.3 EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION 
7.3.1 DEFINITIONS  
Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not related to the medicinal product.  
Adverse Drug Reaction  
An Adverse Drug Reaction (ADR) is defined as an adverse experience which is a 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. 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. 


 
7.3.2 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.  
 
7.3.3 RECORDING 
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.  
 
 


7.3.4 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: 
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 using the definitions in the Table below. For each 
episode, the highest severity grade attained should be reported. 
Severity of the Adverse Event 
Mild 
Grade 1 - Does not interfere with patient’s usual function (awareness of 
symptoms or signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with patient’s usual function (enough 
discomfort to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with patient’s usual function (incapacity to 
work or to do usual activities [unacceptable]) 
 
7.3.5 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 stabilization of the condition. It is the Investigator's responsibility to ensure 
that the subjects experiencing AEs receive definite treatment for any AE, if required. 
If subject was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded to the 
Sponsor as soon as it becomes available.  
In addition, a letter from the Investigator that summarizes the events related to the case as well as results 
of any relevant laboratory tests also may be requested. Further, depending upon the nature of the SAE, 
Dompé may request copies of applicable segments of the patient’s medical records. In case of death, a 
copy of the autopsy report, if performed, should also be provided. 
The Investigator shall inform the Sponsor with an appropriate written communication, whenever he 
becomes aware of new available information regarding the SAE, once the condition is resolved or 


stabilized and when no more information about the event is expected. Follow-up SAE information should 
be processed as initial SAE notification (see Par. 7.3.6). 
For pharmacovigilance purposes, all SAEs should be followed-up in order to clarify as completely as 
possible their nature and/or causality and until all queries have been resolved. All SAEs will be followed 
up until the events resolve or the events or sequelae stabilize, or it is unlikely that any additional 
information can be obtained after demonstration of due diligence with follow-up efforts (i.e. subject or 
Investigator is unable to provide additional information, or the subject is lost to follow up), unless subject 
has withdrawn his/her consent. 
 
7.3.6 SERIOUS ADVERSE EVENT REPORTING 
Reporting Procedure for Investigators  
The Investigator must report all SAEs, regardless of presumed causal relationship, to Dompé 
Pharmacovigilance Department, preferably by e-mail (to farmacovigilanza@dompe.com) or fax (02 
36026913) within 24 hours of learning of the event. Contact details for SAE reporting are provided in the 
section “Contact Information”. 
The investigator should also report information on SAEs that continue after patient has completed his/her 
participation in the study (whether study completion or withdrawal) unless patient has withdrawn his/her 
consent. 
Information on SAEs will be recorded on the SAE form. Follow-up reports (as many as required) should 
be completed and e-mailed /faxed following the same procedure above, marking the SAE form as “follow 
up Number XX”.   
Whenever more than one SAE is observed, the Investigator should identify which is the primary adverse 
event, i.e. the most relevant one. If other events are listed in the same report, the Investigator, along with 
their relatedness to the Investigational Product, should identify which adverse events are serious and 
which are non-serious. In any case, the Investigator is requested to record his/her opinion about the 
relatedness of the observed event(s) with the investigational medication. 
In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does not usually 
need to actively monitor patients for AEs once the trial has ended, if the Investigator becomes aware of 
a SAE occurring to a patient after that patient has ended his/her participation in the study (whether study 
completion or withdrawal), the SAE should be reported by the Investigator to Dompé Pharmacovigilance. 
Such “post-study cases” should be regarded for expedited reporting purposes by Dompé, as though they 
were study reports. Therefore, a causality assessment and determination of expectedness are needed for 
a decision on whether or not expedited reporting is required.  
 
The following situation shall not be considered SAE: 
 
• 
 Abnormal lab values or test results that do not induce clinical signs and/or symptoms and require 
intervention/therapy, i.e. are clinically significant. 
 
7.3.7 REPORTING PROCEDURE TO ETHIC COMMITTEES (EC) AND TO REGULATORY 
AUTHORITIES 
The Investigator shall report all serious adverse events immediately to Dompé Pharmacovigilance. 
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 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) 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. 
 
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.   
 
7.3.8 EXPOSURE TO INVESTIGATIONAL PRODUCT DURING PREGNANCY 
Women of childbearing potential are not excluded from the study as long as adequate birth control 
methods are being utilized. Women of childbearing potential are defined as all women physiologically 
capable of becoming pregnant. Prior to enrolment in the clinical trial, female patients of childbearing 
potential and their partners must be advised of the importance of avoiding pregnancy during the entire 
course of the study treatment and for the 30 days after the study treatment period ends and of the potential 
risks associated with an unintentional pregnancy. During the trial, female patients are to be instructed to 
contact the Investigator immediately if they suspect they might be pregnant. In the same way, male 
patients who become aware that the partner might be pregnant, are to be instructed to contact the 
Investigator immediately. 
The Investigator must report every pregnancy on a pregnancy report form as soon as possible (within 24 
hours of learning of the pregnancy to Dompé Pharmacovigilance (contacts specified in the section 
“Contact Information”), even if no AE has occurred, and follow it to term. If, however, the pregnancy is 
associated with an SAE (eg, if the mother is hospitalized for dehydration), in addition to the pregnancy 
report form, a separate SAE report form must be filed as described in Section 7.3.6, with the appropriate 
serious criterion (eg, hospitalization) indicated on the SAE report form. Miscarriage, stillbirth and any 
malformation/disease must be reported as a SAE. 
Any pregnancy leads to the immediate exclusion from the trial.  
 
7.3.9 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. 
 
7.3.10 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 Dompé Medical Expert, 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.  
 
 
7.4 Study Procedures and Randomization 
 
Potential study patients with confirmed COVID-19 diagnosis will be identified from those hospitalized 
at the participating clinical sites for management of their COVID-19 associated severe pneumonia.  
Screening will be performed and completed in consented patients and potential study patients will be 
treated. All the subjects who sign the informed consent form for the present study and will be screened 
will be coded with “unique subject identifiers” (see section 10.5). 
Each patient will be involved in the study for the entire duration of the hospital treatment and for a 
maximum of 31 days (one month) including the follow-up. 
 
All the laboratory and clinical parameters, including radiography imaging assessments, will be 
collected based on the local procedures of the participating clinical sites.  
The degree of dyspnea will be collected using the “Liker” and Visual Analogues (VAS) scales. 
The Liker scale is used as follows: the patient grades his current breathing compared to when he first 
started the drug (from -3 to 3). "0" = no change, "1" =minimally better, "2" =moderately better, "3" 
=markedly better, "-1" =minimally worse, "-2" =moderately worse, "-3" =markedly worse. 
The VAS scale is used as follows: the patient draws a horizontal line on an axial graph (from 0 to 100) 
to show the degree of how he feels about breathing. The number "0" equals the worst breathing the 
patient has ever felt and the number "100" equals the best he has ever felt. 
 
Before randomization, and any study related procedures, at study entry all patients must have given a 
written informed consent for the study and must be assigned a screening number. 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 definitive enrolment in the 
study. Subjects will be assigned to their treatment according to their randomisation number.   
Patients will be randomized in a 2:1 fashion between Reparixin and standard treatment using a computer 
generated Randomization List generated by the Sponsor. 
 
 


 
8 END OF STUDY, DISCONTINUATION AND WITHDRAWAL 
 
8.1 End of study (EOS): 
The EOS is defined as the last day the last patient completes the last study assessment in the hospital, 
or retracts the consent to participate in the study, or withdraws from the study, or is deceased or 
otherwise lost to follow-up.  
 
 
8.2 Discontinuation and Withdrawal 
A patient has the right to withdraw from this clinical trial at any time and for any reason, without any 
repercussion. 
The 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.  
As no withdrawals have been anticipated in the sample size calculations, patients who are withdrawn 
before completing the minimum of 24hrs treatment with the oral tablets in the active group can be 
replaced to reach the predefined samples size of the Phase 2 segment of the study. Participants who 
whitdraw from the study cannot be re-randomized.  
Considerations on withdrawals for the Phase 3 segment of the study will be reassessed. 
All discontinuations must be recorded by the investigators and reported to the Sponsor and, if possibile, 
an early discontinuation visit should be conducted and data recorded. 
Temporary discontinuation or drug discontinuation is not allowed since treatment with the medication 
is planned for continuous use throughout the treatment phase. 
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. 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. 
 


 
9 STATISTICAL CONSIDERATIONS 
 
 
9.1 Sample size 
The sample size for this trial will be adaptively determined through a phase 2/3 design. Enrollment is 
planned to last approximately 2 months. Each patient will be randomly allocated to Reparixin or 
Control according to a randomization ratio of 2:1 and he/she will be followed for the entire treatment 
and follow-up duration for collecting the efficacy endpoints of each study phase. 
 
For the Phase 2 portion of the study, the primary analysis will compare Reparixin versus Control in 
terms of time to a composite endpoint (primary endpoint of phase 2) including the following events: 
requirement of supplemental oxygen treatment, mechanical ventilation use, admission to ICU, and any 
requirement of rescue medication. Based on clinical experience, an improvement of the median time 
freedom from composite event of 1.5 times is expected. Assuming an exponential distribution, a total 
sample size of 48 patients will allow to provide 80% power to show superiority of Reparixin compared 
to control using a log-rank test at a one-sided significance level of 0.025. 
 
The sample size for the phase 3 is based on assessment of superiority of Reparixin compared to control 
arm in terms of freedom from a composite endpoint (primary endpoint of phase 3) of severe events 
including death, admission to the ICU, requirement of mechanical ventilation. 
Based on same assumptions of phase 2 regarding randomization (2:1) and expecting to double the 
median time freedom from severe composite event using Reparixin compared to control (from 2-4 to 4-
8 days), a total sample size of 111 patients will allow to achieve a power of 90% to show superiority of 
Reparixin over control using a log-rank test at a one-sided significance level of 0.025. No drop-out are 
expected to happen. The number of patients to be included may be revised based on considerations 
from Phase 2 data analysis. 
Primary endpoint of phase 3 will be tested only if superiority of Reparixin is shown in phase 2. Thus, 
the overall type I error of the study will be controlled at 0.025 via the hierarchical testing procedure. 
 
9.2 Overview of planned statistical analyses 
The study plans for the following statistical analyses: 
• Phase II analysis: this analysis will be conducted when all planned enrolled subjects for phase II 
have reached the primary composite endpoint of phase II and the study database has been 
(interim) locked. 
• Phase III analysis: in case of success of phase II, this analysis will be conducted when all 
planned enrolled subjects for phase III have reached the primary composite endpoint of phase 
III and the study database has been locked. 
• Analyses for the Data Monitoring Committee: these analyses will be produced periodically  
 
9.3 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 (either Reparixin or Standard of Care). 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 (either Reparixin or Standard of Care). FAS 
population will be analyzed according to ITT principle, i.e. by treatment allocation. The FAS 
population will be used for the primary analyses of the study and to present results on efficacy 
data. 
• The Per Protocol (PP) population will consist of all randomized patients who received at least 
one dose of the investigational product and do not have Major Protocol Deviations. The PP 
population will be used for sensitivity analyses. 
 
 
9.4 Statistical Methodology 
9.4.1 General Considerations 
This trial’s design will allow for adaptations based but not limited to the following: 
• Interruption of an experimental treatment route of administration in favour of the other due to 
safety reasons; 
• Confirmation or modification of the primary, secondary and exploratory endpoints; 
• Confirmation or modification of the sample size for the Phase 3 segment; 
• Early closure of the study for efficacy, futility or safety reasons. 
All study adaptation will be carefully detailed in the Statistical Analysis Plan and in the Clinical Study 
Report. 
 
Appropriate descriptive statistics will be produced by treatment arms and by route of administration of 
Reparixin, 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 ongoing and who are free from event at the analysis cut-off date will be censored at the 
analysis cut-off date. Subjects who have discontinued 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 database lock with more technical and detailed 
elaboration of the principal features of statistical analyses. Additional post-hoc analysis may be 
produced to further allow comparison between treatment and control, according to the results obtained. 
Any deviations from the original statistical plan (including unplanned analyses) will be documented in 
the Clinical Study Report.   


 
 
9.4.2 Analysis of efficacy variables 
9.4.2.1 Primary analysis of phase II 
 
In phase II, the primary endpoint to assess the efficacy of Reparixin versus the Control is the time 
freedom from a composite endpoint of events including supplemental oxygen treatment, mechanical 
ventilation use, admission to ICU, and any use of rescue medication. The time to the first event (any 
one of the components defined in the phase II composite endpoint) will be used for analysis. In case of 
no events, the rules for censoring defined in section 9.4.1 will be used. 
 
The primary endpoint will be evaluated by means of Kaplan-Meier estimates and log-rank test. 
The null hypothesis H0phaseII is that the freedom form events in Reparixin (TREPARIXIN) is lower or equal 
than control (TCONTROL): 
 
H0phaseII: TREPARIXIN ≤ TCONTROL 
H1phaseII: TREPARIXIN > TCONTROL 
 
where TREPARIXIN and TCONTROL are the freedoms from event for Reparixin and Control, respectively. 
The null hypothesis H0phaseII will be rejected, and superiority of Reparixin concluded (alternative 
hypothesis H1phaseII) if log-rank 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 tare reported in Table 1. 
 
9.4.2.2 Primary analysis of phase III 
In case of rejection of the null hypothesis H0phaseII, the primary endpoint to assess the efficacy of 
Reparixin versus the Control in phase III is the time freedom from a severe composite endpoint of 
events including death, admission to the ICU, mechanical ventilation. The time to the first severe event 
(any one of the components defined in the phase III composite endpoint) will be used for analysis. In 
case of no events, the rules for censoring defined in section 9.4.1 will be used. 
 
The primary endpoint will be evaluated by means of Kaplan-Meier estimates and log-rank test. 
The null hypothesis H0phaseIII is that the freedom form severe events in Reparixin (REPARIXIN) is lower 
or equal than control (CONTROL): 
 
H0phaseIII: REPARIXIN ≤ CONTROL 
H1phaseIII: REPARIXIN > CONTROL 
 
where REPARIXIN and CONTROL are the freedoms from severe event for Reparixin and Control, 
respectively. 
The null hypothesis H0phaseIII will be rejected, and superiority of Reparixin concluded (alternative 
hypothesis H1phaseIII) if log-rank 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 tare reported in Table 2. 
 
Primary endpoint of phase 3 will be tested only if superiority of Reparixin is shown in phase 2.  


Both null hypotheses H0phaseII and H0phaseIII must be rejected in order to claim superiority on Reparixin 
over Standard of Care. Consequently, no multiplicity correction of type I error will be applied on 
primary endpoints. 
 
9.4.2.3 Handling of 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.  
9.4.2.4 Sensitivity analyses 
The following sensitivity analyses are defined to assess the robustness of results on primary endpoints 
versus adherence to protocol and presence of confouning factors: 
Comparison between treatment and control will be performed in the PP population (see section 9.3 for 
definition) instad of FAS; 
Comparison between treatment and control will be performed by means of a Cox regression model, 
using pre-specified baseline charateristics as covariates (details will be provided in the SAP). 
The above sensistivity assessemnts will be performed at the time of phase III analysis.  
Additional sensitivity analyses may be added in the SAP. 
9.4.2.5 Secondary Efficacy Analyses 
Each component of the primary composite endpoints will be evaluated separately, and their 95% C.I. 
will be reported. In addition to descriptive statistics, all secondary endpoints will be analyzed by 
appropriate parametric tests depending on the nature of the variable and its distribution. Data 
transformation might be used in order to satisfy the assumption of normality requested by parametric 
statistical tests. In case such assumptions are not met, non-parametric counterpart tests will be used. 
Details will be provided in the SAP. 
Change from baseline value (for continuous variables) and shift tables versus baseline (for categorical 
variables) will also be summarized for all post-baseline visits. 
 
9.4.3 Safety Analysis 
Treatment-Emergent Adverse Events (TEAEs), Adverse Drug Reactions (ADRs) and Serious Adverse 
Events (SAEs) will be presented treatment arm (and route of administration if required) in terms of 
number of AEs and their incidence by System Organ Class (SOC) and Preferred Terms (PT) using 
MedDRA. Analyses will be provided also by severity and relationship to the treatment. 
Vital signs and laboratory tests will be presented using descriptive statistics at each available visit. 
Additionally, the frequency of subjects reporting an abnormal or abnormal clinically significant 
laboratory value at each available visit will be presented for each laboratory parameter. Shift tables 
versus baseline will compare abnormal laboratory findings at each post-baseline visit. 
 
9.4.4 Analysis of exploratory variables 
In addition to descriptive statistics at each available timepoint, explorative variables will be analyzed 
by means of inferential tests depending on their nature and distribution (all confidence intervals and 
statistical tests on explorative endpoints are of descriptive nature).  
 
9.4.5 Intermediate analyses for DMC 
 


Due to the open-label nature of this trial, an indipendent data monitoring committee is foreseen to 
provide timely recommendations about the early closures or modifications. This monitoring committee 
will include 2 to 4 indipendent physicians, supported by a statistician. 
 
Safety and efficacy data will be reviewed on an ongoing basis by a DMC.  
The DMC will give careful consideration to the appropriateness of trial continuation if there is 
emerging evidence that Reparixin is harmful. Similarly, DMC may suggest to interrupt one of the 
routes of administration of Reparixin. In making any recommendations about termination for safety 
reasons, the totality of data will be considered, including the number of unexpected deaths in the 
control group, and the available evidence about efficacy and the overall safety profile. 
Early termination would be considered if the rate of clinically significant post-surgical complications 
that require reoperation reliably exceeds the rate expected currently in standard practice settings.  
The DMC will also consider early termination if the quality of conduct of the trial is such that the trial 
will not be able to provide a timely and reliable answer to the questions it was designed to address. 
 
Primary endpoint data will be evaluated by DMC for identification of early superiority of Reparixin 
(efficacy) or for an early stop of the trial for futility (nonbinding). During phase II it has been planned 
to have 1 interim analysis, while 2 interim analyses will be performed during phase III. 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 final analyses for phase 2 and 
phase 3 are reported in Table 1 and Table 2, respectively. Unplanned DMC interim analyses might be 
performed. In that case, only safety data will be evaluated. 
 
Table 1: O’Brien-Fleming spending functions boundaries for primary analysis in phase II 
Analysis 
Sample 
Size 
Boundaries for primary endpoint 
(C-peptide) 
Efficacy 
Futility 
Interim #1 
⁓27 
p-value <0.00258 
p-value ≥0.23349 
Final 
48 
p-value <0.02400 
p-value ≥0.02400 
 
Table 2: O’Brien-Fleming spending functions boundaries for primary analysis in phase III 
Analysis 
Sample 
Size 
Boundaries for primary endpoint 
(C-peptide) 
Efficacy 
Futility 
Interim #1 
⁓60 
p-value <0.00296 
p-value ≥0.26674 
Interim #2 
⁓81 
p-value <0.00892 
p-value ≥0.09841 
Final 
111 
p-value <0.02151 
p-value ≥0.02151 
 
 
 
 
 
 
 
 
 


 
10 SUPPORTING DOCUMENTATION 
 
10.1 
Clinical and non clinical pharmacology 
 
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 the first low molecular weight blocker of CXCL8 biological activity in 
clinical development. Relevant pre-clinical, toxicological and phase 1 to 3 clinical data are summarized 
below. It is anticipated that data on human exposition to oral 1200 mg TID, as proposed in this trial, is 
available from the study REP0111 (Phase 1b pilot study to evaluate reparixin in combination with 
chemotherapy with weekly paclitaxel in patients with HER-2 negative metastatic breast cancer). In 
particular from the pharmacokinetics data at the 21st day of treatment with 1200 mg reparixin oral tablets 
(i.e. no paclitaxel from day 15th ) sufficient elements  are available to estimate the drug concentration 
(mean) at the steady state. The Css at steady state (after repeated oral administration) can calculated form 
the following formula: Css = AUC/τ  where AUC is the area under curve (mg*h/ml) and τ is the dose 
interval (h). The mean AUC 0-8h(τ) at 21st  day is 191 mcg*h/ml, the interval of dose is 8 hours; 
consequently the mean Css is 23,88 mcg/ml, which is comparable to the Css obtained by IV continuous 
infusion. Please also refer to the Investigator’s Brochure for more detailed information.  
Reparixin (formerly repertaxin) 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 grated 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. 
 
10.1.1 RELEVANT NON-CLINICAL PHARMACOLOGY 
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 [Bertini, 2004; Allegretti, 
2005]. 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 [Bertini, 
2004; Cugini, 2005; Souza, 2004; Cavalieri, 2005; Garau, 2005; Villa, 2007; Gorio, 2007]. More 
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. 
 
10.1.2 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. 
 
10.1.3 PHARMACOKINETICS AND PRODUCT METABOLISM 
PK studies by i.v. injection revealed that reparixin is very rapidly eliminated in rats and humans (t1/2 
0.5-3hrs and 1.0-1.5hrs, respectively) whereas elimination is slower in dogs (12-28hrs). 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 48hrs (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-incubated with vehicle or different concentrations of reparixin for 15 min at 37°C and 
next placed onto 13-mm 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. 
 
 
10.1.4 SAFETY DATA 
A total of 448 subjects have been exposed to reparixin in the clinical studies completed to date, of whom 
337 and 112 received i.v. formulation and oral tablets, respectively. The patient population exposed to 
i.v. formulation includes 103 adult healthy subjects (100M/3F), 17 patients with different grades of renal 
impairment (12M/5F), 16 patients undergoing cardiopulmonary by pass (10M/6F), 46 patients 
undergoing lung transplantation (23M/23F), 48 patients undergoing kidney transplant (31M/17F), 22 
undergoing liver transplant (18M/4F) and 85 receiving intrahepatic pancreatic islet infusion (32M/53F), 
with 22 patients in this group receiving reparixin twice. Exposure included short or prolonged i.v. 
infusion up to 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 receiving either single 
agent reparixin (REP0210, operable breast cancer: 20 patients) or the combination of reparixin and 
weekly paclitaxel in metastatic breast cancer (REP0111, phase 1b: 30 patients; REP0114, randomized 
phase 2: 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 (REP0114). In addition, one patient in clinical trial REP0114 
experienced serious ADRs including grade 4 peritonitis and grade 5 intestinal perforation. 
The most frequent (>10%) ADRs observed in the three studies were: 
Gastrointestinal disorders (31.8%), including nausea, vomiting, abdominal pain, discomfort or 
distension, dyspepsia, flatulence, constipation. 
General disorders and administration site conditions (16.4%), including fatigue and peripheral oedema. 
 
10.2 
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. 
 
10.3 
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 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. 
 
10.4 
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. 
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. 
 
10.5 
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. 
 
10.6 
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.  
   
10.7 
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 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 
(“/”).  
  
10.8 
Database management  
The Sponsor will provide a double data entry with total re-entry of data and discrepancy resolution by a 
second data entrist and will update and verify the database and create the final data sets. 
 
10.9 
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 Enhanced (WHODDE). The version of the coding dictionaries will be stated in 
the study report. 
 
10.10 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. 
 
10.11 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.  
 
 


 
11 TABLES AND FIGURES 
 
11.1 
Study outline ± 
 
 
  
 
Phase 2 study to continue with Phase 3. In fase 3 Reparixin will be offered as rescue medication. Final 
design of Phase 3 to be adapted based on Phase 2 results. 
 


 
11.2 
Schedule of Evaluations 
The following schedule reports the relative timeframes and all the evaluations and assessments that are 
performed during the study: 
Study procedures 
Screening 
Baseline 
Day 1 
Day 2 Week 1 
End of 
treatment 
End of 
follow up 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Previous And 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Clinical severity 
score 
X 
X 
X 
X 
X 
X 
X 
Liker scale 
X 
X 
X 
X 
X 
X 
X 
Dyspnea VAS scale 
X 
X 
X 
X 
X 
X 
X 
Body temperature 
X 
X 
X 
X 
X 
X 
X 
Hematology 
evaluations* 
X 
X 
X 
X 
X 
X 
X 
Oxigen treatment 
(time and quantity) 
X 
X 
X 
X 
X 
X 
X 
Mechanical 
ventilation (Yes/No) 
X 
X 
X 
X 
X 
X 
X 
ICU admission 
(Yes/no) 
X 
X 
X 
X 
X 
X 
X 
Chest radiologic 
imaging 
X 
X§ 
X§ 
X§ 
X§ 
X 
X§ 
PaO2, SpO2, FiO2 
X 
X 
X 
X 
X 
X 
X 
CRP, Hs-CRP 
X 
X 
X 
X 
X 
X 
X 
Cytokine profile ** 
X 
X 
X 
X 
X 
X 
X 
Reparixin blood 
concentration ** 
 
 
X 
X 
X 
X 
X 
SARS-CoV-2 
virologic counts ** 
 
X 
 
 
X 
X 
X 
Study drug 
dispensation 
 
X 
 
 
 
 
 
Verify study 
medication dosing 
compliance 
 
 
X 
X 
X 
X 
 
Record AEs / SAEs 
X 
X 
X 
X 
X 
X 
X 
* Including routine hematology as for local laboratory procedures and predefined hematochemical 
evaluations required for this study; ** Not mandatory; § When deemed appropriate by the investigators. 
 
 


 
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autoantibody: interleukin 8 complexes in the acute respiratory distress syndrome. Relationship between 
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antibodies: potential therapeutics for the treatment of inflammatory disease states. J Leukoc Biol 
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mice against acute pancreatitis and associated lung injury. Regul Pept 2007;138:40-48 
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hemorrhage-induced priming for acute lung injury in mice. J Leukoc Biol 2004;76:58-64 
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antagonist prevents neutrophil accumulation in hyperoxia-exposed newborn rats. J Pharmacol Exp Ther 
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Ardehali A, Saggar R, Lynch JP, 3rd, Ross DJ, Strieter RM: CXCR2/CXCR2 ligand biology during lung 
transplant ischemia-reperfusion injury. J Immunol 2005;175:6931-6939 
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role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. J Clin 
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APPENDICES 
 
Appendix 1-INVESTIGATOR’S SIGNATURE PAGE 
 
Investigator’s Statement 
 
I have read study protocol REPAVID-19 from the title “Adaptive phase 2/3, randomized, controlled 
multicenter study on the efficacy and safety of Reparixin in the treatment of hospitalized patients with 
COVID-19 pneumonia” 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: 
_________________________  
 
 
 


Appendix 2-SPONSOR SIGNATURE PAGE 
 
 
Adaptive phase 2/3, randomized, controlled multicenter study on the efficacy and safety of Reparixin in 
the treatment of hospitalized patients with COVID-19 pneumonia 
 
 
Sponsor Medical Expert:            _____________________________________Date: _____/____/____ 
Flavio Mantelli, Chief Medical Officer 
 
 
 
 
Sponsor Research & Development Director ____________________________Date: _____/____/____ 
Marcello Allegretti, Chief Scientific Officer 
 
 


Appendix 3. Investigator’s Brocure (IB) 
Please refer to dedicated document 
 
Appendix 4. Investigational Drug Labels 
Please refer to dedicated document 
 
Appendix 5. Severe Adverse Event (SAE) reporting form and compltion guideline 
Please refer to dedicated document 
 
Appendix 6. Pregnancy reporting form and completion guideline 
Please refer to dedicated document 
 
Appendix 7. Informed consent form 
Please refer to dedicated document 
 
 

SAP_001.pdf: 
Dompé Farmaceutici S.p.A.                          Clinical Study Report REPAVID-19                                    Appendix 16.1.9 
 
16.1.9 Documentation of statistical methods  
 
Statistical analysis plan 
 


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STATISTICAL ANALYSIS PLAN 
 
PROTOCOL: REPAVID-19 
Adaptive phase 2/3, randomized, controlled multicenter study on 
the efficacy and safety of Reparixin in the treatment of 
hospitalized patients with COVID-19 pneumonia. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
Information in this statistical analysis plan and accompanying documents contains privileged or 
confidential information that is the property of Dompé farmaceutici s.p.a. It is understood that the 
information will not be used, divulged, or published without prior written consent of Dompé farmaceutici, 
except to the extent such disclosure is required by applicable laws and regulations. 
 
 


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STATISTICAL ANALYSIS PLAN 
APPROVAL PAGE 
 
Document Information  
Protocol Number: 
REPAVID-19 
Version: 
1.0 
Document Date: 
29 November 2020 
Prepared for: 
Dompé farmaceutici s.p.a. [Dompé] 
Via Santa Lucia 6; 20122 Milan, Italy 
Prepared by: 
Giovanni Goisis – Principal Biostatistician 
 
The Statistical Analysis Plan has been completed and reviewed and the contents are approved for 
use for the analysis. 
 
Lead Statistician details: 
Name: 
Giovanni Goisis 
Job Role: 
Principal Biostatistician 
Company: 
Dompé 
Signature: 
 
Date of signature: 
(DD Mmm YYYY) 
 
 
Sponsor Approver details: 
Name: 
Flavio Mantelli 
Job Role: 
Chief Medical Officer 
Company: 
Dompé 
Signature: 
 
Date of signature: 
(DD Mmm YYYY) 
 
 
 
29 Nov 2020
29 Nov 2020


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Contents 
Abbreviations ...................................................................................................................................... 5 
Revision History ................................................................................................................................. 6 
1. 
Introduction ............................................................................................................................. 7 
2. 
Study Objectives ...................................................................................................................... 7 
3. 
Study Design ............................................................................................................................ 7 
3.1 
Visit Schedule and Visit Windows ................................................................................... 7 
3.2 
Sample size justification ................................................................................................... 8 
3.3 
Randomization and blinding ............................................................................................ 9 
3.4 
Overview of planned statistical analyses ......................................................................... 9 
3.5 
Efficacy endpoints .......................................................................................................... 10 
3.5.1 
Primary endpoints ....................................................................................................... 10 
3.5.2 
Secondary Endpoints: ................................................................................................. 10 
3.5.3 
Exploratory Endpoints (not mandatory): .................................................................... 10 
3.6 
Safety endpoints ............................................................................................................. 11 
4. 
Statistical Analysis ................................................................................................................ 11 
4.1 
General ........................................................................................................................... 11 
4.2 
Analysis sets ................................................................................................................... 11 
4.2.1 
Enrolled set ................................................................................................................. 11 
4.2.2 
Randomized set ........................................................................................................... 11 
4.2.3 
Safety set ..................................................................................................................... 12 
4.2.4 
Full Analysis set ......................................................................................................... 12 
4.2.5 
Per Protocol set ........................................................................................................... 12 
4.3 
Usage of analysis sets ..................................................................................................... 12 
4.4 
Sub-group analyses ........................................................................................................ 13 
4.5 
Interim analyses .............................................................................................................. 13 
4.6 
DMC Safety Integrity Review ........................................................................................ 14 
4.7 
Study adaptation ............................................................................................................. 15 
4.8 
Handling of missing and incomplete data ...................................................................... 15 
4.9 
Changes in the planned analysis ..................................................................................... 15 
4.10 
Data Review Meeting ..................................................................................................... 16 
4.11 
Software ......................................................................................................................... 16 
5. 
Evaluation of Demographic and Baseline Characteristics .................................................... 16 
5.1 
Subject enrolment and disposition ................................................................................. 16 
5.2 
Protocol violations .......................................................................................................... 16 
5.3 
Study discontinuations ................................................................................................... 16 
5.4 
Patient status ................................................................................................................... 17 
5.5 
Demographics and baseline characteristics .................................................................... 17 
5.6 
Medical/Surgical History and Concomitant Diseases .................................................... 17 
5.7 
Prior and concomitant medications ................................................................................ 17 
5.8 
Other baseline characteristics ......................................................................................... 18 


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6. 
Evaluation of Treatment Compliance and Exposure ............................................................. 18 
6.1 
Treatment information .................................................................................................... 18 
6.2 
Exposure to IMP ............................................................................................................. 19 
7. 
Evaluation of Efficacy ........................................................................................................... 19 
7.1 
Analysis of primary efficacy endpoints ......................................................................... 19 
7.1.1 
Testing strategy and multiplicity adjustment .............................................................. 19 
7.1.2 
Analysis details ........................................................................................................... 19 
7.1.3 
Sensitivity analysis ..................................................................................................... 20 
7.2 
Analysis of secondary efficacy endpoints ...................................................................... 21 
7.2.1 
Descriptive Analysis ................................................................................................... 21 
7.2.2 
Comparison between treatments ................................................................................. 21 
7.3 
Analysis of exploratory efficacy endpoints .................................................................... 22 
8. 
Evaluation of Safety .............................................................................................................. 23 
8.1 
Adverse events ............................................................................................................... 23 
8.2 
Clinical laboratory evaluation ........................................................................................ 24 
8.3 
Vital signs ....................................................................................................................... 24 
8.4 
Pregnancy test over the study ......................................................................................... 24 
9. 
Derivations and date conventions .......................................................................................... 25 
9.1 
Variable derivation ......................................................................................................... 25 
9.2 
Partial date conventions ................................................................................................. 31 
10. 
Tables, Figures and Listings .................................................................................................. 34 
10.1 
Output conventions ........................................................................................................ 34 
10.2 
Format requirements: ..................................................................................................... 34 
10.3 
Table Conventions .......................................................................................................... 34 
10.4 
Listing Conventions ....................................................................................................... 35 
11. 
Reference ............................................................................................................................... 35 
 
 
Index of Tables 
Table 1: Schedule of evaluations ........................................................................................................ 8 
Table 2: Assumptions for primary endpoints ..................................................................................... 8 
Table 3: Usage of analysis set .......................................................................................................... 12 
Table 4: O’Brien-Fleming spending functions boundaries for primary analysis in phase 2 ............ 13 
Table 5: O’Brien-Fleming spending functions boundaries for primary analysis in phase 3 ............ 13 
Table 6: Adaptations and triggers ..................................................................................................... 15 
Table 7: Variable derivation rules .................................................................................................... 25 
Table 8: Algorithm for Treatment Emergence of Adverse Events ................................................... 31 
Table 9: Algorithm for Prior/Concomitant medications ................................................................... 32 
 


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Abbreviations 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ARDS 
Acute Respiratory Distress Syndrome 
ATC 
Anatomical Therapeutic Chemical 
COVID-19 
Corona Virus Disease 2019 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
DRM 
Data Review Meeting 
ENR 
Enrolled set 
FAS 
Full Analysis set 
ICH 
International Council for Harmonisation 
ICU 
Intensive Care Unit 
IMP 
Investigational Medicinal Product 
IRS 
Interactive Response System 
ITT 
Intent to Treat 
IV 
Intravenous therapy 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
PP 
Per Protocol set 
PT 
Preferred Term 
Q1 
1st Quartile 
Q3 
3rd Quartile 
RND 
Randomized set 
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 
Standard Error 
SI 
Standard International 
SOC 
System Organ Class 
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 
 
 


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Revision History 
Document Version 
Changes Made 
Document Date 
Final 1.0 
First release 
29 November 2020 
 
 
 
 
 
 
 
 


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1.  Introduction 
This document outlines the statistical methods to be implemented in the analysis of the data of REPAVID-19 
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 n. 1.5 - April 23, 20201 and Case Report Form Version 1.0 – 
April 30, 20202. 
2.  Study Objectives 
The objective of this clinical trial is to assess efficacy and safety of reparixin as compared to the Standard of 
care in hospitalized adult subjects with severe COVID-19 pneumonia. 
3.  Study Design 
General design and plan  
The study is designed as an adaptive, randomized, controlled, multicenter study to evaluate efficacy and safety 
of reparixin in hospitalized adult subjects with severe COVID-19 pneumonia.  
In the phase 2 segment of this study, subjects will be randomized 2:1 to reparixin oral tablets 1200 mg (Group 
1, active treatment) or standard of care (Group 2, control arm). In case of worsening (e.g. need of Intensive 
Care Unit (ICU) and/or mechanical ventilation) after the first 24hrs, subjects will be offered a rescue 
medication based on their physicians’ judgement, without any constrain from the sponsor. The administration 
of rescue medications is allowed, without constituting a protocol deviation. 
In the phase 3 segment of this study, it is planned that subjects will be randomized 2:1 to reparixin or standard 
of care. In case of worsening after the first 24hrs, subjects under the control arm will be offered a rescue 
medication with the active treatment (reparixin 1200 mg oral tablets TID) or reparixin 2.772 mg/kg body 
weight/hour IV infusion, if the oral route is unfeasible for the clinical condition. The phase 3 design will be 
reassessed and decided based on the results of the phase 2.  
3.1 
Visit Schedule and Visit Windows 
Assessments and study visits will be performed as listed in Table 1. Paragraph no. 7 “Assessments and 
procedures” of Study Protocol contains additional details about scheduled visits, evaluations and assessments 
that are performed during the study. 
Baseline is defined as the last visit prior to randomization. Unless otherwise specified, baseline values are 
defined as the measurements taken during this visit. 
 
 


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Table 1: Schedule of evaluations 
Study procedures 
Screening 
Baseline 
Day 1 
Day 2 
Week 1 
End of 
treatment 
End of 
follow up 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Previous And Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Clinical severity score 
X 
X 
X 
X 
X 
X 
X 
Liker scale 
X 
X 
X 
X 
X 
X 
X 
Dyspnea VAS scale 
X 
X 
X 
X 
X 
X 
X 
Body temperature 
X 
X 
X 
X 
X 
X 
X 
Hematology evaluations* 
X 
X 
X 
X 
X 
X 
X 
Oxigen treatment (time and quantity) 
X 
X 
X 
X 
X 
X 
X 
Mechanical ventilation (Yes/No) 
X 
X 
X 
X 
X 
X 
X 
ICU admission (Yes/no) 
X 
X 
X 
X 
X 
X 
X 
Chest radiologic imaging 
X 
X§ 
X§ 
X§ 
X§ 
X 
X§ 
PaO2, SpO2, FiO2 
X 
X 
X 
X 
X 
X 
X 
CRP, Hs-CRP 
X 
X 
X 
X 
X 
X 
X 
Cytokine profile ** 
X 
X 
X 
X 
X 
X 
X 
Reparixin blood concentration ** 
 
 
X 
X 
X 
X 
X 
SARS-CoV-2 virologic counts ** 
 
X 
 
 
X 
X 
X 
Study drug dispensation 
 
X 
 
 
 
 
 
Verify study medication dosing compliance 
 
 
X 
X 
X 
X 
 
Record AEs / SAEs 
X 
X 
X 
X 
X 
X 
X 
* Including routine hematology as for local laboratory procedures and predefined hematochemical evaluations required 
for this study;  
** Not mandatory; § When deemed appropriate by the investigators. 
 
3.2 
Sample size justification 
The sample size of the full phase 2/3 study is calculated based on data from clinical experience and on Sponsor 
expectations as reported in Table 2: 
Table 2: Assumptions for primary endpoints 
Primary endpoint* 
Standard of care (control) 
Reparixin 
Time to primary endpoint of phase 2 
2 days 
5 days 
Time to primary endpoint of phase 3 
2-4 days 
4-8 days 
* see section 3.5.1. 
 
Based on the following assumptions: 
 
an enrollment phase of 2 months, 


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 
a total follow-up of 21 days, 
 
a randomization ratio (reparixin:control) of 2:1 
 
an exponential distribution for survival probability S(t) = e−λt,  
 
a comparison between treatment by means of a log-rank test, 
 
an interim analysis framework as described in section 4.5, and  
 
a correction of the type I and II errors by means of O’Brien-Fleming spending functions 
a total of 109 events (corresponding to approximately 111 subjects) will allow to provide >80% power to 
show superiority of reparixin vs standard of care in terms of primary endpoint of phase 3, controlling the type 
I error under 0.025. 
Based on the same assumptions reported above, phase 2 portion of the study will be performed when a total 
of 46 events (corresponding to approximately 48 subjects) has happened. This allow to achieve approximately 
80% power to show superiority of reparixin vs standard of care in terms of (not severe) primary endpoint of 
phase 2, controlling the type I error under 0.025. 
The remaining portion of the 111 patients will be enrolled in the phase 3 study segment. Anyhow, due to the 
novel nature of the COVID-19 pandemic and being the primary efficacy endpoint planned in phase 3 not well 
established, it may require confirmation based on phase 2 data. For this reason, at the end of the phase 2 
portion, power calculations may be reassessed, and sample size may be re-estimated for phase 3. 
The adaptive design allows for the assessment of efficacy endpoint in phase 2 which are then seamlessly 
confirmed in the phase 3. Since primary endpoint of phase 3 will be tested only if superiority of reparixin is 
shown in phase 2 (at interim or final stage), the overall type I error of the study will be controlled at 0.025 via 
the hierarchical testing procedure. 
3.3 
Randomization and blinding 
Eligible subjects will be randomized in a 2:1 fashion to either reparixin or standard of care through an 
Interactive Response System (IRS). 
Randomization will be stratified by site to ensure balanced assignment across treatment groups. A stratified 
permuted block randomization list will be generated with a computer procedure, randomizing an excess of 
subjects to allow competitive recruitment within each center. Each randomized subject will be allocated with 
randomization number according to the stratified randomization list.  
Given the open-label nature of the trial and the stratification by site, random block sizes will be adopted in the 
randomization list to avoid that treatment assignments might be forecasted by investigators. 
The master randomization list will be kept confidential and will not be disclosed to any other person than 
those for which is strictly required (i.e. independent statistician who create the list, and IRS provider 
personnel). 
Mis-randomization events will be recorded as major deviation and reported in the final study report. 
Randomization codes will not be reused in case of subject’s dropouts. 
3.4 
Overview of planned statistical analyses 
The study plans for the following statistical analyses: 
 
Phase 2: 
o Interim analysis for efficacy or futility: this analysis will be conducted by Data Monitoring 
Committee (DMC) when half of the planned events of primary endpoint of phase 2 has 
happened; 


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o Final analysis: this analysis will be conducted when all randomized phase 2 subjects has 
performed the final visit. 
 
Phase 3 (in case of success of phase 2): 
o Interim analyses for efficacy or futility: this analysis will be conducted by DMC when 
approximately 55% and 74% of the planned severe events of primary endpoint of phase 3 has 
happened; 
o Final analysis: this analysis will be conducted all randomized phase 3 subjects has performed 
the final visit. 
 
Analyses for the DMC: these analyses will be produced periodically according to the DMC charter. 
In addition to the above interim analyses, analyses for safety integrity reviews will be performed 
according to DMC charter. 
3.5 
Efficacy endpoints 
3.5.1 Primary endpoints  
 
Primary Endpoint for phase 2: Composite endpoint of clinical events (the subject requires at least one 
of the following: supplemental oxygen requirement, invasive mechanical ventilation use, admission 
to ICU, and use of a rescue medication for any reason);  
 
Primary Endpoint for phase 3: Composite endpoint of death and clinical severe events (the subject 
dies or requires invasive mechanical ventilation use and/or admission to ICU). 
3.5.2 Secondary Endpoints: 
 
Clinical severity score (a seven-category ordinal scale) at any available time point 
 
Dyspnea severity (Liker categorical scale and VAS continuous scale) at any available time point; 
 
Changes in body temperature at any available time point; 
 
Duration and quantity of supplemental oxygen treatment at any available time point; 
 
Incidence and duration of mechanical ventilation use at any available time point; 
 
Incidence of ICU admission need at any available time point; 
 
Lung damage extension changes from baseline (assessed by Chest CT or Rx) at any available time 
point; 
 
Change from baseline in lung exudation degree (assessed by Chest CT or Rx) at any available time 
point; 
 
PaO2 at any available time point;  
 
SpO2 at any available time point; 
 
Partial arteriolar oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) ratio at any available 
time point; 
 
CRP at any available time point; 
 
Hs-CRP at any available time point; 
3.5.3 Exploratory Endpoints (not mandatory): 
 
Cytokine profile at any available time point; 


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 
Concentration of reparixin in serum over time; 
 
SARS-CoV-2 virologic counts at any available time point. 
3.6 
Safety endpoints 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) throughout the study. 
 
Safety Laboratory Tests at any available time point; 
 
Vital signs at any available time point; 
 
Pregnancy at any available time point. 
4.  Statistical Analysis 
4.1 
General 
Appropriate descriptive statistics will be produced, according to the variable: 
 
for continuous data n, mean, standard deviation (SD), median, Q1-Q3, and range (minimum and 
maximum) will be presented; 
 
for categorical data, frequency distributions and percentages will be presented; 
 
for time-to-event variables, cumulative freedom from event will be evaluated using Kaplan-Meier 
(KM) method. The degree of uncertainty will be expressed with 95% confidence limits (calculated 
per the method proposed by Greenwood3). 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. Subjects who have discontinued/terminated the study without an event will be censored at the 
date of study discontinuation/termination. Subjects ongoing and who are free from event at the time 
of database lock (for example at interim analyses) will be censored at the last available date.  
Unless otherwise specified, hypothesis testing will be carried out at the alpha = 0.050 level (two-sided) when 
comparing treatments. For all inferential analyses, p-value will be rounded to three decimal places. Statistical 
significance will be declared if the rounded p-value will be less than or equal to 0.050. For primary analysis 
only (section 7.1.2), p-values will be provided at 5th decimal place, in order to compare with efficacy and 
futility thresholds specified in section 4.5. 
Additional post-hoc analysis may be produced to further allow comparison between reparixin and control, 
according to the results obtained. Any unplanned analyses as well as deviations from the original statistical 
plan will be clearly documented in the Clinical Study Report. 
Derivation rules for efficacy and safety analyses are reported in Table 7 in section 9.  
All the data collected and derived in the study will be presented in subject data listings by centre. 
4.2 
Analysis sets 
4.2.1 Enrolled set 
The Enrolled set (ENR) will consist of all subjects with signed written informed consent and undergoing to 
study evaluations/procedures. 
4.2.2 Randomized set 
The Randomized set (RND) will consist of all subjects in the ENR set who are randomized to the study, 


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regardless of whether they receive the Investigational Medicinal Product (IMP) or not. 
4.2.3 Safety set 
The Safety set (SAF) will consist of all randomized subjects 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. 
4.2.4 Full Analysis set 
The Full Analysis Set (FAS) will consist of all randomized subjects who receive at least one dose of the IMP. 
FAS population will be analyzed according to ITT principle, i.e. by treatment allocation regardless happening 
of intercurrent events. The FAS population will be used for the primary analyses of the study and to present 
results on efficacy data. 
4.2.5 Per Protocol set 
The Per Protocol set (PP) will consist of all randomized subjects who receive at least one dose of the IMP 
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 Data Review Meeting 
(DRM) before the database lock and described in the DRM Report. 
4.3 
Usage of analysis sets 
The usage of the analysis sets (see previous section) for the creation of tables and figures are illustrated in 
Table 3  
Table 3: Usage of analysis set 
Analysis 
ENR 
RND 
FAS 
SAF 
PP 
Subject enrolment and disposition 
X 
 
 
 
 
Protocol violations 
 
X 
 
 
 
Study discontinuations 
 
X 
 
 
 
Patient status 
 
X 
 
X 
 
Demographics and baseline characteristics 
 
 
X 
 
 
Medical/Surgical History and Concomitant Diseases 
 
 
X 
 
 
Prior and concomitant medications 
 
 
X 
 
 
Other baseline characteristics 
 
 
X 
 
 
Treatment information 
 
 
 
X 
 
Exposure to IMP 
 
 
 
X 
 
Analysis of primary efficacy endpoints 
 
 
X 
 
 
Sensitivity analysis 
 
 
X 
 
X 
Analysis of secondary efficacy endpoints 
 
 
X 
 
 
Analysis of exploratory efficacy endpoints 
 
 
X 
 
 
Adverse events 
 
 
 
X 
 
Clinical laboratory evaluation 
 
 
 
X 
 
Vital signs 
 
 
 
X 
 
Pregnancy test over the study 
 
 
 
X 
 
 
 


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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 in the listing (according to Table 3).  
4.4 
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 Cox 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 (≤65yrs vs >65yrs);  
 
gender (Male, Female);  
 
clinical severity score at baseline (<median vs ≥median); 
 
dyspnea VAS scale at baseline (<median vs ≥median). 
Subgroup analysis will be performed if interaction tests are statistically significant at 15% nominal level. In 
this case all efficacy endpoints will be analyzed within as described in sections 7.1.2, 7.2.1 and 7.2.2. 
4.5 
Interim analyses 
Interim analyses are planned at specific time point during phase 2 and phase 3 for identification of early 
superiority of reparixin (efficacy) or for early stop 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 final analyses for phase 2 and phase 3 
are reported in Table 4 and Table 5, respectively.  
Table 4: O’Brien-Fleming spending functions boundaries for primary analysis in phase 2 
Analysis 
Sample Size 
Boundaries for primary endpoint 
Efficacy 
Futility 
Interim #1 
⁓27 (23 events) 
p-value <0.00258 
p-value ≥0.23349 
Final 
48 (46 events) 
p-value <0.02400 
p-value ≥0.02400 
Table 5: O’Brien-Fleming spending functions boundaries for primary analysis in phase 3 
Analysis 
Sample Size 
Boundaries for primary endpoint 
Efficacy 
Futility 
Interim #1 
⁓60 (60 events) 
p-value <0.00296 
p-value ≥0.26674 
Interim #2 
⁓81 (81 events) 
p-value <0.00892 
p-value ≥0.09841 
Final 
111 (109 events) 
p-value <0.02151 
p-value ≥0.02151 
 
The interim analyses will be conducted by DMC who will communicate to the Sponsor the result of the interim 
analysis and the consequent decision on the continuation of the study. 
The following scenarios may emerge from the interim analysis: 
 
the communication from the DMC to the Sponsor will be “Not enough evidence for demonstrate 
superiority of reparixin”. Since results are not considered enough to draw conclusions on primary 


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endpoints, the study enrolment will continue up to the next analysis step, and treatments and follow-
ups will proceed without modifications. 
 
the communication from the DMC to the Sponsor will be “Superiority of reparixin is shown”. In this 
case, the following action will be taken according to the study phase: 
o Phase 2:  
 
enrollment of subjects in phase 2 is stopped 
 
already enrolled subjects continue their residual treatment and follow-up as planned 
 
adaptation of phase 3, if needed; 
 
enrollment of subjects in phase 3 may start; 
o Phase 3:  
 
enrollment of subjects is stopped 
 
already enrolled subjects continue their residual treatment and follow-up as planned 
 
when last enrolled subject completes the follow-up and database is close, final 
analysis is performed and clinical study report will be released. 
 
the communication from the DMC to the Sponsor will be “Superiority of reparixin is excluded”. In 
this case, independently from the study phase, the enrollment (if still ongoing) will be stopped, and 
all subjects will discontinue the treatment and will be follow-up till the next scheduled visit where 
they will be notified of the termination of the study.  
4.6 
DMC Safety Integrity Review 
In addition to the above interim analyses, analysis of safety data will be performed for supporting Safety 
Integrity Review meetings during the trial.  
Safety Integrity Review meetings will be performed on ongoing basis (frequency will be defined by DMC 
members also considering feedbacks from REPAVID-19 Investigators) and at the end of the phase 2 in order 
to ensure that, in addition to superiority in efficacy, reparixin has an adequate safety profile. 
The following information will be analyzed for safety reason at each Safety Integrity Review: 
 
Major protocol changes, 
 
Information on subject screening,  
 
Study accrual by month and by institution, 
 
Eligibility violations, 
 
Demographics, 
 
Length of follow-up data available (pooled by treatment regimen), 
 
Analyses of adverse events, 
 
Analyses of vital signs, including basic summaries and longitudinal analyses, 
 
Analyses of lab values, including basic summaries and longitudinal analyses, 
 
Discontinuation of medications, 
 
Information on crossover subjects. 
 
 


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4.7 
Study adaptation 
REPAVID-19 trial’s design will allow for adaptations based on results from efficacy and safety data through 
the study. The spectrum of possible adaptations for the phase 3 study segment with the corresponding trigger 
rules is reported in Table 6.  
In case of decision of continuation of the study, results of the phase 2 portion of study will be submitted to the 
competent authority with the final version of the Phase 3 segment of the study (as an amendment to study 
protocol) prior to proceed. In that case, the SAP will be updated accordingly. 
Table 6: Adaptations and triggers 
Action 
Trigger 
Modification of the experimental treatment 
route of administration. 
Safety reasons based on DMC recommendation or 
Sponsor evaluation. 
Confirmation or modification of the primary, 
secondary and exploratory endpoints (at 
beginning of phase 3). 
DMC indication based on review of phase 2 results. 
Refining the sample size. 
In case of relevant discrepancies between sample size 
assumptions (section 3.2) and phase 2 results. 
Population enrichment. 
Based on safety and efficacy results (including subgroup 
analyses), it may be identified a subset of subjects most 
likely to benefit from treatment. 
Change the allocation ratio of subjects to 
trial arms. 
Safety and ethical reasons based on DMC 
recommendation or Sponsor evaluation. 
4.8 
Handling of missing and incomplete data 
The number of subjects 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. 
4.9 
Changes in the planned analysis 
No change has been implemented in this SAP. 
However, in order to clarify the analysis of the primary endpoint, a clarification of the meaning of 
“supplemental oxygen treatment” is provided: since all patients enrolled in this study had a respiratory distress, 
it is intended in all the analysis that the term “supplemental” refers to additional and/or increased oxygen 
requirement as compared to the baseline. In fact, all patients were expected to be already on oxygen treatment 
before the start of treatment. Details are provided in section 9.1. 
 
 


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4.10 Data Review Meeting 
A DRM will be held before final database lock.  
4.11 Software 
All statistical analyses and data processing will be performed using Statistical Analysis Systems (SAS®) 
Software (release 9.4 or later). 
5.  Evaluation of Demographic and Baseline Characteristics 
5.1 
Subject enrolment and disposition 
All presentations for 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 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. 
5.2 
Protocol violations 
All the protocol violations will be discussed case by case with the clinical team during the DRM and described 
in the DRM Report. 
Number of occurrences and of subjects with at least one major and minor protocol violations will be 
summarized for each treatment. 
5.3 
Study discontinuations 
The following information will be summarized by treatment and overall: 
 
Trial completers; 
 
Subjects who discontinued the IMP (and reasons); 
 
Subjects who discontinued the trial prematurely (and reasons); 
 
Subjects who discontinued the IMP but complete the study; 
 
Subjects who discontinued the IMP and discontinued the trial prematurely. 
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. 


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5.4 
Patient status 
The following information will be summarized by treatment at each time point: 
 
Subjects continuing treatment with oral reparixin/standard of care (yes, no, NA); 
 
Subjects switching to rescue medication (yes, no, NA); 
 
Subjects continuing treatment with IV reparixin (yes, no, NA), if applicable; 
5.5 
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: 
 
Demography 
 
Age (years) 
 
Gender (Male, Female) 
o If female, potential childbearing (yes, no) 
 
Race (White / Caucasian, Black or African American, Asian, Other) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown, Not Reported) 
 
Pregnancy test result (Positive or Negative), if appropriate 
5.6 
Medical/Surgical History and Concomitant Diseases 
A disease is considered as medical/surgical history if it is ended before screening visit. A disease is considered 
as concomitant disease if it is ongoing at screening visit. 
Medical history and concomitant diseases will be coded using 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. 
5.7 
Prior and concomitant medications 
Medications will be coded using World Health Organization Drug Dictionary (WHO DD). 
Prior medications are those which stop 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 any 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 9). The medication will be allocated to the first category allowed by the available data, according 
to the following order: 


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 
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 experiencing 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. 
5.8 
Other baseline characteristics 
The following information at baseline will be descriptively reported by means summary statistics: 
 
Clinical severity score (categorical) 
 
Dyspnea VAS scale (continuous) 
 
Respiratory parameters (continuous) 
o FiO2 (%) 
o Respiration rate (Breath/min) 
o PaO2 (mmHg) 
o SpO2 (%) 
o PaO2/FiO2 (Ratio) 
 
Acute Respiratory Distress Syndrome (ARDS) severity 
and their categorical evaluation, if applicable. 
 
Additional information 
o Did the subject experience any Adverse Events? (yes, no); 
o Has the subject been admitted to the ICU? (yes, no); 
o Was oxygen administered to the subject? (yes, no);  
o Has the subject been mechanically ventilated? (yes, no). 
6.  Evaluation of Treatment Compliance and Exposure 
6.1 
Treatment information 
Descriptive analyses of the following parameters will be presented at each available time point: 
 
For subjects treated with oral reparixin: 
o Total number of oral treatment days 
o Total n° oral tablets administered 
 
For subjects treated with standard of care: 
o Total number of oral treatment days 
 
For subjects treated with IV reparixin (if applicable): 
o Total number of IV treatment days 


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o Total n° IV Vials administered 
6.2 
Exposure to IMP 
The extent of exposure to IMP in days will be summarized with descriptive statistics by treatment group. The 
extent of exposure (days) will be calculated using the formula reported in Table 7. 
7.  Evaluation of Efficacy 
As described in section 0, possible modifications in the phase 3 study might be introduced as adaptation from 
phase 2. In this case, all the impacted below sections will be amended. 
7.1 
Analysis of primary efficacy endpoints 
7.1.1 Testing strategy and multiplicity adjustment 
7.1.1.1 Phase 2 
The following null hypothesis is defined: the freedom from composite endpoint (section 3.5.1) in reparixin is 
lower or equal than control: 
H0: TREPARIXIN ≤ TCONTROL 
H1: TREPARIXIN > TCONTROL 
where TREPARIXIN and TCONTROL are the freedoms from composite endpoint for reparixin and standard of care, 
respectively. The null hypothesis H0 will be rejected, and preliminary (to be confirmed in phase 3) superiority 
of reparixin shown if log-rank 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 4. 
7.1.1.2 Phase 3 
The following null hypothesis is defined: that the freedom from severe composite endpoint (section 3.5.1) in 
reparixin is lower or equal than control: 
H0: REPARIXIN ≤ CONTROL 
H1: REPARIXIN > CONTROL 
where REPARIXIN and CONTROL are the freedoms from severe composite endpoint for reparixin and standard 
of care, respectively. The null hypothesis will be rejected, and superiority of reparixin concluded if log-rank 
p-value will be lower than pre-specified threshold, depending at which analysis (first or second interim or 
final) the test is performed. Thresholds are calculated according to O’Brien-Fleming spending function 
boundaries and are reported in Table 5. 
Phase 3 null and alternative hypotheses will be tested only if superiority of reparixin is shown in phase 2. Null 
hypotheses of both phases must be rejected in order to claim superiority of reparixin over standard of care. 
Consequently, no multiplicity correction of type I error will be applied on primary analyses. 
7.1.2 Analysis details 
The composite endpoints for phase 2 and phase 3 (section 3.5.1) will be summarized along with their single 
component by a binomial response rate at each time point (only the first event will be considered). The 
Clopper-Pearson method will be used to estimate the two-sided 95% CIs. 
Primary analyses on time to composite endpoint(s) will be performed using the KM methodology and the one-


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sided log-rank test will be used to test for differences between treatment groups. See section 4.1 for more 
details on time-to-event analysis and representation. 
The primary endpoint of phase 2 will be assessed also in phase 3 as secondary analysis, and vice versa. 
7.1.3 Sensitivity analysis 
7.1.3.1 Phase 2 
Results of primary analysis will be assessed in sensitivity analyses as detailed below. 
 
The comparison between treatment and control will be performed by means of a Cox regression 
model, using age class, gender and clinical severity score at baseline as covariates, to assess the 
robustness of results on primary endpoint versus the presence of confounding factors. Additional 
covariates might be included after DRM in case relevant baseline imbalance will be identified between 
groups, despite randomization. The assumptions of proportionality will be investigated with a time-
dependent exploratory variable, which is defined as treatment*{log[time to event ]}. If the p-value 
from the Wald Chi-squared statistic for this variable is less than 5% there is evidence of a departure 
from the adjusted model assumptions. In case of non-proportional hazards, a Weibull model will be 
assumed as parametric form of the distribution of survival times. The treatment group will be included 
in the model as covariate.  
 
Time to event for each single component of the primary endpoint will be performed separately in 
order to adjust for the presence of possible competing risks. The following events: 
o first supplemental oxygen requirement,  
o first mechanical ventilation use,  
o first admission to ICU, and  
o first use of a rescue medication for any reason 
will be analyzed according to survival analysis methodology detailed in section 4.1 with the following 
modifications: 
o the common representation of survival curves using the Kaplan-Meier estimator will be 
replaced by the cumulative incidence function,  
o the presence of other competing event(s) is/are treated as censored. 
 
A modified composite endpoint of phase 2 will be analyzed adding “death” as fifth component. It will 
be analyzed according to section 7.1.2 to assess the robustness of results on primary endpoint versus 
the presence of censoring due to fatal events. 
Decision to proceed/not proceed to phase 3 will be based only on primary analysis results, despite 
inconsistencies with sensitivity analyses. Sensitivity results will be interpreted and discussed in the clinical 
study report and will be used to eventually adjust adaptations for the phase 3. 
7.1.3.2 Phase 3 
Results of primary analysis will be assessed in sensitivity analyses as detailed below. 
 
The comparison between treatment and control will be performed by means of a regression model, 
using the same method (Cox or Weibull model) and covariates identified during phase 2, to assess the 
robustness of results on primary endpoint versus the presence of confounding factors.  
 
Time to event for each single component of the severe primary endpoint will be performed separately 
in order to adjust for the presence of possible competing risks. The following events: 
o death,  
o first invasive mechanical ventilation use, and 
o first admission to ICU 


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will be analyzed according to survival analysis methodology detailed in section 4.1 with the following 
modifications: 
o the common representation of survival curves using the Kaplan-Meier estimator will be 
replaced by the cumulative incidence function,  
o the presence of other competing event(s) is/are treated as censored. 
 
The comparison between treatment and control will be performed in the PP population instead of FAS 
as described in section 7.1.2, to assess the robustness of trial results versus the adherence to protocol.  
7.2 
Analysis of secondary efficacy endpoints 
7.2.1 Descriptive Analysis 
Descriptive in nature analyses will be performed on all secondary endpoints (section 3.5.2) at each available 
time points by means of descriptive statistics (section 4.1). 
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 
might be provided. 
7.2.2 Comparison between treatments 
Along with the above summary statistics, comparisons between treatments will be performed as detailed in 
the next sub-sections. Parametric test (i.e. two-sample t-test for continuous variables, Chi-square test for 
categorical) will be adopted as first choice. In case the required assumptions are not met, the corresponding 
non-parametric counterpart will be used (i.e. the two-sample Mann–Whitney U test for continuous variables, 
and the Fisher’s Exact test for the categorical). Normality of continuous data is assessed by Kolmogorov-
Smirnov test.  
Comparison will be performed at each available time point, where applicable. Any exception will be declared. 
7.2.2.1 Composite endpoint of phase 2 using Oxygen Delivery System Classification 
The composite endpoints will be summarized along with their single component by a binomial response rate 
at each time point (only the first event will be considered). The Clopper-Pearson method will be used to 
estimate the two-sided 95% CIs. 
Time to composite endpoint(s) will be performed using the KM methodology and the one-sided log-rank test 
will be used to test for differences between treatment groups.  
7.2.2.2 Changes in clinical severity score 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of subjects with 
a clinical severity score improvement of at least two points compared to randomization or live discharge from 
the hospital will be calculated and compared.  
7.2.2.3 Dyspnea severity (Liker scale and VAS scale) 
The comparison of the Liker scale between the two study treatment arms will be performed by means of 
Wilcoxon signed-rank test, given its ordinal nature. 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of subjects with 


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any improvement (improved vs not-improved) will be calculated and compared.  
VAS scale comparison between treatments will be performed according to its continuous nature. 
7.2.2.4 Changes in body temperature 
Comparison between treatments in change from baseline of the body temperature will be performed according 
to the continuous nature of the variable. 
7.2.2.5 Incidence of supplemental oxygen treatment 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of subjects who 
worsened according to PaO2/FiO2 and to Oxygen Delivery System Classification based on oxygen support 
will be calculated and compared.  
At each time point the number and proportion of patients within each class (Severe, Moderate, or Mild for 
PaO2/FiO2; Invasive, High Flow, or Low Flow for the type of support) will be provided. 
Finally, summary of cumulative quantity (L) and cumulative duration (hours) of oxygen treatment will be 
performed at 7 days and subsequent time points considering the variable as continuous. 
7.2.2.6 Incidence and duration of mechanical ventilation use 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of subjects 
requiring mechanical ventilation will be calculated and compared.  
Comparison between treatments in cumulative duration (hours) of mechanical ventilation will be performed 
at 7 days and subsequent time points considering the variable as continuous. Analysis will be performed 
overall and stratified by Invasive/Non-invasive mechanical ventilation. 
7.2.2.7 Incidence of ICU admission need 
Number and proportion along with the 95% confidence interval (Clopper-Pearson’s formula) of subjects 
requiring ICU admission will be calculated and compared.  
Comparison between treatments in duration (days) of ICU stay will be performed considering the variable as 
continuous.  
7.2.2.8 Change from baseline in lung damage extension and lung exudation degree (assessed by 
Chest CT or Rx) 
The comparison of the clinical evaluation of lung damage extension and lung exudation between the two study 
treatment arms will be performed by means of Wilcoxon signed-rank test. 
7.2.2.9 Respiratory parameters 
Change from baseline of FiO2, Respiration rate, PaO2, SpO2 and PaO2/FiO2 will be compared between 
treatments considering the continuous nature of these variables. 
7.2.2.10 CRP and Hs-CRP 
CRP (mg/L) and Hs-CRP (mg/L) will be compared between treatments considering their continuous nature. 
7.3 
Analysis of exploratory efficacy endpoints 
Explorative endpoints (section 3.5.3) will be analyzed at each available time points by means of descriptive 
statistics. 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 Kolmogorov-Smirnov test), two-sample 
Mann–Whitney U test. 
In case of different units of measure considered for the same laboratory parameter, all values will be converted 


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into Standard International (SI) units (if applicable) or to the same unit. 
8.  Evaluation of Safety 
8.1 
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 8). The AE will be allocated to the first category allowed by 
the available data, according to the following order: 
 
TEAE; 
 
Pre-treatment AE. 
All AEs will be assigned to a PT and will be classified by primary SOC according to the MedDRA thesaurus. 
In addition, each AE will be graded according to severity definitions as “Mild”, “Moderate” or “Severe”. 
TEAEs will be reported on a per-subject basis, i.e. if a subject reported the same event repeatedly (i.e. events 
mapped to the PT) the event will be counted only once. 
For summaries, the drug-event relationship will be assessed as “None”, “Unlikely”, “Possible” “Probable” or 
“Highly probable”. 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 subjects 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, number of TEAEs, number of non-serious TEAEs, number of TESAEs, 
number of ADRs, number of serious ADRs, number of deaths, number of subjects who temporarily 
interrupted IMP due to a TEAE, number of subjects who permanently interrupted IMP due to a TEAE; 
 
Summary of TEAEs by primary SOC and PT; 
 
Summary of TEAEs by primary SOC, PT and Severity; 
 
Summary of Serious TEAEs by Primary SOC and PT; 
 
Summary of ADRs by Primary SOC and PT; 
 
Summary of ADRs by Primary SOC and PT and Severity; 
 
Summary of TEAEs leading to IMP temporary interruption by Primary SOC and PT; 
 
Summary of TEAEs leading to IMP permanently interruption by Primary SOC and PT; 
 
Summary of TEAEs leading to Death by Primary SOC and PT; 
 
Listing of all AEs by Subject; 
 
Listing of SAEs by Subject; 
 
Listing of ADR by Subject; 
 
Listing of Deaths. 
 
 


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8.2 
Clinical laboratory evaluation 
Analysis of clinical laboratories data will be performed by treatment for Hematology and Biochemistry tests. 
In case of different units of measure considered for the same laboratory parameter, all values will be converted 
into SI units (if applicable) or to the same unit. 
The following summaries will be provided: 
 
A summary table showing for all laboratory tests the values and changes from baseline to each 
subsequent time points; 
 
A summary table showing for all laboratory tests the frequency of subjects reporting laboratory values 
out of normal range (yes, no) at baseline and at subsequent time points. 
8.3 
Vital signs 
Summary statistics by treatment will be provided at each available time point: 
 
Weight (Kg), 
 
Height (cm) if applicable, 
 
Systolic Blood Pressure (mmHg), 
 
Diastolic Blood Pressure (mmHg),  
 
Heart Rate (bpm), 
 
Body temperature (°C), 
 
Respiration Rate (breath / min) 
8.4 
Pregnancy test over the study 
A summary table showing test results (Negative/Positive) over the study will be produced by treatment group, 
where applicable. 
 
 


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9.  Derivations and date conventions 
9.1 
Variable derivation 
Table 7: Variable derivation rules 
Parameter 
Derivation 
ARDS Severity 
classification based on 
PaO2/FiO2 
According to PaO2/FiO2 (RESPIRATORY PARAMETERS form) the 
classification is: 
 
if 200 ≤ PaO2/FiO2 < 300 mmHg then ARDS Severity=Mild 
 
if 100 ≤ PaO2/FiO2 < 200 mmHg then ARDS Severity=Moderate 
 
if PaO2/FiO2 < 100 mmHg then ARDS Severity=Severe 
Worsening based on 
PaO2/FiO2  
A patient with ARDS (PaO2/FiO2<300 mmHg) is considered “Worsened” 
in case of a decrease of PaO2/FiO2 of at least one third (-33,3%) from the 
baseline PaO2/FiO2 value. 
Oxygen Delivery System 
Classification based on 
type of oxygen support 
According to Type of oxygen support (RESPIRATORY PARAMETERS 
form) the classification is: 
 
If 
“Invasive 
Medicinal 
Ventilation” 
or 
“ECMO” 
then 
Class=Invasive 
 
Else if “High Flow Nasal Cannula” or “BIPAP or CPAP” then 
Class=High Flow 
 
Else if “Nasal Cannula” or “Mask” then Class=Low Flow 
Worsening based on 
Oxygen Delivery System 
Classification 
A patient is considered “Worsened” after baseline if he/she increase the 
level of severity within the oxygen delivery system classification (Invasive 
> High Flow > Low Flow). 
Last available date (for 
censoring time-to-event 
analysis) 
Last date will be considered as the most recent dates collect in: 
 
Last assessment, 
 
Start and stop dates of AEs 
Last date = max (date of last assessment, start AEs, Stop AEs) 


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Parameter 
Derivation 
Composite endpoint of 
phase 2 and Time to event 
(days) 
From ADDITIONAL INFORMATION form:  
 
if “Has the patient been admitted to the ICU?” = “Yes”, then 
component1 = “Yes” and date of event1 = Date of Visit 
 
if “Has the patient been admitted to the ICU?” = “No”, then 
component1 = “No”  
 
From PATIENT STATUS form:  
 
if “Is the subject eligible to switch to rescue medication?” = “Yes”, 
then component2 = “Yes” and date of event2 = Rescue treatment 
start date 
o If Rescue treatment start date is missing, then Date of Visit will 
be used 
 
if “Is the subject eligible to switch to rescue medication?” = “No”, 
then component2 = “No” 
 
From 
ADDITIONAL 
INFORMATION 
and 
MECHANICAL 
VENTILATION forms:  
 
If “Has the patient been mechanically ventilated?” = “Yes” and type 
= “Invasive mechanical ventilation”, then component3 = “Yes” and 
date of event3 = mechanical ventilation start date 
o If mechanical ventilation start date is missing, then Date of Visit 
will be used 
 
If “Has the patient been mechanically ventilated?” is not empty and 
type ≠ “Invasive mechanical ventilation”, then component3 = “No” 
 
From “Worsening based on PaO2/FiO2” (see above): 
 
if a patient is classified as “Worsened”, then component4 = “Yes” 
and date of event4 = Date of Visit 
 
if a patient is classified as not “Worsened” (excluding missing 
classification), then component4 = “No” 
 
The composite endpoint is equal to “Yes” if at least one post-baseline 
component (1-4) is equal to “Yes” and the date of event is the corresponding 
date of event. In case of more component equal to “Yes”, the first date will 
be used. 
Otherwise, if all component (1-4) are equal to “No” the composite endpoint 
will set as “No”. The date of event will be last date where is known that all 
components are equal to “No”.  
Time to composite endpoint (days) = Date of event - Date of randomization 


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Parameter 
Derivation 
Modified Composite 
endpoint of phase 2 and 
Time to event (days) 
[sensitivity analysis] 
From ADDITIONAL INFORMATION form:  
 
if “Has the patient been admitted to the ICU?” = “Yes”, then 
component1 = “Yes” and date of event1 = Date of Visit 
 
if “Has the patient been admitted to the ICU?” = “No”, then 
component1 = “No”  
 
From PATIENT STATUS form:  
 
if “Is the subject eligible to switch to rescue medication?” = “Yes”, 
then component2 = “Yes” and date of event2 = Rescue treatment 
start date 
o If Rescue treatment start date is missing, then Date of Visit will 
be used 
 
if “Is the subject eligible to switch to rescue medication?” = “No”, 
then component2 = “No” 
 
From 
ADDITIONAL 
INFORMATION 
and 
MECHANICAL 
VENTILATION forms:  
 
If “Has the patient been mechanically ventilated?” = “Yes” and type 
= “Invasive mechanical ventilation”, then component3 = “Yes” and 
date of event3 = mechanical ventilation start date 
o If mechanical ventilation start date is missing, then Date of Visit 
will be used 
 
If “Has the patient been mechanically ventilated?” is not empty and 
type ≠ “Invasive mechanical ventilation”, then component3 = “No” 
 
From “Worsening based on PaO2/FiO2” (see above): 
 
if a patient is classified as “Worsened”, then component4 = “Yes” 
and date of event4 = Date of Visit 
 
if a patient is classified as not “Worsened” (excluding missing 
classification), then component4 = “No” 
 
From DEATH REPORT form: 
 
If “Date of death” is not missing, then component5 = “Yes” and 
date of event5 = date of death 
 
Otherwise component5 = “No” 
 
The composite endpoint is equal to “Yes” if at least one post-baseline 
component (1-5) is equal to “Yes” and the date of event is the corresponding 
date of event. In case of more component equal to “Yes”, the first date will 
be used. 
Otherwise, if all component (1-4) are equal to “No” the composite endpoint 
will set as “No”. The date of event will be last date where is known that all 
components are equal to “No”.  
Time to composite endpoint (days) = Date of event - Date of randomization 


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Parameter 
Derivation 
Composite endpoint of 
phase 3 and time to event 
(days) 
From ADDITIONAL INFORMATION form:  
 
if “Has the patient been admitted to the ICU?” = “Yes”, then 
component1 = “Yes” and date of event1 = Date of Visit 
 
if “Has the patient been admitted to the ICU?” = “No”, then 
component1 = “No”  
 
From 
ADDITIONAL 
INFORMATION 
and 
MECHANICAL 
VENTILATION forms:  
 
If “Has the patient been mechanically ventilated?” = “Yes” and type 
= “Invasive mechanical ventilation”, then component3 = “Yes” and 
date of event3 = mechanical ventilation start date 
o If mechanical ventilation start date is missing, then Date of Visit 
will be used 
 
If “Has the patient been mechanically ventilated?” is not empty and 
type ≠ “Invasive mechanical ventilation”, then component3 = “No” 
 
From DEATH REPORT form: 
 
If “Date of death” is not missing, then component5 = “Yes” and 
date of event5 = date of death 
 
Otherwise component5 = “No” 
 
The composite endpoint is equal to “Yes” if at least one post-baseline 
component (1, 3 and 5) is equal to “Yes” and the date of event is the 
corresponding date of event. In case of more component equal to “Yes”, the 
first date will be used. 
Otherwise, if all component (1, 3) are equal to “No” the composite endpoint 
will set as “No”. The date of event will be last date where is known that all 
components are equal to “No”.  
Time to composite endpoint (days) = Date of event - Date of randomization 
 


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Parameter 
Derivation 
Composite endpoint of 
phase 2 and Time to event 
(days) using Oxygen 
Delivery System 
Classification 
From ADDITIONAL INFORMATION form:  
 
if “Has the patient been admitted to the ICU?” = “Yes”, then 
component1 = “Yes” and date of event1 = Date of Visit 
 
if “Has the patient been admitted to the ICU?” = “No”, then 
component1 = “No”  
 
From PATIENT STATUS form:  
 
if “Is the subject eligible to switch to rescue medication?” = “Yes”, 
then component2 = “Yes” and date of event2 = Rescue treatment 
start date 
o If Rescue treatment start date is missing, then Date of Visit will 
be used 
 
if “Is the subject eligible to switch to rescue medication?” = “No”, 
then component2 = “No” 
 
From 
ADDITIONAL 
INFORMATION 
and 
MECHANICAL 
VENTILATION forms:  
 
If “Has the patient been mechanically ventilated?” = “Yes” and type 
= “Invasive mechanical ventilation”, then component3 = “Yes” and 
date of event3 = mechanical ventilation start date 
o If mechanical ventilation start date is missing, then Date of Visit 
will be used 
 
If “Has the patient been mechanically ventilated?” is not empty and 
type ≠ “Invasive mechanical ventilation”, then component3 = “No” 
 
From “Worsening based on Oxygen Delivery System Classification” (see 
above): 
 
if a patient is classified as “Worsened”, then component4 = “Yes” 
and date of event4 = Date of Visit 
 
if a patient is classified as not “Worsened” (excluding missing 
classification), then component4 = “No” 
 
The composite endpoint is equal to “Yes” if at least one post-baseline 
component (1-4) is equal to “Yes” and the date of event is the corresponding 
date of event. In case of more component equal to “Yes”, the first date will 
be used. 
Otherwise, if all component (1-4) are equal to “No” the composite endpoint 
will set as “No”. The date of event will be last date where is known that all 
components are equal to “No”.  
Time to composite endpoint (days) = Date of event - Date of randomization 
Time from randomization 
to discontinuation (days) 
Time from randomization to discontinuation (days) =  
Date of study withdrawal – Date of randomization 
Extent of exposure (days) 
Extent of exposure (days) =  
Date of last drug administration - Date of first drug administration 


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Parameter 
Derivation 
Time to supplemental 
oxygen requirement (days) 
Time to supplemental oxygen requirement (days) =  
First Administration start date - Date of randomization 
Time to mechanical 
invasive ventilation use 
(days) 
Time to (invasive) mechanical ventilation use (days) =  
First (invasive) Mechanical Ventilation start date - Date of randomization 
Time to admission to ICU 
(days) 
Time to admission to ICU (days) = Admission date - Date of randomization 
Time to rescue medication 
(days) 
Time to rescue medication (days) = First rescue treatment start date - Date 
of randomization 
Overall survival (days) 
Overall survival (days) = Date of death - Date of randomization 
Subject with improvement 
based on Liker scale 
Improvement = any of these answers: 
 
1 = minimally better,  
 
2 = moderately better, and  
 
3 = markedly better 
Cumulative quantity (L) of 
oxygen treatment 
Cumulative quantity of oxygen treatment (L) = 
Sum of all Quantity (L) in CONCOMITANT OXYGEN TREATMENT 
form, from randomization to time point of interest. 
It is defined as supplemental oxygen requirement any increased used of 
oxygen compared to baseline. 
Cumulative duration 
(hours) of oxygen 
treatment 
Cumulative duration of oxygen treatment (hours) = 
Sum of duration of oxygen administration (hours) in CONCOMITANT 
OXYGEN TREATMENT form, from randomization to time point of 
interest. 
Duration of oxygen administration (hours) = 
Administration end date/time - Administration start date/time / 60 
Cumulative duration 
(hours) of mechanical 
ventilation 
Cumulative duration of mechanical ventilation (hours) = 
Sum of duration of mechanical ventilation (hours) in MECHANICAL 
VENTILATION form, from randomization to time point of interest. 
Duration of mechanical ventilation (hours) = 
End date/time - Start date/time / 60 
Duration (days) of ICU 
stay 
Duration of ICU stay (days) = Discharge date - Admission date 
Change from baseline 
For changes from baseline the baseline value will constitute the minuend 
and the later value the subtrahend.  
Conversion of Time 
Intervals  
 
If a time interval was calculated in minutes, hours or days and needs to be 
converted into months or years 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  
 


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9.2 
Partial date conventions 
Table 8: Algorithm for Treatment Emergence of Adverse Events 
START DATE 
STOP DATE 
ACTION 
Known 
Known, 
Partial or 
Missing 
If start date < IMP start date, then not TEAE 
If start date >= IMP start date, then TEAE 
 
 
 
Partial, but known 
components show that 
it cannot be on or after 
IMP start date 
Known, 
Partial or 
Missing 
Not TEAE 
 
 
 
Partial or Missing 
Known 
If stop date < IMP start date, then not TEAE 
If stop date >= IMP start date, then TEAE 
 
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 stop date < IMP start date, then not TEAE 
If stop date >= IMP start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 


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Table 9: Algorithm for Prior/Concomitant medications 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < date of informed consent, assign as prior  
If stop date >= date of informed consent and start date <= 
end of treatment, assign as concomitant  
If stop date >= date of informed consent and start date > 
end of treatment, assign as post study  
 
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 stop date < date of informed consent, assign as prior 
If stop date >= date of informed consent and start date <= 
end of treatment, assign as concomitant 
If stop date >= date of informed consent and start date > 
end of treatment, assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior 
medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown), then: 
If stop date < date of informed consent, assign as prior 
If stop date >= date of informed consent and start date <= 
end of treatment, assign as concomitant 
If stop date >= date of informed consent date and start 
date > end of treatment, assign as post treatment 
 
Partial 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown) and 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 stop date < date of informed consent, assign as prior 
If stop date >= date of informed consent and start date <= 
end of treatment, assign as concomitant 
If stop date >= date of informed consent and start date > 
end of treatment, assign as post treatment 


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START DATE 
STOP DATE 
ACTION 
 
Missing 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown), then: 
If stop date is missing could never be assumed a prior 
medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < date of informed consent, assign as prior 
If stop date >= date of informed consent, assign as 
concomitant 
Cannot be assigned as ‘post treatment’ 
 
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 stop date < date of informed consent, assign as prior 
If stop date >= date of informed consent, assign as 
concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 
 
 
 
 
 
 


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10.  
Tables, Figures and Listings 
10.1 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> 
o 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. 
10.2 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. 
10.3 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 


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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 “-”. 
10.4 Listing Conventions 
 
Listings will be sorted for presentation in order of subject number, treatment groups, and visit. 
 
Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates 
are represented on subject listings as dashes (--JUL2000). 
11.  
Reference 
1. 
Adaptive phase 2/3, randomized, controlled multicenter study on the efficacy and safety of Reparixin in the treatment of 
hospitalized patients with COVID-19 pneumonia, Version n. 1.5 April 23, 2020 
2. 
Case Report Form, Version 1.0 – 30 April 2020 
3. 
Kalbfleisch, J. D., and Prentice, R. L. (1980). The Statistical Analysis of Failure Time Data. New York: John Wiley & 
Sons.