Trial Outcomes & Findings for Study on Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients With Severe COVID-19 Pneumonia. (NCT NCT04878055)

Last Updated: 2024-06-13

Results Overview

The event variable is defined as "the proportion of patients alive and free of respiratory failure at Day 28". This means no need of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) or admission to intensive care unit (ICU) linked to worsening of respiratory parameters compared to baseline.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

287 participants

Primary outcome timeframe

At day 28

Results posted on

2024-06-13

Participant Flow

The eligible patient population consisted of hospitalized adult patients with reverse transcriptase polymerase chain reaction (rt-PCR)-confirmed severe COVID-19. Patients were considered to have severe disease in the presence of respiratory distress and requiring supplemental oxygen. No gender and/or ethnicity restrictions applied.

A total of 287 patients were enrolled and 279 of them were randomized to the assigned treatment group (8 patients were not randomized): 185 patients were randomized to receive Reparixin and 94 patients were randomized to receive placebo (N=279). Nine of these latter were randomized but not treated (3 Reparixin and 6 Placebo). Hence, the number of treated patients (starters) was 270 (182 in Reparixin and 88 in placebo).

Participant milestones

Participant milestones
Measure	Reparixin Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Overall Study STARTED	182	88
Overall Study FAS Population	182	88
Overall Study COMPLETED	147	70
Overall Study NOT COMPLETED	35	18

Reasons for withdrawal

Reasons for withdrawal
Measure	Reparixin Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Overall Study Patient transferred in another department	0	2
Overall Study Physician Decision	1	1
Overall Study Day 60 visit not performed by mistake	0	4
Overall Study Adverse Event	12	7
Overall Study Other	5	0
Overall Study Withdrawal by Subject	7	3
Overall Study Lost to Follow-up	10	1

Baseline Characteristics

Study on Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients With Severe COVID-19 Pneumonia.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Total n=270 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	112 Participants n=5 Participants	58 Participants n=7 Participants	170 Participants n=5 Participants
Age, Categorical >=65 years	70 Participants n=5 Participants	30 Participants n=7 Participants	100 Participants n=5 Participants
Age, Continuous	61.3 years STANDARD_DEVIATION 11.8 • n=5 Participants	60.0 years STANDARD_DEVIATION 12.0 • n=7 Participants	60.9 years STANDARD_DEVIATION 11 • n=5 Participants
Sex: Female, Male Female	50 Participants n=5 Participants	25 Participants n=7 Participants	75 Participants n=5 Participants
Sex: Female, Male Male	132 Participants n=5 Participants	63 Participants n=7 Participants	195 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	50 Participants n=5 Participants	22 Participants n=7 Participants	72 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	132 Participants n=5 Participants	66 Participants n=7 Participants	198 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Italy	182 participants n=5 Participants	88 participants n=7 Participants	270 participants n=5 Participants

PRIMARY outcome

Timeframe: At day 28

Population: The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Proportion of Patients Alive and Free of Respiratory Failure at Day 28	152 participants	71 participants

SECONDARY outcome

Timeframe: At day 60

Population: FAS population is used in this table. Discrepancies between the total number of patients in the FAS and patients actually analyzed in the logistic regression model are due to the presence of missing data for which no imputation methods are expected for this endpoint.

This key secondary efficacy endpoint of the study is defined as "the proportion of patients alive and free of respiratory failure at Day 60", i.e. with no need of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) or admission to intensive care unit (ICU) linked to worsening of respiratory parameters compared to baseline.

Outcome measures

Outcome measures
Measure	Reparixin n=159 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=78 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Proportion of Patients Alive and Free of Respiratory Failure at Day 60	141 participants	66 participants

SECONDARY outcome

Timeframe: Up to Day 28

This key secondary efficacy endpoint describes number and proportion along with the 95% CI (Clopper-Pearson's formula) of patients who died up to Day 28.

Outcome measures

Outcome measures
Measure	Reparixin n=168 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=81 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Mortality Rates up to Day 28	10 participants	7 participants

SECONDARY outcome

Timeframe: Until day 28

This is a key secondary efficacy endpoint. Admissions to Intensive Care Unit (ICU) had to be considered only in presence of significant worsening of respiratory status. This condition was objectively identified by means of a decrease of PaO2/FiO2 ratio of at least 40% from the baseline value or by a worsening of Investigator's Interpretation.

Outcome measures

Outcome measures
Measure	Reparixin n=171 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=83 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Incidence of ICU Admission Until Day 28	27 participants	18 participants

SECONDARY outcome

Timeframe: Until Day 28

Population: The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP.

This is a key secondary efficacy endpoint. The event "recovery" was considered as such, if the patient has scored category 1, 2 or 3 from the 7-point WHO Ordinal Scale of clinical improvement (WHO-OS), otherwise it will be considered free of event. Category 1: not hospitalized, with resumption of normal activities; 2: not hospitalized, but unable to resume normal activities; 3: hospitalized, not requiring supplemental oxygen; \[4: hospitalized, requiring supplemental oxygen; 5: hospitalized, requiring high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 6: hospitalized, requiring ECMO, invasive mechanical ventilation, or both; 7: death\]. The lower the category, the better the outcome.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Time to Recovery (Category 1 - 2 - 3 of the 7-point WHO Ordinal Scale of Clinical Improvement (WHO-OS)) Until Day 28	141 number of patients with event (recovery)	63 number of patients with event (recovery)

SECONDARY outcome

Timeframe: At Days 3, 7(±1),14(±2), 21(±2) and 90(±2) after randomization (randomization = day 1)

Population: The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP.

The event variable is defined as the proportion of patients alive and free of respiratory failure at fixed timepoints. This means no need of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) or admission to intensive care unit (ICU) linked to worsening of respiratory parameters compared to baseline. Admissions to ICU had to be considered only in presence of significant worsening of respiratory status. This condition was objectively identified by means of a decrease of PaO2/FiO2 ratio of at least 40% from the baseline value or by a worsening of Investigator's Interpretation.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Proportion of Patients Alive and Free of Respiratory Failure at Fixed Timepoints Day 3	179 participants	87 participants
Proportion of Patients Alive and Free of Respiratory Failure at Fixed Timepoints Day 7 (+/-1)	171 participants	79 participants
Proportion of Patients Alive and Free of Respiratory Failure at Fixed Timepoints Day 14 (+/-2)	160 participants	73 participants
Proportion of Patients Alive and Free of Respiratory Failure at Fixed Timepoints Day 21 (+/-2)	155 participants	71 participants
Proportion of Patients Alive and Free of Respiratory Failure at Fixed Timepoints Day 90	15 participants	5 participants

SECONDARY outcome

Timeframe: At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)

Population: The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of the IMP.

Changes from baseline in clinical severity score are analyzed based on the 7-point WHO-OS. The 7-point WHO Ordinal Scale of clinical improvement (WHO-OS), comprises the following categories: 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 ECMO, invasive mechanical ventilation, or both; 7: death.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints Day 3	-0.1 score on a scale Standard Deviation 0.4	0.0 score on a scale Standard Deviation 0.5
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints Day 7	-0.4 score on a scale Standard Deviation 1.0	-0.3 score on a scale Standard Deviation 0.9
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints Day 14	-1.7 score on a scale Standard Deviation 1.5	-1.5 score on a scale Standard Deviation 1.6
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints Day 21	-2.4 score on a scale Standard Deviation 1.5	-2.3 score on a scale Standard Deviation 1.6
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints EoT	-0.9 score on a scale Standard Deviation 1.0	-0.7 score on a scale Standard Deviation 1.1
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints Day 28	-2.8 score on a scale Standard Deviation 1.4	-2.6 score on a scale Standard Deviation 1.5
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints Hospital Discharge	-1.6 score on a scale Standard Deviation 0.9	-1.6 score on a scale Standard Deviation 0.8
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints Day 60	-3.4 score on a scale Standard Deviation 0.6	-3.2 score on a scale Standard Deviation 0.9
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints Day 90	-3.4 score on a scale Standard Deviation 0.6	-3.5 score on a scale Standard Deviation 0.6
Mean Changes From Baseline in Clinical Severity Score Based on the 7-point WHO-OS at Fixed Timepoints EOS	-3.0 score on a scale Standard Deviation 1.5	-2.6 score on a scale Standard Deviation 1.8

SECONDARY outcome

Timeframe: Day 1 (baseline), Days 3, 7, 14, 21, 28.

Population: The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of the IMP.

Clinical improvement 1 is defined as the decline of 1 category in the 7-point WHO-OS up to Date 28. The clinical improvement 1 up to Day 28 was analyzed as described for time to recovery: an event was considered as such, if patient declined of at least 1 category in the 7-point WHO-OS respect to the baseline, otherwise it was be considered free of event.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Number of Patients With Clinical Improvement 1 up to Day 28 (Decline of 1 Category in the 7-point WHO-OS) Day 28	152 number of patients with event	68 number of patients with event
Number of Patients With Clinical Improvement 1 up to Day 28 (Decline of 1 Category in the 7-point WHO-OS) Day 1	0 number of patients with event	0 number of patients with event
Number of Patients With Clinical Improvement 1 up to Day 28 (Decline of 1 Category in the 7-point WHO-OS) Day 3	19 number of patients with event	6 number of patients with event
Number of Patients With Clinical Improvement 1 up to Day 28 (Decline of 1 Category in the 7-point WHO-OS) Day 7	56 number of patients with event	22 number of patients with event
Number of Patients With Clinical Improvement 1 up to Day 28 (Decline of 1 Category in the 7-point WHO-OS) Day 14	123 number of patients with event	50 number of patients with event
Number of Patients With Clinical Improvement 1 up to Day 28 (Decline of 1 Category in the 7-point WHO-OS) Day 21	146 number of patients with event	66 number of patients with event

SECONDARY outcome

Timeframe: At day 28

Population: The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP.

Clinical improvement 1 up to Date 28 for this outcome is expressed as cumulative incidence function (CIF in %). CIF allows for estimation of the occurrence of an event while taking into account the following competing risks: death, reasons for discontinuation for Adverse events and patient transferred to another institution. Estimates are calculated using a nonparametric method. The null hypothesis is that the cumulative incidence functions are identical across treatment groups.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Percentage of Participants With Clinical Improvement 1 up to Day 28	87.2 % of participants Interval 81.2 to 91.4	81.1 % of participants Interval 70.6 to 88.2

SECONDARY outcome

Timeframe: Day 1 (baseline), Days 3, 7, 14, 21, 28

Population: The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of the IMP.

Clinical improvement 2 is defined as the decline of 2 categories in the 7-point WHO-OS) up to Date 28. Clinical improvement 2 up to Date 28 was analyzed as described for time to recovery. An event was considered as such, if patient declined of at least 2 categories in the 7-point WHO-OS respect to the baseline, otherwise it was considered free of event.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Number of Patients With Clinical Improvement 2 up to Day 28 (Decline of 2 Categories in the 7-point WHO-OS) Day 1	0 number of patients with event	0 number of patients with event
Number of Patients With Clinical Improvement 2 up to Day 28 (Decline of 2 Categories in the 7-point WHO-OS) Day 3	0 number of patients with event	0 number of patients with event
Number of Patients With Clinical Improvement 2 up to Day 28 (Decline of 2 Categories in the 7-point WHO-OS) Day 7	19 number of patients with event	6 number of patients with event
Number of Patients With Clinical Improvement 2 up to Day 28 (Decline of 2 Categories in the 7-point WHO-OS) Day 14	78 number of patients with event	35 number of patients with event
Number of Patients With Clinical Improvement 2 up to Day 28 (Decline of 2 Categories in the 7-point WHO-OS) Day 21	105 number of patients with event	50 number of patients with event
Number of Patients With Clinical Improvement 2 up to Day 28 (Decline of 2 Categories in the 7-point WHO-OS) Day 28	120 number of patients with event	56 number of patients with event

SECONDARY outcome

Timeframe: At Day 28

Population: FAS Full Analysis Set: set which consisted of all randomized subjects who received at least one dose of the IMP. But FAS patients with at least one major (i.e. error in IMP administration, I/E criteria violation) or minor protocol deviation (i.e. not respecting visit schedule) up to Day 28 couldn't be considered in the analysis.

Clinical improvement 2 up to Day 28 is defined as cumulative incidence function (CIF, in %). CIF allows for estimation of the occurrence of an event while taking into account the following competing risks: death, reasons for discontinuation for Adverse events and patient transferred to another institution. Estimates are calculated using a nonparametric method. The null hypothesis is that the cumulative incidence functions are identical across treatment groups.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Percentage of Participants With Clinical Improvement 2 up to Day 28	69.9 Percentage of patients Interval 62.3 to 76.2	67.7 Percentage of patients Interval 56.3 to 76.7

SECONDARY outcome

Timeframe: Day 1 (baseline), Days 3, 7, 14, 21, 28

Population: FAS Full Analysis Set: set which consisted of all randomized subjects who received at least one dose of the IMP.

Time to discharge from hospital up to Day 28 is analyzed as described for time to recovery.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Time to Discharge From Hospital up to Day 28 Day 1	0 number of patients with event	0 number of patients with event
Time to Discharge From Hospital up to Day 28 Day 3	2 number of patients with event	0 number of patients with event
Time to Discharge From Hospital up to Day 28 Day 7	19 number of patients with event	10 number of patients with event
Time to Discharge From Hospital up to Day 28 Day 14	100 number of patients with event	40 number of patients with event
Time to Discharge From Hospital up to Day 28 Day 21	127 number of patients with event	58 number of patients with event
Time to Discharge From Hospital up to Day 28 Day 28	143 number of patients with event	64 number of patients with event

SECONDARY outcome

Timeframe: At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)

Population: FAS Full Analysis Set: set which consisted of all randomized subjects who received at least one dose of the IMP.

Clinical status is analyzed based on the 7-point WHO-OS. The 7-point WHO Ordinal Scale of clinical improvement (WHO-OS), comprises the following categories: 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 ECMO, invasive mechanical ventilation, or both; 7: death. The higher the score, the worse the outcome.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 3 score 3	5 number of patients with event	1 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 14 score 4	29 number of patients with event	13 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 3 score 1	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 3 score 2	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 3 score 4	85 number of patients with event	40 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 3 score 5	81 number of patients with event	42 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 3 score 6	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 3 score 7	0 number of patients with event	1 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 7 score 1	7 number of patients with event	2 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 7 score 2	1 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 7 score 3	31 number of patients with event	16 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 7 score 4	66 number of patients with event	27 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 7 score 5	54 number of patients with event	30 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 7 score 6	6 number of patients with event	5 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 7 score 7	1 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 14 score 1	52 number of patients with event	24 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 14 score 2	10 number of patients with event	3 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 14 score 3	28 number of patients with event	12 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 14 score 5	17 number of patients with event	10 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 14 score 6	4 number of patients with event	4 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 14 score 7	2 number of patients with event	1 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 21 score 1	74 number of patients with event	36 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 21 score 2	8 number of patients with event	2 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 21 score 3	13 number of patients with event	5 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 21 score 4	14 number of patients with event	5 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 21 score 5	6 number of patients with event	5 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 21 score 6	5 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 21 score 7	1 number of patients with event	2 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points HD score 1	11 number of patients with event	6 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points HD score 2	2 number of patients with event	4 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points HD score 3	109 number of patients with event	48 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points HD score 4	10 number of patients with event	3 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points HD score 5	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points HD score 6	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points HD score 7	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 28 score 1	100 number of patients with event	40 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 28 score 2	8 number of patients with event	8 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 28 score 3	7 number of patients with event	1 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 28 score 4	8 number of patients with event	5 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 28 score 5	2 number of patients with event	2 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 28 score 6	4 number of patients with event	2 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points day 28 score 7	2 number of patients with event	1 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoT score 1	3 number of patients with event	2 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoT score 2	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoT score 3	92 number of patients with event	36 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoT score 4	36 number of patients with event	18 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoT score 5	25 number of patients with event	15 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoT score 6	7 number of patients with event	5 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoT score 7	1 number of patients with event	1 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 60 score 1	125 number of patients with event	56 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 60 score 2	9 number of patients with event	6 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 60 score 3	1 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 60 score 4	0 number of patients with event	1 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 60 score 5	1 number of patients with event	2 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 60 score 6	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 60 score 7	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 90 score 1	14 number of patients with event	4 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 90 score 2	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 90 score 3	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 90 score 4	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 90 score 5	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 90 score 6	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points Day 90 score 7	0 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoS score 1	132 number of patients with event	57 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoS score 2	7 number of patients with event	6 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoS score 3	1 number of patients with event	0 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoS score 4	2 number of patients with event	1 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoS score 5	3 number of patients with event	4 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoS score 6	1 number of patients with event	2 number of patients with event
Clinical Status Either in Hospital or at Home (7-point WHO-OS) at Fixed Time Points EoS score 7	8 number of patients with event	5 number of patients with event

SECONDARY outcome

Timeframe: At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)

Population: FAS Full Analysis Set: set which consisted of all randomized subjects who received at least one dose of the IMP.

The number of patients with Dyspnea severity Likert scale by score and treatment group is calculated for each time point. Likert scale: grading the current experience of breathing discomfort compared to baseline (randomization) status (from -3 to 3) where: "-1 = minimally worse; -2 = moderately worse; -3 = markedly worse; 0 = no change; 1 = minimally better; 2 = moderately better; 3 = markedly better" More negative the score, the worse the outcome.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 21 score 2	9 participants	7 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 21 score 3	35 participants	20 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 14 score -3	0 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 14 score -2	2 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 14 score -1	0 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 14 score 0	9 participants	1 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 14 score 1	6 participants	6 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 14 score 2	18 participants	7 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 14 score 3	41 participants	25 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 21 score -3	1 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 21 score -2	0 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 21 score -1	0 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 21 score 0	6 participants	3 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 21 score 1	9 participants	2 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints HD score -3	0 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints HD score -2	0 participants	1 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints HD score -1	0 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints HD score 0	2 participants	2 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints HD score 1	3 participants	1 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints HD score 2	5 participants	4 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints HD score 3	28 participants	19 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 28 score -3	0 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 28 score -2	0 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 28 score -1	0 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 28 score 0	9 participants	3 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 28 score 1	7 participants	3 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 28 score 2	9 participants	7 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 28 score 3	48 participants	20 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EoT score -3	3 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EoT score -2	1 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EoT score -1	0 participants	1 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EoT score 0	4 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EoT score 1	12 participants	7 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EoT score 2	17 participants	6 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EoT score 3	40 participants	24 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EOS score -3	0 participants	—
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EOS score -2	0 participants	—
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EOS score -1	0 participants	—
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EOS score 0	1 participants	—
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EOS score 1	1 participants	—
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EOS score 2	0 participants	—
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints EOS score 3	0 participants	—
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 3 score -3	1 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 3 score -2	1 participants	3 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 3 score -1	5 participants	1 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 3 score 0	22 participants	10 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 3 score 1	37 participants	18 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 3 score 2	26 participants	17 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 3 score 3	11 participants	3 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 7 score -3	1 participants	0 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 7 score -2	0 participants	1 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 7 score -1	0 participants	1 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 7 score 0	9 participants	6 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 7 score 1	19 participants	8 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 7 score 2	31 participants	13 participants
The Number of Patients With Different Dyspnea Severity Scores Using the Likert Scale at Fixed Timepoints day 7 score 3	36 participants	18 participants

SECONDARY outcome

Timeframe: At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)

Population: The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP.

Peripheral oxygen saturation (SpO2) monitoring by pulse oximetry is used to estimate the oxygen saturation of arterial blood (SaO2) and provides vital information about a patient's cardiorespiratory function.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2). Day 3	0.79 percentage of oxygenated hemoglobin Standard Deviation 2.88	0.36 percentage of oxygenated hemoglobin Standard Deviation 2.78
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2). Day 7	0.76 percentage of oxygenated hemoglobin Standard Deviation 2.89	0.49 percentage of oxygenated hemoglobin Standard Deviation 3.38
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2). Day 14	0.46 percentage of oxygenated hemoglobin Standard Deviation 2.93	-0.83 percentage of oxygenated hemoglobin Standard Deviation 3.99
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2). Day 21	-0.85 percentage of oxygenated hemoglobin Standard Deviation 4.92	-5.35 percentage of oxygenated hemoglobin Standard Deviation 11.82
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2). Day 28	-0.99 percentage of oxygenated hemoglobin Standard Deviation 6.15	-1.56 percentage of oxygenated hemoglobin Standard Deviation 6.78
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2). day 60 EoS	-2.70 percentage of oxygenated hemoglobin Standard Deviation 000	-2.00 percentage of oxygenated hemoglobin Standard Deviation 0.00
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2). EoT	0.24 percentage of oxygenated hemoglobin Standard Deviation 2.69	-0.68 percentage of oxygenated hemoglobin Standard Deviation 3.76
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2). HD	0.57 percentage of oxygenated hemoglobin Standard Deviation 2.60	0.28 percentage of oxygenated hemoglobin Standard Deviation 2.76
Change From Baseline to Fixed Timepoints in Pulse Oximetry by Measurement of Peripheral Arterial Oxygen Saturation (SpO2). EoS	-7.57 percentage of oxygenated hemoglobin Standard Deviation 11.12	-11.01 percentage of oxygenated hemoglobin Standard Deviation 18.49

SECONDARY outcome

Timeframe: At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)

Population: FAS Full Analysis Set: set which consisted of all randomized subjects who received at least one dose of the IMP.

The pain VAS is a unidimensional measure of pain intensity, used to record patients' pain progression, or compare pain severity between paints with similar conditions.The VAS scale is from 0 to 100. The number 0 means the worst breathing the patient has ever felt, and the number 100 means the best the patient has ever felt.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Change From Baseline in Dyspnea Severity (VAS Scale) at Fixed Timepoints day 3	6.4 score on a scale Standard Deviation 25.3	2.2 score on a scale Standard Deviation 20.6
Change From Baseline in Dyspnea Severity (VAS Scale) at Fixed Timepoints day 7 (+/-1)	8.3 score on a scale Standard Deviation 31.1	-0.2 score on a scale Standard Deviation 31.1
Change From Baseline in Dyspnea Severity (VAS Scale) at Fixed Timepoints day 14(+/-2)	12.7 score on a scale Standard Deviation 38.5	6.6 score on a scale Standard Deviation 37.4
Change From Baseline in Dyspnea Severity (VAS Scale) at Fixed Timepoints day 21 (+/-2)	16.0 score on a scale Standard Deviation 39.5	32.5 score on a scale Standard Deviation 14.3
Change From Baseline in Dyspnea Severity (VAS Scale) at Fixed Timepoints day 28 (+/-2)	31.1 score on a scale Standard Deviation 20.3	40.7 score on a scale Standard Deviation 8.3
Change From Baseline in Dyspnea Severity (VAS Scale) at Fixed Timepoints Hospital discharge	12.3 score on a scale Standard Deviation 44.0	10.2 score on a scale Standard Deviation 41.5
Change From Baseline in Dyspnea Severity (VAS Scale) at Fixed Timepoints EoT	17.1 score on a scale Standard Deviation 32.6	8.6 score on a scale Standard Deviation 37.8

SECONDARY outcome

Timeframe: From baseline up to day 28

This endpoint is expressed as: * The number and proportion along with the 95% CI (Clopper-Pearson's formula) of patients using supplemental oxygen treatment by treatment group; * The Cumulative duration of supplemental oxygen treatment in days analyzed by means of descriptive statistics by treatment. This latter is reported in the system.

Outcome measures

Outcome measures
Measure	Reparixin n=174 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=81 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Duration of Supplemental Oxygen Treatment up to Day 28	10.5 day Standard Deviation 7.3	10.8 day Standard Deviation 6.8

SECONDARY outcome

Timeframe: day 28 and Day 60

Population: FAS population is used in this table. Discrepancies between the total number of patients in the FAS and patients actually analyzed in the model at Day 28 are due to the presence of missing data for which no imputation methods are expected for this endpoint.

Invasive mechanical ventilation is defined as the delivery of positive pressure to the lungs via an endotracheal or tracheostomy tube. During mechanical ventilation, a predetermined mixture of air (ie, oxygen and other gases) is forced into the central airways and then flows into the alveoli.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Number of Patients Requiring Invasive Mechanical Ventilation Use, or ECMO up to Day 28 and up to Day 60 Up to day 28	9 Number of patient with event	10 Number of patient with event
Number of Patients Requiring Invasive Mechanical Ventilation Use, or ECMO up to Day 28 and up to Day 60 Up to day 60	9 Number of patient with event	10 Number of patient with event

SECONDARY outcome

Timeframe: From baseline up to day 60

Non-invasive ventilation (NIV) is the delivery of oxygen (ventilation support) via a face mask and therefore eliminating the need of an endotracheal airway. NIV achieves comparative physiological benefits to conventional mechanical ventilation by reducing the work of breathing and improving gas exchange.

Outcome measures

Outcome measures
Measure	Reparixin n=66 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=32 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Duration of Non-invasive Mechanical Ventilation up to Day 60	9.0 days Standard Deviation 7.9	10.1 days Standard Deviation 7.5

SECONDARY outcome

Timeframe: Up to day 60

Outcome measures

Outcome measures
Measure	Reparixin n=9 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=9 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Duration of Invasive Mechanical Ventilation, or ECMO up to Day 60	24.8 Days Standard Deviation 16.8	15.9 Days Standard Deviation 13.9

SECONDARY outcome

Timeframe: Up to day 60

Admission to intensive care unit or ICU is linked to worsening of respiratory parameters compared to baseline.

Outcome measures

Outcome measures
Measure	Reparixin n=12 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=12 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Duration of ICU Admission up to Day 60	17.9 Days Standard Deviation 10.1	11.4 Days Standard Deviation 6.7

SECONDARY outcome

Timeframe: At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)

Population: The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP.

PaO2-the oxygen pressure in arterial blood. The PaO2 reflects how well oxygen is able to move from the lungs to the blood. It is often altered by severe illnesses, with the PaO2 test results used to guide treatment.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2) Day 3	13.377 mmHg Standard Deviation 36.568	-5.274 mmHg Standard Deviation 41.103
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2) Day 7	3.147 mmHg Standard Deviation 33.541	12.777 mmHg Standard Deviation 81.367
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2) Day 14	4.002 mmHg Standard Deviation 54.235	-7.257 mmHg Standard Deviation 50.645
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2) Day 21	3.388 mmHg Standard Deviation 43.520	-14.014 mmHg Standard Deviation 54.603
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2) Day 28	-6.700 mmHg Standard Deviation 31.896	-52.171 mmHg Standard Deviation 76.278
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2) HD	-3.633 mmHg Standard Deviation 29.723	-8.869 mmHg Standard Deviation 37.953
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2) EOT	3.020 mmHg Standard Deviation 50.296	-7.189 mmHg Standard Deviation 55.550
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2) EOS	1.825 mmHg Standard Deviation 20.570	51.950 mmHg Standard Deviation 215.446
Change From Baseline to Fixed Timepoints of Partial Pressure of Oxygen (PaO2) Day 60	1 mmHg Standard Deviation 73.000	—

SECONDARY outcome

Timeframe: At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)

Population: The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP.

The PaO2/FiO2 ratio is used to determine the severity of lung injury in mechanically ventilated patients. A normal P/F Ratio is ≥ 400 and equivalent to a PaO2 ≥ 80 mmHg on room air. Low values of the PaO2/FIO2 ratio may be due to pathological conditions, primarily those of a respiratory nature (atelectasis, ARDS, acute pulmonary edema, pneumonia, etc.), as well as to alterations in hemodynamic status (cardiogenic shock, septic shock, etc.), or even both.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio. Day 3	30.329 PaO2/FiO2 Ratio Standard Deviation 81.291	0.398 PaO2/FiO2 Ratio Standard Deviation 87.607
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio. Day 7 ± 1	77.528 PaO2/FiO2 Ratio Standard Deviation 106.383	65.291 PaO2/FiO2 Ratio Standard Deviation 138.832
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio. Day 14 ± 2	127.111 PaO2/FiO2 Ratio Standard Deviation 135.063	111.220 PaO2/FiO2 Ratio Standard Deviation 171.013
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio. Day 21 ± 2	122.746 PaO2/FiO2 Ratio Standard Deviation 114.603	62.520 PaO2/FiO2 Ratio Standard Deviation 163.712
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio. EoT	140.575 PaO2/FiO2 Ratio Standard Deviation 139.619	106.332 PaO2/FiO2 Ratio Standard Deviation 144.608
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio. Day 28 ± 2	145.043 PaO2/FiO2 Ratio Standard Deviation 146.515	-22.125 PaO2/FiO2 Ratio Standard Deviation 123.435
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio. HD (hospital discharge)	228.999 PaO2/FiO2 Ratio Standard Deviation 119.337	210.765 PaO2/FiO2 Ratio Standard Deviation 112.418
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio. Day 60 ± 2	200.000 PaO2/FiO2 Ratio Standard Deviation 000	334.000 PaO2/FiO2 Ratio Standard Deviation 53.740
Change From Baseline to Fixed Timepoints in PaO2/FiO2 Ratio. EOS	-5.333 PaO2/FiO2 Ratio Standard Deviation 89.844	-30.714 PaO2/FiO2 Ratio Standard Deviation 191.669

SECONDARY outcome

Timeframe: At days 3, 7, 14, 21, 28 and End of Treatment (EoT, up to 30 days); days 60 and 90; at hospital discharge (HD, up to 2 months), and at the EoS (up to 3 months)

Population: FAS population is used in this table. Discrepancies between the total number of patients in the FAS and patients actually analyzed in the model are due to the presence of missing data for which no imputation methods are expected for this endpoint. Please note that the Number Analyzed per Row includes those participants who contributed data at the specified time point.

The high-sensitivity C-reactive protein (hs-CRP) test is more sensitive than the standard CRP test measuring slight increases in CRP levels even when within the normal range. Because of this greater sensitivity, the hs-CRP test can help determine your risk of cardiovascular disease (CVD).

Outcome measures

Outcome measures
Measure	Reparixin n=46 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=31 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Change From Baseline to Fixed Endpoints in High-Sensitivity C Reactive Protein (Hs-CRP) Day 3	-30.7 mg/L Standard Deviation 23.13	-21.67 mg/L Standard Deviation 53.33
Change From Baseline to Fixed Endpoints in High-Sensitivity C Reactive Protein (Hs-CRP) Day 7 ± 1	-25.90 mg/L Standard Deviation 95.74	-29.62 mg/L Standard Deviation 37.85
Change From Baseline to Fixed Endpoints in High-Sensitivity C Reactive Protein (Hs-CRP) Day 14 ± 2	-25.21 mg/L Standard Deviation 66.53	-45.24 mg/L Standard Deviation 62.83
Change From Baseline to Fixed Endpoints in High-Sensitivity C Reactive Protein (Hs-CRP) Day 21 ± 2	-27.50 mg/L Standard Deviation 72.23	-47.05 mg/L Standard Deviation 99.48
Change From Baseline to Fixed Endpoints in High-Sensitivity C Reactive Protein (Hs-CRP) EOT	37.50 mg/L Standard Deviation 151.54	-37.68 mg/L Standard Deviation 76.26
Change From Baseline to Fixed Endpoints in High-Sensitivity C Reactive Protein (Hs-CRP) Day 28 ± 2	-42.60 mg/L Standard Deviation 30.15	9.65 mg/L Standard Deviation 26.94
Change From Baseline to Fixed Endpoints in High-Sensitivity C Reactive Protein (Hs-CRP) HD (hospital discharge)	-54.46 mg/L Standard Deviation 63.12	-84.83 mg/L Standard Deviation 76.02

SECONDARY outcome

Timeframe: up to Days 60 and 90

Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. The death event variable is defined as the proportion of patients died up to Day 90.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Mortality Rates up to Days 60 and 90 Day 60	11 dead patients	7 dead patients
Mortality Rates up to Days 60 and 90 Day 90	11 dead patients	7 dead patients

SECONDARY outcome

Timeframe: at baseline, day 3, day 7, day 14, day 21, day 28, day 60, day 90

Population: The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP.

Freedom from (time to) death or respiratory failure (need of invasive mechanical ventilation or ECMO or admission to ICU linked to worsening of respiratory parameters compared to baseline) at baseline, day 3, day 7, day 14, day 21, day 28, day 60, day 90 was performed using the same Kaplan-Meier analysis and the one-sided log-rank test that were used to test for differences between groups.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Freedom From (Time to) Death or Respiratory Failure up to Day 90 day 60	103 participants with event	49 participants with event
Freedom From (Time to) Death or Respiratory Failure up to Day 90 day 1	0 participants with event	0 participants with event
Freedom From (Time to) Death or Respiratory Failure up to Day 90 day 3	2 participants with event	1 participants with event
Freedom From (Time to) Death or Respiratory Failure up to Day 90 day 7	4 participants with event	2 participants with event
Freedom From (Time to) Death or Respiratory Failure up to Day 90 day 14	9 participants with event	5 participants with event
Freedom From (Time to) Death or Respiratory Failure up to Day 90 day 21	11 participants with event	5 participants with event
Freedom From (Time to) Death or Respiratory Failure up to Day 90 day 28	16 participants with event	6 participants with event
Freedom From (Time to) Death or Respiratory Failure up to Day 90 day 90	154 participants with event	72 participants with event

SECONDARY outcome

Timeframe: Throughout the study, till Day 90 (= end of the follow-up period).

Population: The Safety set (SAF) consisted of all randomized subjects who received at least one dose of the IMP. The SAF population was analyzed according to the actual treatment received and was used to present results on safety data.

AE= An adverse event is any untoward or unfavorable medical occurrence in a human. subject, including any abnormal sign (for example, abnormal physical exam or. laboratory finding), symptom, or disease, temporally associated with the subject's. serious AE=a SAE iA serious adverse event (SAE) in human drug trials is defined as any untoward medical occurrence that at any dose results in death Is life-threatening Requires inpatient hospitalization or causes prolongation of existing hospitalization Results in persistent or significant disability/incapacity May have caused a congenital anomaly/birth defect Requires intervention to prevent permanent impairment or damage. The term "life-threatening" in the definition of "serious" refers to an event in which 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. Do note that starting from this point the safety endpoint is analysed.

Outcome measures

Outcome measures
Measure	Reparixin n=182 Participants Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo n=88 Participants Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Number of Subjects Who Exhibited at Least 1 TEAE, at Least 1 Severe TEAE, at Least 1 Serious TEAE, at Least 1 Non-serious TEAE, at Least 1 ADR, at Least 1 Serious ADR, at Least 1 TEAE Leading to Discontinuation of IMP, Etc. Number of Subjects with at least one TEAE	83 number of subjects	48 number of subjects
Number of Subjects Who Exhibited at Least 1 TEAE, at Least 1 Severe TEAE, at Least 1 Serious TEAE, at Least 1 Non-serious TEAE, at Least 1 ADR, at Least 1 Serious ADR, at Least 1 TEAE Leading to Discontinuation of IMP, Etc. Number of Subjects with at least one serious TEAE	20 number of subjects	13 number of subjects
Number of Subjects Who Exhibited at Least 1 TEAE, at Least 1 Severe TEAE, at Least 1 Serious TEAE, at Least 1 Non-serious TEAE, at Least 1 ADR, at Least 1 Serious ADR, at Least 1 TEAE Leading to Discontinuation of IMP, Etc. Number of Subjects with at least one severe TEAE	16 number of subjects	12 number of subjects
Number of Subjects Who Exhibited at Least 1 TEAE, at Least 1 Severe TEAE, at Least 1 Serious TEAE, at Least 1 Non-serious TEAE, at Least 1 ADR, at Least 1 Serious ADR, at Least 1 TEAE Leading to Discontinuation of IMP, Etc. N. sub with at least 1TEAE leading to quit IMP	19 number of subjects	11 number of subjects
Number of Subjects Who Exhibited at Least 1 TEAE, at Least 1 Severe TEAE, at Least 1 Serious TEAE, at Least 1 Non-serious TEAE, at Least 1 ADR, at Least 1 Serious ADR, at Least 1 TEAE Leading to Discontinuation of IMP, Etc. Number of subjects with at least 1TEAE leading to quit the study	1 number of subjects	0 number of subjects
Number of Subjects Who Exhibited at Least 1 TEAE, at Least 1 Severe TEAE, at Least 1 Serious TEAE, at Least 1 Non-serious TEAE, at Least 1 ADR, at Least 1 Serious ADR, at Least 1 TEAE Leading to Discontinuation of IMP, Etc. Number of Subjects with TEAEs leading to death	10 number of subjects	7 number of subjects

Adverse Events

Reparixin SAF

Serious events: 20 serious events

Other events: 75 other events

Deaths: 11 deaths

Placebo SAF

Serious events: 13 serious events

Other events: 42 other events

Deaths: 7 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Development & Operations

Dompé Farmaceutici SpA

Phone: +39 02 583831

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Reparixin SAF n=182 participants at risk Reparixin oral tablets, 1200 mg three times daily (TID) (2 tablets 600 mg each, TID) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care Reparixin: 2 tablets of Reparixin (600 mg each), for the total of three daily administrations (6 tablets daily). Please note that patients randomized to Reparixin were 185, but the ones receiving at least one dose of IMP were 182. Three patients, hence, in this group were excluded from the primary FAS analysis of efficacy and from the safety analysis.	Placebo SAF n=88 participants at risk Placebo, 2 tablets TID (identical to Reparixin tablets) for up to 21 days or until decision of discharge from the hospital, on top of standard supportive care. For each administration, two tablets of Reparixin (600 mg each) or placebo were taken, for the total of three daily administrations (6 tablets daily). It was advisable to take the tablets with a glass of water to facilitate swallowing. Please note that patients randomized to placebo were 94, but the ones receiving it were 88. Six patients in this group, hence, were excluded from the primary FAS analysis of efficacy and from the safety analysis.
Vascular disorders Circulatory collapse	0.55% 1/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	1.1% 1/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Vascular disorders Thrombosis	0.00% 0/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	1.1% 1/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Respiratory, thoracic and mediastinal disorders Respiratory failure	6.0% 11/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	8.0% 7/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.55% 1/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	1.1% 1/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	2.3% 2/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.55% 1/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	0.00% 0/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
General disorders Multiple organ dysfunction syndrome	0.00% 0/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	1.1% 1/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Psychiatric disorders Psychotic disorder	0.55% 1/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	0.00% 0/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Gastrointestinal disorders Diarrhoea	0.55% 1/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	0.00% 0/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Renal and urinary disorders Hydronephrosis	0.55% 1/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	0.00% 0/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Infections and infestations Sepsis	1.1% 2/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	1.1% 1/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Infections and infestations Clostridium difficile infection	1.1% 2/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	0.00% 0/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Infections and infestations Pneumonia bacterial	0.55% 1/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	1.1% 1/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Infections and infestations Bacterial infection	0.00% 0/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	1.1% 1/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.
Infections and infestations Bacterial sepsis	0.55% 1/182 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.	0.00% 0/88 • From Baseline up to day 90 of the trial (=the end of the follow-up period). In the system AEs are reported for the overall period.