Reparixin in COVID-19 Pneumonia - Efficacy and Safety

• ClinicalTrials.gov Identifier: NCT04794803
• Recruitment Status: Terminated
• First Posted: March 12, 2021
• Results First Posted: March 17, 2022
• Last Update Posted: May 24, 2022
• Sponsor: Dompé Farmaceutici S.p.A
• Information provided by (Responsible Party): Dompé Farmaceutici S.p.A

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Severe Pneumonia
• Interventions: Drug: Reparixin; Drug: Standard of care
• Enrollment: 56

Participant Flow

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

Arm/Group Title	Reparixin	Standard of Care
Arm/Group Description	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Period Title: Overall Study
Started	37	19
FAS Population	36	19
Safety Set	36	19
Per Protocol Set	17	11
Completed	27	11
Not Completed	10	8
Reason Not Completed
Death	1	3
Lost to Follow-up	2	2
Withdrawal by Subject	1	0
Physician Decision	1	1
Patient transferred to another centre for oxygen rehabilitation	4	1
Refused to continue the treatment	1	0
Patient admitted to ICU	0	1

Baseline Characteristics

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)	Total
Arm/Group Description		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care	Total of all reporting groups
Overall Number of Baseline Participants		36	19	55
Baseline Analysis Population Description		The Full Analysis Set (FAS), which consisted of all randomized subjects who received at least one dose of the IMP. The FAS population was analyzed according to intention to treat (ITT) principle, i.e. by treatment allocation regardless the occurrence of intercurrent events.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	36 participants	19 participants	55 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	22 61.1%	11 57.9%	33 60.0%
	>=65 years	14 38.9%	8 42.1%	22 40.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	36 participants	19 participants	55 participants
		60.6 (13.5)	63.6 (14.2)	61.6 (13.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	36 participants	19 participants	55 participants
	Female	10 27.8%	3 15.8%	13 23.6%
	Male	26 72.2%	16 84.2%	42 76.4%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	36 participants	19 participants	55 participants
Black or African American		1 2.8%	0 0.0%	1 1.8%
Hispanic or Latino		3 8.3%	2 10.5%	5 9.1%
Not Hispanic Or Latino		18 50.0%	8 42.1%	26 47.3%
Not reported		3 8.3%	1 5.3%	4 7.3%
Unknown		11 30.6%	8 42.1%	19 34.5%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	36 participants	19 participants	55 participants
White/Caucasian		32 88.9%	16 84.2%	48 87.3%
Black Or African American		1 2.8%	1 5.3%	2 3.6%
Brown		3 8.3%	1 5.3%	4 7.3%
Other Ethnic Group		0 0.0%	1 5.3%	1 1.8%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	36 participants	19 participants	55 participants
Brazil		2	2	4
Italy		34	17	51

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:	Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed	36	19
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Composite event	16.7; (6.4 to 32.8)	42.1; (20.3 to 66.5)
Supplemental oxygen requirement based on PaO2/FiO2	13.9; (4.7 to 29.5)	26.3; (9.1 to 51.2)
Invasive Mechanical ventilation	2.8; (0.1 to 14.5)	5.3; (0.1 to 26.0)
Admission to ICU	2.8; (0.1 to 14.5)	0.0; (0.0 to 17.6)
Use of a rescue medication for any reason	0.0; (0.0 to 9.7)	26.3; (9.1 to 51.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.02164
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Sensitivity analysis of time to event for each single component of the primary endpoint: Supplemental oxygen requirement based on PaO2/FiO2
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.20043
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Sensitivity analysis of time to event for each single component of the primary endpoint: time to first invasive mechanical ventilation
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.30215
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Sensitivity analysis of time to event for each single component of the primary endpoint: time to first admission to ICU
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.56370
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Sensitivity analysis of time to event for each single component of the primary endpoint: time to first use of a rescue medication for any reason
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.00132
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

2. Secondary Outcome

Title	Phase 2 - Percentage of Patients With Improvement in Clinical Severity Score (as Recommended by WHO for COVID Studies) of at Least Two Points
Description	Changes in clinical severity score are defined as the time to clinical improvement of two points from the time of randomization on a seven-category ordinal scale or live discharge from the hospital, whichever came first. The seven-category ordinal scale consisted of the following: 1) not hospitalized, with resumption of normal activities; 2) not hospitalized, but unable to resume normal activities; 3) hospitalized, not requiring supplemental oxygen; 4) hospitalized, requiring supplemental oxygen; 5) hospitalized, requiring high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 6) hospitalized, requiring Extracorporeal Membrane Oxygenation (ECMO), invasive mechanical ventilation, or both; and 7) death. The higher the score, the worse the outcome. A subject is considered "improved" with a clinical severity score improvement of at least two points compared to randomization or live discharge from the hospital. n are the subjects improved at each time point vs baseline.
Time Frame	At day 1, day 2, week 1, day 21(end of treatment, EOT), EOS (end of study, i.e. 7±3 days after EOT)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of patients
Day 1	Number Analyzed	35 participants	19 participants
		0.0; (0.0 to 10.0)	0.0; (0.0 to 17.6)
Day 2	Number Analyzed	35 participants	18 participants
		0.0; (0.0 to 10.0)	0.0; (0.0 to 18.5)
Week 1	Number Analyzed	34 participants	17 participants
		23.5; (10.7 to 41.2)	17.6; (3.8 to 43.4)
EOT	Number Analyzed	34 participants	19 participants
		26.5; (12.9 to 44.4)	26.3; (9.1 to 51.2)
EOS	Number Analyzed	26 participants	9 participants
		61.5; (40.6 to 79.8)	55.6; (21.2 to 86.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	comparison at week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.731
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

3. Secondary Outcome

Title	Phase 2 - Percentage of Improved Subjects in Dyspnea Severity, Assessed by Liker Scale
Description	The severity of dyspnea can be measured through the Liker scale. The Liker scale is used as follows: the patient grades his current breathing compared to when he first started the drug (from -3 to 3). "0" = no change, "1" =minimally better, "2" =moderately better, "3" =markedly better, "-1" =minimally worse, "-2" =moderately worse, "-3" =markedly worse. The higher the score, the better the outcome. N is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n is the number of subjects improved at each time point in comparison with the randomization.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Measure Type: Count of Participants; Unit of Measure: Participants
Baseline	Number Analyzed	11 participants	6 participants
		0 0.0%	1 16.7%
Day 1	Number Analyzed	16 participants	9 participants
		7 43.8%	2 22.2%
Day 2	Number Analyzed	16 participants	7 participants
		12 75.0%	2 28.6%
Week 1	Number Analyzed	25 participants	9 participants
		23 92.0%	6 66.7%
EOT	Number Analyzed	23 participants	9 participants
		20 87.0%	6 66.7%
EOS	Number Analyzed	18 participants	3 participants
		16 88.9%	3 100.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.353
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At Day 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.401
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At Day 2
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.066
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.102
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.314
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

4. Secondary Outcome

Title	Phase 2 - Change From Baseline in Dyspnea Severity, Assessed by VAS Scale
Description	The severity of dyspnea is measured also through the VAS scale. The VAS scale is used as follows: the patient draws a horizontal line on an axial graph (from 0 to 100) to show the degree of how he feels about breathing. The number "0" equals the worst breathing the patient has ever felt and the number "100" equals the best he has ever felt. N is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n is the number of subjects improved at each time point in comparison with the randomization.
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)

Outcome Measure Data

Analysis Population Description

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

Please note that N (36 for Reparixin and 19 for SoC) is the number of subjects for which the evaluation of the dyspnea severity scale at each time point is available. n - hereunder reported (28 for Reparixin and 19 for SoC) - is the number of subjects improved at each time point in comparison with the randomization.

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Mean (Standard Deviation); Unit of Measure: score on a scale
Baseline	Number Analyzed	8 participants	5 participants
		56.9 (37.3)	4.0 (5.5)
to Day 1	Number Analyzed	4 participants	4 participants
		4.3 (8.5)	20.0 (40.0)
to Day 2	Number Analyzed	4 participants	4 participants
		32.3 (40.3)	44.8 (51.7)
Week 1	Number Analyzed	5 participants	3 participants
		29.0 (34.0)	86.0 (5.3)
EOT	Number Analyzed	5 participants	3 participants
		33.0 (41.8)	89.7 (0.6)
EOS	Number Analyzed	2 participants	0 participants
		22.5 (31.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	>0.999
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	>0.999
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.050
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0227
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Mean (Standard Deviation); Unit of Measure: F°
Baseline	Number Analyzed	36 participants	19 participants
		36.4 (0.5)	36.5 (0.5)
to Day 1	Number Analyzed	34 participants	19 participants
		-0.2 (0.5)	0.2 (0.9)
to Day 2	Number Analyzed	35 participants	18 participants
		-0.1 (0.7)	-0.1 (0.6)
to Week 1	Number Analyzed	32 participants	14 participants
		-0.1 (0.6)	-0.2 (0.6)
to EOT	Number Analyzed	32 participants	15 participants
		-0.2 (0.6)	-0.4 (0.6)
to EOS	Number Analyzed	10 participants	3 participants
		-0.1 (0.5)	-0.5 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At Day 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.122
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At Day 2
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.985
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.857
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	at EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.436
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	At EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.350
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

6. Secondary Outcome

Title	Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to PaO2/FiO2
Description	Cumulative quantity of oxygen treatment (L) = Sum of all Quantity (L) in CONCOMITANT OXYGEN TREATMENT form, from randomization to time point of interest. According to PaO2/FiO2, the classification is 'mild' if 200 <= PaO2/FiO2 < 300 mmHg, 'moderate' if 100 <= PaO2/FiO2 < 200 mmHg, 'severe' if PaO2/FiO2 < 100 mmHg. A patient with ARDS (PaO2/FiO2<300 mmHg) is considered 'worsened' in case of a decrease of PaO2/FiO2 of at least one third (-33,3%) from the baseline PaO2/FiO2 value. NOTE that: N is the number of subjects for which the evaluation of the PaO2/FiO2 ratio at each time point is available. While n is the number of subjects worsened at each time point in comparison with the randomization, expressed in percentage.
Time Frame	At day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Measure Type: Number; Number (90% Confidence Interval); Unit of Measure: percentage of subjects
Day 1 - subjects worsened (%)	Number Analyzed	27 participants	14 participants
		7.4; (0.9 to 24.3)	14.3; (1.8 to 42.8)
Day 2 - subjects worsened (%)	Number Analyzed	31 participants	15 participants
		12.9; (3.6 to 29.8)	20.0; (4.3 to 48.1)
Week 1 - subjects worsened (%)	Number Analyzed	26 participants	14 participants
		0.0; (0.0 to 13.2)	21.4; (4.7 to 50.8)
EOT - subjects worsened (%)	Number Analyzed	29 participants	12 participants
		0.0; (0.0 to 11.9)	8.3; (0.2 to 38.5)
EOS - subjects worsened (%)	Number Analyzed	10 participants	3 participants
		0.0; (0.0 to 30.8)	0.0; (0.0 to 70.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
Statistical Test of Hypothesis	P-Value	0.596
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
Statistical Test of Hypothesis	P-Value	0.667
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
Statistical Test of Hypothesis	P-Value	0.037
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
Statistical Test of Hypothesis	P-Value	0.293
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments	[Not Specified]

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
Day 1 - subjects worsened	Number Analyzed	36 participants	19 participants
		5.6; (0.7 to 18.7)	0.0; (0.0 to 17.6)
Day 2 - subjects worsened	Number Analyzed	36 participants	19 participants
		5.6; (0.7 to 18.7)	5.3; (0.1 to 26.0)
Week 1 - subjects worsened	Number Analyzed	34 participants	17 participants
		2.9; (0.1 to 15.3)	17.6; (3.8 to 43.4)
EOT - subjects worsened	Number Analyzed	35 participants	19 participants
		2.9; (0.1 to 14.9)	15.8; (3.4 to 39.6)
EOS - subjects worsened	Number Analyzed	28 participants	12 participants
		3.6; (0.1 to 18.3)	8.3; (0.2 to 38.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.539
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening and
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.102
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.119
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.515
	Comments	p-values are referred to a two-sided Fisher's Exact test for worsening
	Method	Fisher Exact
	Comments	[Not Specified]

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Mean (Standard Deviation); Unit of Measure: hours
week 1	Number Analyzed	34 participants	18 participants
		141.93 (55.68)	130.22 (80.89)
EOT	Number Analyzed	34 participants	18 participants
		151.55 (75.53)	134.00 (86.21)
EOS	Number Analyzed	36 participants	18 participants
		195.26 (198.62)	155.71 (135.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.366
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative duration.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.489
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative duration.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.486
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative duration.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Mean (Standard Deviation); Unit of Measure: liters
Week 1	Number Analyzed	33 participants	18 participants
		24.99 (22.22)	29.20 (29.51)
EOT	Number Analyzed	33 participants	18 participants
		25.64 (22.16)	29.73 (31.53)
EOS	Number Analyzed	35 participants	18 participants
		26.54 (22.31)	33.38 (31.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.790
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative quantity
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.961
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative quantity
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.619
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative quantity
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of subjects
Baseline - subjects requiring	Number Analyzed	36 participants	19 participants
		11.1; (3.1 to 26.1)	10.5; (1.3 to 33.1)
Day1 - subjects requiring	Number Analyzed	36 participants	19 participants
		11.1; (3.1 to 26.1)	10.5; (1.3 to 33.1)
Day 2 - subjects requiring	Number Analyzed	35 participants	18 participants
		11.4; (3.2 to 26.7)	16.7; (3.6 to 41.4)
Week 1- subjects requiring	Number Analyzed	34 participants	17 participants
		8.8; (1.9 to 23.7)	11.8; (1.5 to 36.4)
EOT - subjects requiring	Number Analyzed	35 participants	19 participants
		8.6; (1.8 to 23.1)	5.3; (0.1 to 26.0)
EOS -subjects requiring	Number Analyzed	27 participants	10 participants
		0.0; (0.0 to 12.8)	0.0; (0.0 to 30.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS)
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.678
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments	[Not Specified]

11. Secondary Outcome

Title	Phase 2 - Cumulative Duration of Mechanical Ventilation Use, Overall
Description	Cumulative duration of mechanical ventilation (in hours) = Sum of duration of mechanical ventilation (hours) in mechanical ventilation form, from randomization to time point of interest. Duration of mechanical ventilation (hours) = End date/time - Start date/time / 60. n is the number of subjects for which the evaluation of the use of mechanical ventilation is available
Time Frame	Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Mean (Standard Deviation); Unit of Measure: hours
Week 1	Number Analyzed	4 participants	3 participants
		162.54 (58.92)	142.42 (44.89)
EOT	Number Analyzed	4 participants	3 participants
		149.99 (53.23)	146.86 (43.80)
EOS	Number Analyzed	4 participants	3 participants
		179.51 (78.30)	154.86 (56.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.696
	Comments	p-values are referred to a two-sided Wilcoxon test for cumulative duration
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	>0.999
	Comments	p-values are referred to a-sided Wilcoxon test for cumulative duration
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.596
	Comments	p-values are referred to a-sided Wilcoxon test for cumulative duration
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
Baseline - subjects admitted to ICU	Number Analyzed	36 participants	19 participants
		2.8; (0.1 to 14.5)	5.3; (0.1 to 26.0)
Day 1 - subjects admitted to ICU	Number Analyzed	36 participants	19 participants
		2.8; (0.1 to 14.5)	5.3; (0.1 to 26.0)
Day 2 - subjects admitted to ICU	Number Analyzed	35 participants	18 participants
		5.7; (0.7 to 19.2)	5.6; (0.1 to 27.3)
Week 1 - subjects admitted to ICU	Number Analyzed	34 participants	17 participants
		2.9; (0.1 to 15.3)	0.0; (0.0 to 19.5)
EOT - subjects admitted to ICU	Number Analyzed	35 participants	19 participants
		2.9; (0.1 to 14.9)	0.0; (0.0 to 17.6)
EOS - subjects admitted to ICU	Number Analyzed	27 participants	10 participants
		0.0; (0.0 to 30.8)	0.0; (0.0 to 12.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	p-values are referred to a two-sided Fisher's Exact test for proportion
	Method	Fisher Exact
	Comments	[Not Specified]

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Median (Full Range); Unit of Measure: days
Day 1 - cumulative ICU stay	Number Analyzed	1 participants	1 participants
		1.0; (1 to 1)	1.0; (1 to 1)
Day 2 - cumulative ICU stay	Number Analyzed	1 participants	1 participants
		2.0; (2 to 2)	2.0; (2 to 2)
Week 1 - cumulative ICU stay	Number Analyzed	1 participants	1 participants
		7.0; (7 to 7)	3.0; (3 to 3)
EOT - cumulative ICU stay	Number Analyzed	1 participants	1 participants
		6.0; (6 to 6)	3.0; (3 to 3)
EOS - cumulative ICU stay	Number Analyzed	36 participants	1 participants
		50.0; (50 to 50)	3.0; (3 to 3)

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Measure Type: Number; Unit of Measure: participants
baseline - none	Number Analyzed	36 participants	19 participants
		0	0
baseline - trace	Number Analyzed	36 participants	19 participants
		1	2
baseline - mild	Number Analyzed	36 participants	19 participants
		9	3
baseline - moderate	Number Analyzed	36 participants	19 participants
		23	11
baseline - severe	Number Analyzed	36 participants	19 participants
		3	3
Day 1 - none	Number Analyzed	1 participants	1 participants
		0	0
Day 1 - trace	Number Analyzed	1 participants	1 participants
		0	0
Day 1 - mild	Number Analyzed	1 participants	1 participants
		0	1
Day 1 - moderate	Number Analyzed	1 participants	1 participants
		1	0
Day 1 - severe	Number Analyzed	1 participants	1 participants
		0	0
Day 2 - none	Number Analyzed	1 participants	1 participants
		0	0
Day 2 - trace	Number Analyzed	1 participants	1 participants
		0	0
Day 2 - mild	Number Analyzed	1 participants	1 participants
		0	1
Day 2 - moderate	Number Analyzed	1 participants	1 participants
		0	0
Day 2 - severe	Number Analyzed	1 participants	1 participants
		1	0
week 1 - none	Number Analyzed	12 participants	4 participants
		0	0
week 1- trace	Number Analyzed	12 participants	4 participants
		1	0
week 1 - mild	Number Analyzed	12 participants	4 participants
		6	2
week 1 - moderate	Number Analyzed	12 participants	4 participants
		4	0
week 1 - severe	Number Analyzed	12 participants	4 participants
		1	2
EOT - none	Number Analyzed	16 participants	19 participants
		1	0
EOT - trace	Number Analyzed	16 participants	19 participants
		3	0
EOT - mild	Number Analyzed	16 participants	19 participants
		8	2
EOT - moderate	Number Analyzed	16 participants	19 participants
		3	0
EOT - severe	Number Analyzed	16 participants	19 participants
		1	2
EOS - none	Number Analyzed	2 participants	19 participants
		0	0
EOS - trace	Number Analyzed	2 participants	19 participants
		0	0
EOS - mild	Number Analyzed	2 participants	19 participants
		1	1
EOS - moderate	Number Analyzed	2 participants	19 participants
		1	1
EOS - severe	Number Analyzed	2 participants	19 participants
		0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.760
	Comments	p-values are referred to a two-sided Wilcoxon test
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.394
	Comments	p-values are referred to a two-sided Wilcoxon test
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.141
	Comments	p-values are referred to a two-sided Wilcoxon test
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	>0.999
	Comments	p-values are referred to a two-sided Wilcoxon test
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Measure Type: Number; Unit of Measure: participants
baseline - none	Number Analyzed	36 participants	19 participants
		32	18
baseline - trace	Number Analyzed	36 participants	19 participants
		0	0
baseline - mild	Number Analyzed	36 participants	19 participants
		1	0
baseline - moderate	Number Analyzed	36 participants	19 participants
		3	1
baseline - severe	Number Analyzed	36 participants	19 participants
		0	0
Day 1 - none	Number Analyzed	1 participants	1 participants
		0	0
Day 1 - trace	Number Analyzed	1 participants	1 participants
		0	0
Day 1 - mild	Number Analyzed	1 participants	1 participants
		0	0
Day 1 - moderate	Number Analyzed	1 participants	1 participants
		1	1
Day 1 - severe	Number Analyzed	1 participants	1 participants
		0	0
Day 2 - none	Number Analyzed	1 participants	1 participants
		0	0
Day 2 - trace	Number Analyzed	1 participants	1 participants
		0	0
Day 2 - mild	Number Analyzed	1 participants	1 participants
		0	1
Day 2 - moderate	Number Analyzed	1 participants	1 participants
		0	0
Day 2 - severe	Number Analyzed	1 participants	1 participants
		1	0
week 1 - none	Number Analyzed	12 participants	4 participants
		12	3
week 1- trace	Number Analyzed	12 participants	4 participants
		0	0
week 1 - mild	Number Analyzed	12 participants	4 participants
		0	0
week 1 - moderate	Number Analyzed	12 participants	4 participants
		0	0
week 1 - severe	Number Analyzed	36 participants	4 participants
		12	1
EOT - none	Number Analyzed	16 participants	4 participants
		15	3
EOT - trace	Number Analyzed	16 participants	4 participants
		0	0
EOT - mild	Number Analyzed	16 participants	4 participants
		1	0
EOT - moderate	Number Analyzed	16 participants	19 participants
		0	4
EOT - severe	Number Analyzed	16 participants	4 participants
		0	0
EOS - none	Number Analyzed	2 participants	2 participants
		2	2
EOS - trace	Number Analyzed	2 participants	2 participants
		0	0
EOS - mild	Number Analyzed	2 participants	2 participants
		0	0
EOS - moderate	Number Analyzed	2 participants	2 participants
		0	0
EOS - severe	Number Analyzed	2 participants	2 participants
		0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.500
	Comments	p-values are referred to a two-sided Wilcoxon test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.112
	Comments	p-values are referred to a two-sided Wilcoxon test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.277
	Comments	p-values are referred to a two-sided Wilcoxon test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	>0.999
	Comments	p-values are referred to a two-sided Wilcoxon test.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

16. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Mean (Standard Deviation); Unit of Measure: mmHg
Baseline	Number Analyzed	17 participants	8 participants
		121.69 (47.15)	68.64 (9.23)
to Day 1	Number Analyzed	8 participants	4 participants
		-19.61 (50.09)	14.20 (25.76)
to Day 2	Number Analyzed	13 participants	4 participants
		12.62 (60.20)	-4.68 (14.03)
to week 1	Number Analyzed	10 participants	3 participants
		11.76 (25.26)	-1.13 (54.80)
to EOT	Number Analyzed	11 participants	1 participants
		8.01 (36.08)	-18.70
to EOS	Number Analyzed	8 participants	1 participants
		-35.76 (47.84)	1.80

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2027
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.0000
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4469
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2466
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1752
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

17. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Mean (Standard Deviation); Unit of Measure: percent of oxygen saturation
Baseline	Number Analyzed	35 participants	18 participants
		95.79 (3.17)	94.97 (2.60)
to Day 1	Number Analyzed	29 participants	18 participants
		0.17 (2.20)	-0.41 (3.57)
to Day 2	Number Analyzed	32 participants	17 participants
		0.38 (2.88)	-0.63 (3.86)
to week 1	Number Analyzed	30 participants	13 participants
		1.18 (3.34)	0.73 (3.71)
to EOT	Number Analyzed	29 participants	14 participants
		0.88 (3.57)	1.19 (3.89)
to EOS	Number Analyzed	10 participants	2 participants
		0.47 (3.17)	-4.00 (1.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6441
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3529
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3581
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1666
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0851
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

18. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Mean (Standard Deviation); Unit of Measure: ratio
Baseline	Number Analyzed	34 participants	17 participants
		186.82 (64.86)	196.91 (58.49)
To day 1	Number Analyzed	27 participants	14 participants
		21.58 (65.81)	6.08 (125.00)
To day 2	Number Analyzed	31 participants	15 participants
		48.29 (154.49)	-8.53 (71.74)
To week 1	Number Analyzed	26 participants	14 participants
		160.80 (137.83)	54.28 (138.36)
To EOT	Number Analyzed	29 participants	12 participants
		171.27 (149.56)	74.65 (113.55)
To EOS	Number Analyzed	10 participants	3 participants
		199.26 (85.45)	84.87 (67.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3359
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3136
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0441
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0965
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0519
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

19. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Reparixin (FAS)	Standard of Care (FAS)
Arm/Group Description:		Reparixin oral tablets 1200 mg TID for 7 days Reparixin: Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.	Standard of care Standard of care: Standard of care
Overall Number of Participants Analyzed		36	19
Mean (Standard Deviation); Unit of Measure: mg/L
baseline	Number Analyzed	35 participants	19 participants
		57.04 (41.44)	58.87 (57.25)
to day 1	Number Analyzed	11 participants	9 participants
		-0.14 (73.28)	38.46 (117.19)
to day 2	Number Analyzed	22 participants	8 participants
		-29.24 (37.66)	-2.15 (52.37)
to week 1	Number Analyzed	26 participants	14 participants
		-39.09 (56.56)	0.52 (80.24)
to EOT	Number Analyzed	24 participants	13 participants
		-40.88 (50.27)	-25.28 (87.16)
to EOS	Number Analyzed	11 participants	7 participants
		-49.43 (57.65)	-45.20 (78.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.470
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	Day 2 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.425
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	week 1 vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.086
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOT vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.600
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Reparixin (FAS), Standard of Care (FAS)
	Comments	EOS vs baseline
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.717
	Comments	p-values are referred to a two-sided Wilcoxon test for differences in the change.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Adverse Events

Time Frame	Throughout the study, till day 21
Adverse Event Reporting Description	The Safety set (SAF), which consisted of all randomized subjects who received at least one dose of the investigational medicinal product (IMP).
Arm/Group Title	Reparixin (SAF)		Standard of Care (SAF)
Arm/Group Description	Reparixin was administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.		Standard of care, which is defined as any drug currently used to treat the COVID-19 pneumonia.
All-Cause Mortality
	Reparixin (SAF)		Standard of Care (SAF)
	Affected / at Risk (%)		Affected / at Risk (%)
Total	1/36 (2.78%)		3/19 (15.79%)
Serious Adverse Events
	Reparixin (SAF)		Standard of Care (SAF)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/36 (2.78%)		1/19 (5.26%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure † 1	1/36 (2.78%)	1	1/19 (5.26%)	1
1 Term from vocabulary, MedDRA 23.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Reparixin (SAF)		Standard of Care (SAF)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/36 (2.78%)		1/19 (5.26%)
Gastrointestinal disorders
Diarrhoea † 1	1/36 (2.78%)	1	1/19 (5.26%)	1
Injury, poisoning and procedural complications
Post procedural discomfort † 1	0/36 (0.00%)	0	1/19 (5.26%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure † 1	1/36 (2.78%)	1	1/19 (5.26%)	1
1 Term from vocabulary, MedDRA 23.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

Results Point of Contact

• Name/Title: Dr Maria De Pizzol, BSc
• Organization: Dompé Farmaceutici
• Phone: +39 02 583831
• EMail: clinops@pec.dompe.it

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Landoni G, Piemonti L, Monforte AD, Grossi P, Zangrillo A, Bucci E, Allegretti M, Goisis G, Gavioli EM, Patel N, De Pizzol M, Pasedis G, Mantelli F. A Multicenter Phase 2 Randomized Controlled Study on the Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients with COVID-19 Pneumonia. Infect Dis Ther. 2022 Aug;11(4):1559-1574. doi: 10.1007/s40121-022-00644-6. Epub 2022 May 26.

• Responsible Party: Dompé Farmaceutici S.p.A
• ClinicalTrials.gov Identifier: NCT04794803
• Other Study ID Numbers: REPAVID-19; 2020-001645-40 ( EudraCT Number )
• First Submitted: March 8, 2021
• First Posted: March 12, 2021
• Results First Submitted: February 21, 2022
• Results First Posted: March 17, 2022
• Last Update Posted: May 24, 2022