Reparixin in COVID-19 Pneumonia - Efficacy and Safety

• Sponsor: Dompé Farmaceutici S.p.A (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04794803
• Collaborator: (none)
• Enrollment: 56
• Locations: 4
• Arms: 2
• Actual Duration (Months): 9
• Patients Per Site: 14
• Patients Per Site Per Month: 1.6

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Severe Pneumonia	Drug: Reparixin; Drug: Standard of care	Phase 2/Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Study on the Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients With COVID-19 Pneumonia
• Actual Study Start Date: May 5, 2020
• Actual Primary Completion Date: Nov 27, 2020
• Actual Study Completion Date: Feb 2, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Reparixin Reparixin oral tablets 1200 mg TID for 7 days	Drug: Reparixin; 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.; Other Names: Repertaxin L-lysine salt
Active Comparator: Standard of care Standard of care	Drug: Standard of care; Standard of care; Other Names: Control

Outcome Measures

Primary Outcome Measures

1. Phase 2 - Percentage of Participants With Composite Endpoint of Clinical Events [Up to Day 1]

   Composite event is defined as the onset of at least one of the following events: supplemental oxygen requirement based on a worsening of PaO2/FiO2 ratio, invasive mechanical ventilation use, admission to Intensive Care Unit (ICU), use of a rescue medication for any reason. Please note that in the measure type "number" actually is a "rate" of patients. Rate is referred to a binomial response rate while the 95% CIs are estimated by using the Clopper-Pearson's method

Secondary Outcome Measures

1. Phase 2 - Percentage of Patients With Improvement in Clinical Severity Score (as Recommended by WHO for COVID Studies) of at Least Two Points [At day 1, day 2, week 1, day 21(end of treatment, EOT), EOS (end of study, i.e. 7±3 days after EOT)]

   Changes in clinical severity score are 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 came first. The seven-category ordinal scale consisted 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, non-invasive mechanical ventilation, or both; 6) hospitalized, requiring Extracorporeal Membrane Oxygenation (ECMO), invasive mechanical ventilation, or both; and 7) death. The higher the score, the worse the outcome. A subject is considered "improved" with a clinical severity score improvement of at least two points compared to randomization or live discharge from the hospital. n are the subjects improved at each time point vs baseline.

2. Phase 2 - Percentage of Improved Subjects in Dyspnea Severity, Assessed by Liker Scale [Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)]

   The severity of dyspnea can be measured through the Liker scale. 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 higher the score, the better the outcome. N is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n is the number of subjects improved at each time point in comparison with the randomization.

3. Phase 2 - Change From Baseline in Dyspnea Severity, Assessed by VAS Scale [Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)]

   The severity of dyspnea is measured also through the VAS scale. 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. N is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n is the number of subjects improved at each time point in comparison with the randomization.

4. Changes From Baseline in Body Temperature to Any Post-baseline Timepoints [Baseline, Day 1, Day 2, Week 1, EOT and EOS]

   Variations in the mean body temperature from baseline to any post-baseline timepoint were assessed. n is the number of subjects for which the evaluation of the body temperature at each time point is available.

5. Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to PaO2/FiO2 [At day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

   Cumulative quantity of oxygen treatment (L) = Sum of all Quantity (L) in CONCOMITANT OXYGEN TREATMENT form, from randomization to time point of interest. According to PaO2/FiO2, the classification is 'mild' if 200 <= PaO2/FiO2 < 300 mmHg, 'moderate' if 100 <= PaO2/FiO2 < 200 mmHg, 'severe' if PaO2/FiO2 < 100 mmHg. 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. NOTE that: N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio at each time point is available. While n is the number of subjects worsened at each time point in comparison with the randomization, expressed in percentage.

6. Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to Oxygen Delivery System Classification [day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

   Duration of oxygen administration (hours) = Administration end date/time - Administration start date/time / 60. N is the number of subjects for which the evaluation of the Oxygen Delivery System Classification at each time point is available. n is the number of subjects worsened at each time point, expressed in percentage, in comparison with the randomization. According to Oxygen Delivery System, the classification is 'invasive' if there is Invasive Medicinal Ventilation or ECMO, else 'high flow' if there is High Flow Nasal Cannula or BIPAP or CPAP, else 'low flow' if there is Nasal Cannula or Mask then Class=Low Flow Classification. A patient is considered 'Worsened' after baseline if there is an increase in the level of severity within the oxygen delivery system classification (Invasive > High Flow > Low Flow).

7. Phase 2 - Oxygen Cumulative Duration During the Study [Week 1, EOT, EOS]

   This outcome assesses the oxygen cumulative duration during the study. N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio or Oxygen Delivery System Classification at each time point is available. n is the number of subjects worsened at each time point in comparison with the randomization.

8. Phase 2 - Oxygen Cumulative Quantity During the Study [Week 1, EOT and EOS]

   In this endpoint is assessed the oxygen cumulative quantity needed at each single timepoint. N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio or Oxygen Delivery System Classification at each time point is available. n is the number of subjects worsened at each time point in comparison with the randomization.

9. Phase 2 - Percentage of Subjects Requiring Mechanical Ventilation Use, Overall [Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

   Percentage along with the 95% confidence interval (Clopper-Pearson's formula) of subjects requiring mechanical ventilation are calculated and compared. N is the number of subjects for which the evaluation of the use of mechanical ventilation is available. n is the number, expressed in percentage, of subjects requiring mechanical ventilation, overall.

10. Phase 2 - Cumulative Duration of Mechanical Ventilation Use, Overall [Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

    Cumulative duration of mechanical ventilation (in 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. n is the number of subjects for which the evaluation of the use of mechanical ventilation is available

11. Phase 2 - Percentage of Subjects With Intensive Care Unit (ICU) Admission Need [Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

    Percentage, along with the 95% confidence interval (Clopper-Pearson's formula), of subjects requiring ICU admission are calculated and compared.N is the number of subjects for which the evaluation of the ICU admission need is available.

12. Phase 2 - Cumulative ICU Stay [Day 1, Day 2, Week 1, EOT, EOS]

    Cumulative ICU stay was assessed at different timepoints and measured in days

13. Phase 2 - Lung Damage Extension by Severity and by Timepoint [Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

    Lung damage extensions is assessed by Chest CT or Rx. This damage can be as follows: "none", "trace", "mild", "moderate", or "severe". N is the number of subjects for which the evaluation of the lung damage extension at each time point is available.

14. Phase 2 - Lung Exudation by Severity and by Timepoint [Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

    Lung exudation is assessed by Chest CT or Rx. This can be as follows: "none", "trace", "mild", "moderate", or "severe". N is the number of subjects for which the evaluation of the lung damage extension at each time point is available.

15. Phase 2 - Change From Baseline in Partial Arterial Oxygen Pressure (PaO2) [Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

    PaO2 measures the pressure of oxygen dissolved in the blood and how well oxygen is able to move from the airspace of the lungs into the blood. Normally, PaO2 is between 75 and 100 mmHg (at sea level). Lower levels indicate an unsufficient amount of oxygen flowing from the alveoli to the blood. Please note that a significant proportion of patients in both groups did not have post-baseline assessments of PaO2.

16. Phase 2 - Change From Baseline in Oxygen Saturation (SpO2) [Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

    SpO2 measures the amount of oxygen-carrying hemoglobin in the blood relative to the amount of hemoglobin not carrying oxygen. Acceptable normal ranges for patients without pulmonary pathology are from 95 to 99 percent.

17. Phase 2 - Partial Arterial Oxygen Pressure (PaO2) to Fraction of Inspiration O2 (FiO2) Ratio [PaO2/FiO2 Ratio] [Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

    PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage) also known as the Horowitz index, the Carrico index, and (most conveniently) the P/F ratio at sea level, the normal PaO2/FiO2 ratio is ~ 400-500 mmHg (~55-65 kPa).

18. Phase 2 - Change From Baseline in Reactive Protein (CRP) [Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)]

    For a standard CRP test, a normal reading is less than 10 milligram per liter (mg/L). Levels between 10 mg/L and 100 mg/L are moderately elevated and are usually due to more significant inflammation from an infectious or non-infectious cause. Inflammatory status is documented by C-reactive protein (CRP) ≥ 100mg/L.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Phase 2 Inclusion Criteria:

1. Age 18 to 90.

2. Confirmed COVID-19 diagnosis

3. At least one of the following: # Respiratory distress, RR ≥ 30 breaths/min without oxygen; # 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.

Exclusion Criteria:

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina de São Paulo	São Paulo		Brazil	05403-900
2	Ospedale San Paolo	Milan	Lombardy	Italy	20100
3	Ospedale San Raffaele	Milan	Lombardy	Italy	20100
4	Ospedale di Varese	Varese	Lombardy	Italy

Sponsors and Collaborators

• Dompé Farmaceutici S.p.A

Investigators

• Principal Investigator: Lorenzo Piemonti, MD PhD, Ospedale San Raffaele
• Principal Investigator: Alberto Zangrillo, MD PhD, Ospedale San Raffaele

Study Documents (Full-Text)

• Study Protocol - Apr 23, 2020
• Statistical Analysis Plan - Nov 29, 2020

More Information

Publications

None provided.

• Responsible Party: Dompé Farmaceutici S.p.A
• ClinicalTrials.gov Identifier: NCT04794803
• Other Study ID Numbers: REPAVID-19; 2020-001645-40
• First Posted: Mar 12, 2021
• Last Update Posted: May 24, 2022
• Last Verified: May 1, 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Dompé Farmaceutici S.p.A: COVID-19
• Additional relevant MeSH terms: COVID-19; Pneumonia

Study Results

Participant Flow

Recruitment Details	A total of 56 patients were screened and all of them were randomized to the assigned treatment group: 37 patients were randomised to receive Reparixin and 19 patients were randomised to receive standard of care.

Arm/Group Title	Reparixin	Standard of Care
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Period Title: Overall Study
STARTED	37	19
FAS Population	36	19
Safety Set	36	19
Per Protocol Set	17	11
COMPLETED	27	11
NOT COMPLETED	10	8

Baseline Characteristics

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)	Total
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care	Total of all reporting groups
Overall Participants	36	19	55
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	22 61.1%	11 57.9%	33 60%
>=65 years	14 38.9%	8 42.1%	22 40%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.6 (13.5)	63.6 (14.2)	61.6 (13.7)
Sex: Female, Male (Count of Participants)
Female	10 27.8%	3 15.8%	13 23.6%
Male	26 72.2%	16 84.2%	42 76.4%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	1 2.8%	0 0%	1 1.8%
Hispanic or Latino	3 8.3%	2 10.5%	5 9.1%
Not Hispanic Or Latino	18 50%	8 42.1%	26 47.3%
Not reported	3 8.3%	1 5.3%	4 7.3%
Unknown	11 30.6%	8 42.1%	19 34.5%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	32 88.9%	16 84.2%	48 87.3%
Black Or African American	1 2.8%	1 5.3%	2 3.6%
Brown	3 8.3%	1 5.3%	4 7.3%
Other Ethnic Group	0 0%	1 5.3%	1 1.8%
Region of Enrollment (participants) [Number]
Brazil	2 5.6%	2 10.5%	4 7.3%
Italy	34 94.4%	17 89.5%	51 92.7%

Outcome Measures

1. Primary Outcome

Title	Phase 2 - Percentage of Participants With Composite Endpoint of Clinical Events
Description	Composite event is defined as the onset of at least one of the following events: supplemental oxygen requirement based on a worsening of PaO2/FiO2 ratio, invasive mechanical ventilation use, admission to Intensive Care Unit (ICU), use of a rescue medication for any reason. Please note that in the measure type "number" actually is a "rate" of patients. Rate is referred to a binomial response rate while the 95% CIs are estimated by using the Clopper-Pearson's method
Time Frame	Up to Day 1

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data.

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Composite event	16.7 46.4%	42.1 221.6%
Supplemental oxygen requirement based on PaO2/FiO2	13.9 38.6%	26.3 138.4%
Invasive Mechanical ventilation	2.8 7.8%	5.3 27.9%
Admission to ICU	2.8 7.8%	0.0 0%
Use of a rescue medication for any reason	0.0 0%	26.3 138.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.02164
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Sensitivity analysis of time to event for each single component of the primary endpoint: Supplemental oxygen requirement based on PaO2/FiO2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.20043
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Sensitivity analysis of time to event for each single component of the primary endpoint: time to first invasive mechanical ventilation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.30215
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Sensitivity analysis of time to event for each single component of the primary endpoint: time to first admission to ICU
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.56370
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Sensitivity analysis of time to event for each single component of the primary endpoint: time to first use of a rescue medication for any reason
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.00132
	Comments
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Phase 2 - Percentage of Patients With Improvement in Clinical Severity Score (as Recommended by WHO for COVID Studies) of at Least Two Points
Description	Changes in clinical severity score are 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 came first. The seven-category ordinal scale consisted 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, non-invasive mechanical ventilation, or both; 6) hospitalized, requiring Extracorporeal Membrane Oxygenation (ECMO), invasive mechanical ventilation, or both; and 7) death. The higher the score, the worse the outcome. A subject is considered "improved" with a clinical severity score improvement of at least two points compared to randomization or live discharge from the hospital. n are the subjects improved at each time point vs baseline.
Time Frame	At day 1, day 2, week 1, day 21(end of treatment, EOT), EOS (end of study, i.e. 7±3 days after EOT)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Day 1	0.0	0.0
Day 2	0.0	0.0
Week 1	23.5	17.6
EOT	26.5	26.3
EOS	61.5	55.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	comparison at week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.731
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Phase 2 - Percentage of Improved Subjects in Dyspnea Severity, Assessed by Liker Scale
Description	The severity of dyspnea can be measured through the Liker scale. 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 higher the score, the better the outcome. N is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n is the number of subjects improved at each time point in comparison with the randomization.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Baseline	0 0%	1 5.3%
Day 1	7 19.4%	2 10.5%
Day 2	12 33.3%	2 10.5%
Week 1	23 63.9%	6 31.6%
EOT	20 55.6%	6 31.6%
EOS	16 44.4%	3 15.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.353
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.401
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At Day 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.066
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.102
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.314
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Phase 2 - Change From Baseline in Dyspnea Severity, Assessed by VAS Scale
Description	The severity of dyspnea is measured also through the VAS scale. 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. N is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n is the number of subjects improved at each time point in comparison with the randomization.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of the IMP. Please note that N (36 for Reparixin and 19 for SoC) is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n - hereunder reported (28 for Reparixin and 19 for SoC) - is the number of subjects improved at each time point in comparison with the randomization.

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Baseline	56.9 (37.3)	4.0 (5.5)
to Day 1	4.3 (8.5)	20.0 (40.0)
to Day 2	32.3 (40.3)	44.8 (51.7)
Week 1	29.0 (34.0)	86.0 (5.3)
EOT	33.0 (41.8)	89.7 (0.6)
EOS	22.5 (31.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.050
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0227
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Changes From Baseline in Body Temperature to Any Post-baseline Timepoints
Description	Variations in the mean body temperature from baseline to any post-baseline timepoint were assessed. n is the number of subjects for which the evaluation of the body temperature at each time point is available.
Time Frame	Baseline, Day 1, Day 2, Week 1, EOT and EOS

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Baseline	36.4 (0.5)	36.5 (0.5)
to Day 1	-0.2 (0.5)	0.2 (0.9)
to Day 2	-0.1 (0.7)	-0.1 (0.6)
to Week 1	-0.1 (0.6)	-0.2 (0.6)
to EOT	-0.2 (0.6)	-0.4 (0.6)
to EOS	-0.1 (0.5)	-0.5 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.122
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At Day 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.985
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.857
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.436
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.350
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to PaO2/FiO2
Description	Cumulative quantity of oxygen treatment (L) = Sum of all Quantity (L) in CONCOMITANT OXYGEN TREATMENT form, from randomization to time point of interest. According to PaO2/FiO2, the classification is 'mild' if 200 <= PaO2/FiO2 < 300 mmHg, 'moderate' if 100 <= PaO2/FiO2 < 200 mmHg, 'severe' if PaO2/FiO2 < 100 mmHg. 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. NOTE that: N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio at each time point is available. While n is the number of subjects worsened at each time point in comparison with the randomization, expressed in percentage.
Time Frame	At day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Day 1 - subjects worsened (%)	7.4	14.3
Day 2 - subjects worsened (%)	12.9	20.0
Week 1 - subjects worsened (%)	0.0	21.4
EOT - subjects worsened (%)	0.0	8.3
EOS - subjects worsened (%)	0.0	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
Statistical Test of Hypothesis	p-Value	0.596
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
Statistical Test of Hypothesis	p-Value	0.667
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
Statistical Test of Hypothesis	p-Value	0.037
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
Statistical Test of Hypothesis	p-Value	0.293
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments

7. Secondary Outcome

Title	Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to Oxygen Delivery System Classification
Description	Duration of oxygen administration (hours) = Administration end date/time - Administration start date/time / 60. N is the number of subjects for which the evaluation of the Oxygen Delivery System Classification at each time point is available. n is the number of subjects worsened at each time point, expressed in percentage, in comparison with the randomization. According to Oxygen Delivery System, the classification is 'invasive' if there is Invasive Medicinal Ventilation or ECMO, else 'high flow' if there is High Flow Nasal Cannula or BIPAP or CPAP, else 'low flow' if there is Nasal Cannula or Mask then Class=Low Flow Classification. A patient is considered 'Worsened' after baseline if there is an increase in the level of severity within the oxygen delivery system classification (Invasive > High Flow > Low Flow).
Time Frame	day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Day 1 - subjects worsened	5.6	0.0
Day 2 - subjects worsened	5.6	5.3
Week 1 - subjects worsened	2.9	17.6
EOT - subjects worsened	2.9	15.8
EOS - subjects worsened	3.6	8.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.539
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening and
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.102
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.119
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.515
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Phase 2 - Oxygen Cumulative Duration During the Study
Description	This outcome assesses the oxygen cumulative duration during the study. N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio or Oxygen Delivery System Classification at each time point is available. n is the number of subjects worsened at each time point in comparison with the randomization.
Time Frame	Week 1, EOT, EOS

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
week 1	141.93 (55.68)	130.22 (80.89)
EOT	151.55 (75.53)	134.00 (86.21)
EOS	195.26 (198.62)	155.71 (135.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.366
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative duration.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.489
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative duration.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.486
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative duration.
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Phase 2 - Oxygen Cumulative Quantity During the Study
Description	In this endpoint is assessed the oxygen cumulative quantity needed at each single timepoint. N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio or Oxygen Delivery System Classification at each time point is available. n is the number of subjects worsened at each time point in comparison with the randomization.
Time Frame	Week 1, EOT and EOS

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Week 1	24.99 (22.22)	29.20 (29.51)
EOT	25.64 (22.16)	29.73 (31.53)
EOS	26.54 (22.31)	33.38 (31.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.790
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative quantity
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.961
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative quantity
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.619
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative quantity
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Phase 2 - Percentage of Subjects Requiring Mechanical Ventilation Use, Overall
Description	Percentage along with the 95% confidence interval (Clopper-Pearson's formula) of subjects requiring mechanical ventilation are calculated and compared. N is the number of subjects for which the evaluation of the use of mechanical ventilation is available. n is the number, expressed in percentage, of subjects requiring mechanical ventilation, overall.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Baseline - subjects requiring	11.1	10.5
Day1 - subjects requiring	11.1	10.5
Day 2 - subjects requiring	11.4	16.7
Week 1- subjects requiring	8.8	11.8
EOT - subjects requiring	8.6	5.3
EOS -subjects requiring	0.0	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS)
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.678
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments

11. Secondary Outcome

Title	Phase 2 - Cumulative Duration of Mechanical Ventilation Use, Overall
Description	Cumulative duration of mechanical ventilation (in 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. n is the number of subjects for which the evaluation of the use of mechanical ventilation is available
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Week 1	162.54 (58.92)	142.42 (44.89)
EOT	149.99 (53.23)	146.86 (43.80)
EOS	179.51 (78.30)	154.86 (56.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.696
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative duration
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	p-values are referred to a-sided Wilcoxon test for cumulative duration
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.596
	Comments	p-values are referred to a-sided Wilcoxon test for cumulative duration
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	Phase 2 - Percentage of Subjects With Intensive Care Unit (ICU) Admission Need
Description	Percentage, along with the 95% confidence interval (Clopper-Pearson's formula), of subjects requiring ICU admission are calculated and compared.N is the number of subjects for which the evaluation of the ICU admission need is available.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Baseline - subjects admitted to ICU	2.8	5.3
Day 1 - subjects admitted to ICU	2.8	5.3
Day 2 - subjects admitted to ICU	5.7	5.6
Week 1 - subjects admitted to ICU	2.9	0.0
EOT - subjects admitted to ICU	2.9	0.0
EOS - subjects admitted to ICU	0.0	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments

13. Secondary Outcome

Title	Phase 2 - Cumulative ICU Stay
Description	Cumulative ICU stay was assessed at different timepoints and measured in days
Time Frame	Day 1, Day 2, Week 1, EOT, EOS

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Day 1 - cumulative ICU stay	1.0	1.0
Day 2 - cumulative ICU stay	2.0	2.0
Week 1 - cumulative ICU stay	7.0	3.0
EOT - cumulative ICU stay	6.0	3.0
EOS - cumulative ICU stay	50.0	3.0

14. Secondary Outcome

Title	Phase 2 - Lung Damage Extension by Severity and by Timepoint
Description	Lung damage extensions is assessed by Chest CT or Rx. This damage can be as follows: "none", "trace", "mild", "moderate", or "severe". N is the number of subjects for which the evaluation of the lung damage extension at each time point is available.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of the IMP. Please note that N, hereunder reported, is the number of subjects for which the evaluation of the lung damage extension or lung damage exudation degree at each time point is available (very low at Day 1 and EOS time points in the "Reparixin" Arm and at the Day 1, 2, and Week 1 time points in the "Standard of Care" Arm).

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
baseline - none	0 0%	0 0%
baseline - trace	1 2.8%	2 10.5%
baseline - mild	9 25%	3 15.8%
baseline - moderate	23 63.9%	11 57.9%
baseline - severe	3 8.3%	3 15.8%
Day 1 - none	0 0%	0 0%
Day 1 - trace	0 0%	0 0%
Day 1 - mild	0 0%	1 5.3%
Day 1 - moderate	1 2.8%	0 0%
Day 1 - severe	0 0%	0 0%
Day 2 - none	0 0%	0 0%
Day 2 - trace	0 0%	0 0%
Day 2 - mild	0 0%	1 5.3%
Day 2 - moderate	0 0%	0 0%
Day 2 - severe	1 2.8%	0 0%
week 1 - none	0 0%	0 0%
week 1- trace	1 2.8%	0 0%
week 1 - mild	6 16.7%	2 10.5%
week 1 - moderate	4 11.1%	0 0%
week 1 - severe	1 2.8%	2 10.5%
EOT - none	1 2.8%	0 0%
EOT - trace	3 8.3%	0 0%
EOT - mild	8 22.2%	2 10.5%
EOT - moderate	3 8.3%	0 0%
EOT - severe	1 2.8%	2 10.5%
EOS - none	0 0%	0 0%
EOS - trace	0 0%	0 0%
EOS - mild	1 2.8%	1 5.3%
EOS - moderate	1 2.8%	1 5.3%
EOS - severe	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.760
	Comments	p-values are referred to a two-sided Wilcoxon test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.394
	Comments	p-values are referred to a two-sided Wilcoxon test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.141
	Comments	p-values are referred to a two-sided Wilcoxon test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	p-values are referred to a two-sided Wilcoxon test
	Method	Wilcoxon (Mann-Whitney)
	Comments

15. Secondary Outcome

Title	Phase 2 - Lung Exudation by Severity and by Timepoint
Description	Lung exudation is assessed by Chest CT or Rx. This can be as follows: "none", "trace", "mild", "moderate", or "severe". N is the number of subjects for which the evaluation of the lung damage extension at each time point is available.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
baseline - none	32 88.9%	18 94.7%
baseline - trace	0 0%	0 0%
baseline - mild	1 2.8%	0 0%
baseline - moderate	3 8.3%	1 5.3%
baseline - severe	0 0%	0 0%
Day 1 - none	0 0%	0 0%
Day 1 - trace	0 0%	0 0%
Day 1 - mild	0 0%	0 0%
Day 1 - moderate	1 2.8%	1 5.3%
Day 1 - severe	0 0%	0 0%
Day 2 - none	0 0%	0 0%
Day 2 - trace	0 0%	0 0%
Day 2 - mild	0 0%	1 5.3%
Day 2 - moderate	0 0%	0 0%
Day 2 - severe	1 2.8%	0 0%
week 1 - none	12 33.3%	3 15.8%
week 1- trace	0 0%	0 0%
week 1 - mild	0 0%	0 0%
week 1 - moderate	0 0%	0 0%
week 1 - severe	12 33.3%	1 5.3%
EOT - none	15 41.7%	3 15.8%
EOT - trace	0 0%	0 0%
EOT - mild	1 2.8%	0 0%
EOT - moderate	0 0%	4 21.1%
EOT - severe	0 0%	0 0%
EOS - none	2 5.6%	2 10.5%
EOS - trace	0 0%	0 0%
EOS - mild	0 0%	0 0%
EOS - moderate	0 0%	0 0%
EOS - severe	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.500
	Comments	p-values are referred to a two-sided Wilcoxon test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.112
	Comments	p-values are referred to a two-sided Wilcoxon test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.277
	Comments	p-values are referred to a two-sided Wilcoxon test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	p-values are referred to a two-sided Wilcoxon test.
	Method	Wilcoxon (Mann-Whitney)
	Comments

16. Secondary Outcome

Title	Phase 2 - Change From Baseline in Partial Arterial Oxygen Pressure (PaO2)
Description	PaO2 measures the pressure of oxygen dissolved in the blood and how well oxygen is able to move from the airspace of the lungs into the blood. Normally, PaO2 is between 75 and 100 mmHg (at sea level). Lower levels indicate an unsufficient amount of oxygen flowing from the alveoli to the blood. Please note that a significant proportion of patients in both groups did not have post-baseline assessments of PaO2.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of the IMP. Please note that N, hereunder reported, is the number of subjects for which the evaluation of the PaO2 at each time point is available (very low at Day 1 and EOS time points in the "Reparixin" Arm and at the Day 1, 2, and Week 1 time points in the "Standard of Care" Arm).

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Baseline	121.69 (47.15)	68.64 (9.23)
to Day 1	-19.61 (50.09)	14.20 (25.76)
to Day 2	12.62 (60.20)	-4.68 (14.03)
to week 1	11.76 (25.26)	-1.13 (54.80)
to EOT	8.01 (36.08)	-18.70
to EOS	-35.76 (47.84)	1.80

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2027
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4469
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2466
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1752
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

17. Secondary Outcome

Title	Phase 2 - Change From Baseline in Oxygen Saturation (SpO2)
Description	SpO2 measures the amount of oxygen-carrying hemoglobin in the blood relative to the amount of hemoglobin not carrying oxygen. Acceptable normal ranges for patients without pulmonary pathology are from 95 to 99 percent.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Baseline	95.79 (3.17)	94.97 (2.60)
to Day 1	0.17 (2.20)	-0.41 (3.57)
to Day 2	0.38 (2.88)	-0.63 (3.86)
to week 1	1.18 (3.34)	0.73 (3.71)
to EOT	0.88 (3.57)	1.19 (3.89)
to EOS	0.47 (3.17)	-4.00 (1.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6441
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3529
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3581
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1666
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0851
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

18. Secondary Outcome

Title	Phase 2 - Partial Arterial Oxygen Pressure (PaO2) to Fraction of Inspiration O2 (FiO2) Ratio [PaO2/FiO2 Ratio]
Description	PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage) also known as the Horowitz index, the Carrico index, and (most conveniently) the P/F ratio at sea level, the normal PaO2/FiO2 ratio is ~ 400-500 mmHg (~55-65 kPa).
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
Baseline	186.82 (64.86)	196.91 (58.49)
To day 1	21.58 (65.81)	6.08 (125.00)
To day 2	48.29 (154.49)	-8.53 (71.74)
To week 1	160.80 (137.83)	54.28 (138.36)
To EOT	171.27 (149.56)	74.65 (113.55)
To EOS	199.26 (85.45)	84.87 (67.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3359
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3136
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0441
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0965
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0519
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments

19. Secondary Outcome

Title	Phase 2 - Change From Baseline in Reactive Protein (CRP)
Description	For a standard CRP test, a normal reading is less than 10 milligram per liter (mg/L). Levels between 10 mg/L and 100 mg/L are moderately elevated and are usually due to more significant inflammation from an infectious or non-infectious cause. Inflammatory status is documented by C-reactive protein (CRP) ≥ 100mg/L.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events. The FAS population was used for the primary analyses of the study and to present results on efficacy data;

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: 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.	Standard of care Standard of care: Standard of care
Measure Participants	36	19
baseline	57.04 (41.44)	58.87 (57.25)
to day 1	-0.14 (73.28)	38.46 (117.19)
to day 2	-29.24 (37.66)	-2.15 (52.37)
to week 1	-39.09 (56.56)	0.52 (80.24)
to EOT	-40.88 (50.27)	-25.28 (87.16)
to EOS	-49.43 (57.65)	-45.20 (78.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.470
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.425
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.600
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS vs baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.717
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Throughout the study, till day 21
Adverse Event Reporting Description	The Safety set (SAF), which consisted of all randomized subjects who received at least one dose of the investigational medicinal product (IMP).
Arm/Group Title	Reparixin (SAF)		Standard of Care (SAF)
Arm/Group Description	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.		Standard of care, which is defined as any drug currently used to treat the COVID-19 pneumonia.
All Cause Mortality
	Reparixin (SAF)		Standard of Care (SAF)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/36 (2.8%)		3/19 (15.8%)
Serious Adverse Events
	Reparixin (SAF)		Standard of Care (SAF)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/36 (2.8%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/36 (2.8%)	1	1/19 (5.3%)	1
Other (Not Including Serious) Adverse Events
	Reparixin (SAF)		Standard of Care (SAF)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/36 (2.8%)		1/19 (5.3%)
Gastrointestinal disorders
Diarrhoea	1/36 (2.8%)	1	1/19 (5.3%)	1
Injury, poisoning and procedural complications
Post procedural discomfort	0/36 (0%)	0	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/36 (2.8%)	1	1/19 (5.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.