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Clinical Trial Results:
Adaptive phase 2/3, randomized, controlled multicenter study on the efficacy and safety of Reparixin in the treatment of hospitalized patients with COVID-19 pneumonia

Summary
EudraCT number	2020-001645-40
Trial protocol	IT
Global end of trial date	02 Feb 2021

Results information
Results version number	v1(current)
This version publication date	22 May 2022
First version publication date	22 May 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

REPAVID-19

ISRCTN number

US NCT number

NCT04794803

WHO universal trial number (UTN)

Sponsor organisation name

Dompé farmaceutici S.p.A.,

Sponsor organisation address

Via Santa Lucia, 6, Milano, Italy, 20122

Public contact

Clinical Trial Transparency Manager, Dompé farmaceutici S.p.A., +39 02583831, clinops@pec.dompe.it

Scientific contact

Clinical Trial Transparency Manager, Dompé Farmaceutici s.p.a., +39 02583831, clinops@pec.dompe.it

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Feb 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Nov 2020

Global end of trial reached?

Yes

Global end of trial date

02 Feb 2021

Was the trial ended prematurely?

Yes

Main objective of the trial

The objective of the Phase 2 study was to assess the efficacy and safety of Reparixin treatment as compared to the control arm (standard of care) in adult patients with severe COVID-19 pneumonia. The objective of the Phase 3 part of the study was to assess the efficacy and safety of Reparixin treatment as compared to the control arm in adult patients with moderate or severe COVID-19 pneumonia.

Protection of trial subjects

The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonization (ICH) Consolidated Guideline on Good Clinical Practice (GCP).

Background therapy

Evidence for comparator

Actual start date of recruitment

05 May 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 4

Country: Number of subjects enrolled

Italy: 51

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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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.

Screening details

56 patients were screened and randomized to the assigned treatment group: 37 patients to receive Reparixin and 19 to receive standard of care. One patient in the Reparixin group did not take at least one dose of the IMP and was excluded from both the safety set and the FAS, which comprised 55 patients overall: 36 in the Reparixin and 19 in the SoC.

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

This is an open-label trial, so blinding is not applicable.

Are arms mutually exclusive

Yes

Reparixin

Arm 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.

Arm type

Experimental

Investigational medicinal product name

Reparixin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Standard of Care

Arm description

Standard of care. Frequently used standard of care medications were dexamethasone (or other corticosteroids), anticoagulants (low-molecular weight heparin), antibiotics, as needed.

Arm type

Active comparator

Investigational medicinal product name

Standard of care

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The standard of care is expected to change over time due to the evolving research on effective medications for this infection and the nature of the COVID-19 longitudinal evolution and, thus, it could not be prespecified. Frequently used standard of care medications were dexamethasone (or other corticosteroids), anticoagulants (low-molecular weight heparin), antibiotics, as needed. These were recognized by the Italian Health Authorities as indicated for the treatment of the COVID-19 disease.

Number of subjects in period 1	Reparixin	Standard of Care
Started	36	19
Completed	27	11
Not completed	9	8
Patient transferred to another centre for oxygen r	4	1
Physician decision	1	1
Death	1	3
Refused to continue the treatment	1	-
Lost to follow-up	2	2
Patient admitted to ICU	-	1

Baseline characteristics

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Reporting group title

Reparixin

Reporting group description

Reporting group title

Standard of Care

Reporting group description

Standard of care. Frequently used standard of care medications were dexamethasone (or other corticosteroids), anticoagulants (low-molecular weight heparin), antibiotics, as needed.

Reporting group values	Reparixin	Standard of Care	Total
Number of subjects	36	19	55
Age categorical
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.
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	22	11	33
From 65-84 years	14	7	21
85 years and over	0	1	1
Age continuous
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.
Units: years
arithmetic mean (standard deviation)	60.6 ( 13.5 )	63.6 ( 14.2 )	-
Gender categorical
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.
Units: Subjects
Female	10	3	13
Male	26	16	42

Subject analysis set title

Reparixin (FAS)

Subject analysis set type

Full analysis

Subject analysis set 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.

Subject analysis set title

Standard of Care (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis sets values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects	36	19
Age categorical
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.
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	22	11
From 65-84 years	14	7
85 years and over	0	1
Age continuous
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.
Units: years
arithmetic mean (standard deviation)	60.6 ( 13.5 )	63.6 ( 14.2 )
Gender categorical
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.
Units: Subjects
Female	10	3
Male	26	16

End points

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Reporting group title

Reparixin

Reporting group description

Reporting group title

Standard of Care

Reporting group description

Standard of care. Frequently used standard of care medications were dexamethasone (or other corticosteroids), anticoagulants (low-molecular weight heparin), antibiotics, as needed.

Subject analysis set title

Reparixin (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Standard of Care (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Phase 2 - Percentage of participants with Composite endpoint of clinical events

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End point title

Phase 2 - Percentage of participants with Composite endpoint of clinical events

End point 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

End point type

Primary

End point timeframe

Up to Day 1

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36	19
Units: percentage
number (confidence interval 95%)
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)

Reparixin vs SoC

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02164

Method

Logrank

Confidence interval

Reparixin vs SoC

Statistical analysis description

Sensitivity analysis of time to event for each single component of the primary endpoint: Supplemental oxygen requirement based on PaO2/FiO2

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.20043

Method

Logrank

Confidence interval

Reparixin vs SoC

Statistical analysis description

Sensitivity analysis of time to event for each single component of the primary endpoint: time to first invasive mechanical ventilation

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.03021

Method

Logrank

Confidence interval

Reparixin vs SoC

Statistical analysis description

Sensitivity analysis of time to event for each single component of the primary endpoint: time to first admission to ICU

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5637

Method

Logrank

Confidence interval

Reparixin vs SoC

Statistical analysis description

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

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00132

Method

Logrank

Confidence interval

Secondary: Phase 2 - Percentage of Patients With Improvement in Clinical Severity Score (as Recommended by WHO for COVID Studies) of at Least Two Points

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End point title

Phase 2 - Percentage of Patients With Improvement in Clinical Severity Score (as Recommended by WHO for COVID Studies) of at Least Two Points

End point 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.

End point type

Secondary

End point timeframe

At day 1, day 2, week 1, day 21(end of treatment, EOT), EOS (end of study, i.e. 7±3 days after EOT)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	35 ^[1]	19 ^[2]
Units: percentage
number (confidence interval 95%)
Day 1	0.0 (0.0 to 10.0)	0.0 (0.0 to 17.6)
Day 2	0.0 (0.0 to 10.0)	0.0 (0.0 to 18.5)
Week 1	23.5 (10.7 to 41.2)	17.6 (3.8 to 43.4)
EOT	26.5 (12.9 to 44.4)	26.3 (9.1 to 51.2)
EOS	61.5 (40.6 to 79.8)	55.6 (21.2 to 86.3)

Notes
[1] - n=35 at day 1 and 2; n=34 at week 1 and EOT; n=26 at EOS.
[2] - n=19 at day 1 and EOT; n=18 at day 2; n=17 at week 1; n=9 at EOS.

Reparixin vs SoC

Statistical analysis description

comparison at week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.731

Method

Fisher exact

Confidence interval

Reparixin vs SoC

Statistical analysis description

at EOT. Please note that n= 53 and not 54.

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1

Method

Fisher exact

Confidence interval

Reparixin vs SoC

Statistical analysis description

at EOS. Please note that n=35 and not 54.

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1

Method

Fisher exact

Confidence interval

Secondary: Phase 2 - Number of improved subjects in Dyspnea severity, assessed by Liker scale

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End point title

Phase 2 - Number of improved subjects in Dyspnea severity, assessed by Liker scale

End point 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.

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	25 ^[3]	9 ^[4]
Units: count of participnts
Baseline	0	1
Day 1	7	2
Day 2	12	2
Week 1	23	6
EOT	20	6
EOS	16	3

Notes
[3] - n=11 at baseline n=16 at Day 1 and Day 2 n=25 at week 1 n=23 at EOT n=18 at EOS
[4] - n=6 at baseline n=9 at Day 1 and at week 1, and EOT n=7 at Day 2 n=3 at EOS

Reparixin vs SoC

Statistical analysis description

At baseline. Please note that n=... and not 34

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.353

Method

Fisher exact

Confidence interval

Reparixin vs SoC

Statistical analysis description

At Day 1. Please note that n=... and not 34

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.401

Method

Fisher exact

Confidence interval

Reparixin vs SoC

Statistical analysis description

At Day 2. Please note that n=... and not 34

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.066

Method

Fisher exact

Confidence interval

Reparixin vs SoC

Statistical analysis description

At week 1. Please note that n=... and not 34

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.102

Method

Fisher exact

Confidence interval

Reparixin vs SoC

Statistical analysis description

At EOT. Please note that n=... and not 34

Comparison groups

Standard of Care (FAS) v Reparixin (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.314

Method

Fisher exact

Confidence interval

Reparixin vs SoC

Statistical analysis description

At EOS. Please note that n=... and not 34

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Fisher exact

Confidence interval

Secondary: Phase 2 - Change From Baseline in Dyspnea severity, assessed by VAS Scale

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End point title

Phase 2 - Change From Baseline in Dyspnea severity, assessed by VAS Scale

End point 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. please note that the high number of patients with missing data in the standard of care group did not allow a reliable assessment in this group: in this case mean and SD in the EOS for SoC are missing , hence indicated as a fake "0" in the platform.

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment, EOT), 7±3 days after treatment period (end of study, EOS)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[5]	19 ^[6]
Units: score on a scale
arithmetic mean (standard deviation)
Baseline	56.9 ( 37.3 )	4.0 ( 5.5 )
to day 1	4.3 ( 8.5 )	20.0 ( 40.0 )
to day 2	32.3 ( 40.3 )	44.8 ( 51.7 )
week 1	29.0 ( 34.0 )	86.0 ( 5.3 )
EOT	33.0 ( 41.8 )	89.7 ( 0.6 )
EOS	22.5 ( 31.8 )	0 ( 0 )

Notes
[5] - n=8 Baseline n=4 Days 1 and 2 n=5 week 1, EOT n=2 EOS
[6] - n=5 Baseline n=4 Days 1 and 2 n=3 wee1, EOT n=0 EOS

Reparixin vs Standard of care

Statistical analysis description

Day 1 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

> 0.999 ^[8]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[7] - Please note that the total number of subjects in this analisys is not n=55 but n=8: n=4 for Reparixin and n=4 for the SoC
[8] - p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.

Reparixin vs Standard of care

Statistical analysis description

Day 2 vs baseline

Comparison groups

Standard of Care (FAS) v Reparixin (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

> 0.999 ^[10]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[9] - Please note that the total number of subjects in this analysis is not n=55 but n=8: n=4 for Reparixin and n=4 for the SoC
[10] - p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.

Reparixin vs Standard of care

Statistical analysis description

week 1 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.05 ^[12]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[11] - Please note that the total number of subjects in this analisys is not n=55 but n=8: n=5 for Reparixin and n=3 for the SoC
[12] - p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.

Reparixin vs Standard of care

Statistical analysis description

EOT vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.0227 ^[14]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[13] - Please note that the total number of subjects in this analisys is not n=55 but n=8: n=5 for Reparixin and n=3 for the SoC
[14] - p-values are referred to a two-sided Wilcoxon test for differences in the change of VAS scale.

Secondary: Phase 2 - Changes From Baseline in Body Temperature to Any Post-baseline Timepoints

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End point title

Phase 2 - Changes From Baseline in Body Temperature to Any Post-baseline Timepoints

End point 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.

End point type

Secondary

End point timeframe

Baseline, Day 1, Day 2, Week 1, EOT and EOS

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[15]	19 ^[16]
Units: F°
arithmetic mean (standard deviation)
Baseline	36.4 ( 0.5 )	36.5 ( 0.5 )
Day 1	-0.2 ( 0.5 )	0.2 ( 0.9 )
Day 2	-0.1 ( 0.7 )	-0.1 ( 0.6 )
Week 1	-0.1 ( 0.6 )	-0.2 ( 0.6 )
EOT	-0.2 ( 0.6 )	-0.4 ( 0.6 )
EOS	-0.1 ( 0.5 )	-0.5 ( 0.6 )

Notes
[15] - n= 34 Day 1 n=35 Day 2 n=32 Week 1 , EOT n=10 EOS
[16] - n=18 Day 2 n=14 Week 1 n=15 EOT n=3 EOS

Reparixin vs Standard of care

Statistical analysis description

At Day 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.122

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[17] - Please note that the total number of subjects in this analisys is not n=55 but n=53: n=34 for Reparixin and n=19 for the SoC

Reparixin vs Standard of care

Statistical analysis description

At Day 2

Comparison groups

Standard of Care (FAS) v Reparixin (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.985

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[18] - Please note that the total number of subjects in this analisys is not n=55 but n=53: n=35 for Reparixin and n=18 for the SoC

Reparixin vs Standard of care

Statistical analysis description

at week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.857

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[19] - Please note that the total number of subjects in this analisys is not n=55 but n=46: n=32 for Reparixin and n=14 for the SoC

Reparixin vs Standard of care

Statistical analysis description

at EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.436

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[20] - Please note that the total number of subjects in this analisys is not n=55 but n=47: n=32 for Reparixin and n=15 for the SoC

Reparixin vs Standard of care

Statistical analysis description

At EOS

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.35

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[21] - Please note that the total number of subjects in this analisys is not n=55 but n=13: n=10 for Reparixin and n=3 for the SoC

Secondary: Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to PaO2/FiO2

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End point title

Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to PaO2/FiO2

End point 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.

End point type

Secondary

End point timeframe

At day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[22]	19 ^[23]
Units: percentage
number (confidence interval 90%)
Day 1 - subjects worsened (%)	7.4 (0.9 to 24.3)	14.3 (1.8 to 42.8)
Day 2 - subjects worsened (%)	12.9 (3.6 to 29.8)	20.0 (4.3 to 48.1)
Week 1 - subjects worsened (%)	0.0 (0.0 to 13.2)	21.4 (4.7 to 50.8)
EOT - subjects worsened (%)	0.0 (0.0 to 11.9)	8.3 (0.2 to 38.5)
EOS - subjects worsened (%)	0.0 (0.0 to 30.8)	0.0 (0.0 to 70.8)

Notes
[22] - n=27 Day 1 n=31 Day 2 n=26 Week 1 n=29 EOT n=10 EOS
[23] - n=14 Day 1, Week 1 n=15 Day 2 n=12 EOT n=3 EOS

Reparixin vs Standard of care

Statistical analysis description

Day 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.596 ^[25]

Method

Fisher exact

Confidence interval

Notes
[24] - Please note that the total number of subjects in this analisys is not n=55 but n=41: n=27 for Reparixin and n=14 for the SoC
[25] - p-values are referred to a two-sided Fisher’s Exact test for worsening

Reparixin vs Standard of care

Statistical analysis description

Day 2

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.667 ^[27]

Method

Fisher exact

Confidence interval

Notes
[26] - Please note that the total number of subjects in this analisys is not n=55 but n=46: n=31 for Reparixin and n=15 for the SoC
[27] - p-values are referred to a two-sided Fisher’s Exact test for worsening

Reparixin vs Standard of care

Statistical analysis description

Week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.037 ^[29]

Method

Fisher exact

Confidence interval

Notes
[28] - Please note that the total number of subjects in this analisys is not n=55 but n=40: n=26 for Reparixin and n=14 for the SoC
[29] - p-values are referred to a two-sided Fisher’s Exact test for worsening

Reparixin vs Standard of care

Statistical analysis description

EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.293 ^[31]

Method

Fisher exact

Confidence interval

Notes
[30] - Please note that the total number of subjects in this analisys is not n=55 but n=41: n=29 for Reparixin and n=12 for the SoC
[31] - p-values are referred to a two-sided Fisher’s Exact test for worsening

Secondary: Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to Oxygen Delivery System Classification

Top of page

End point title

Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to Oxygen Delivery System Classification

End point 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).

End point type

Secondary

End point timeframe

day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[32]	19 ^[33]
Units: Percentage
number (confidence interval 95%)
Day 1 - subjects worsened	5.6 (0.7 to 18.7)	0.0 (0.0 to 17.6)
Day 2 - subjects worsened	5.6 (0.7 to 18.7)	5.3 (0.1 to 26.0)
Week 1 - subjects worsened	2.9 (0.1 to 15.3)	17.6 (3.8 to 43.4)
EOT - subjects worsened	2.9 (0.1 to 14.9)	15.8 (3.4 to 39.6)
EOS - subjects worsened	3.6 (0.1 to 18.3)	8.3 (0.2 to 38.5)

Notes
[32] - n=34 Week 1 n=35 EOT n=28 EOS
[33] - n=17 Week 1 n=12 EOS

Reparixin vs Standard of care

Statistical analysis description

Day 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.539 ^[34]

Method

Fisher exact

Confidence interval

Notes
[34] - p-values are referred to a two-sided Fisher’s Exact test for worsening and

Reparixin vs Standard of care

Statistical analysis description

Day 2

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1 ^[35]

Method

Fisher exact

Confidence interval

Notes
[35] - p-values are referred to a two-sided Fisher’s Exact test for worsening

Reparixin vs Standard of care

Statistical analysis description

Week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

= 0.102 ^[37]

Method

Fisher exact

Confidence interval

Notes
[36] - Please note that the total number of subjects in this analisys is not n=55 but n=51: n=34 for Reparixin and n=17 for the SoC
[37] - p-values are referred to a two-sided Fisher’s Exact test for worsening

Reparixin vs Standard of care

Statistical analysis description

EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

= 0.119 ^[39]

Method

Fisher exact

Confidence interval

Notes
[38] - Please note that the total number of subjects in this analisys is not n=54 but n=53: n=35 for Reparixin and n=19 for the SoC
[39] - p-values are referred to a two-sided Fisher’s Exact test for worsening

Reparixin vs Standard of care

Statistical analysis description

EOS

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

P-value

= 0.515 ^[41]

Method

Fisher exact

Confidence interval

Notes
[40] - Please note that the total number of subjects in this analisys is not n=55 but n=40: n=28 for Reparixin and n=12 for the SoC
[41] - p-values are referred to a two-sided Fisher’s Exact test for worsening

Secondary: Phase 2 - Oxygen Cumulative Duration During the Study

Top of page

End point title

Phase 2 - Oxygen Cumulative Duration During the Study

End point 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.

End point type

Secondary

End point timeframe

Week 1, EOT, EOS

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[42]	19 ^[43]
Units: hours
arithmetic mean (standard deviation)
Week 1	141.93 ( 55.68 )	130.22 ( 80.89 )
EOT	151.55 ( 75.53 )	134.00 ( 86.21 )
EOS	195.26 ( 198.62 )	155.71 ( 135.93 )

Notes
[42] - n=34 Week 1, EOT
[43] - n=18 Week 1. EOT, EOS

Reparixin vs Standard of care

Statistical analysis description

Week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

= 0.366 ^[45]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[44] - Please note that the total number of subjects in this analisys is not n=55 but n=52: n=34 for Reparixin and n=18 for the SoC
[45] - p-values are referred to a two-sided Wilcoxon test for cumulative duration.

Reparixin vs Standard of care

Statistical analysis description

EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

P-value

= 0.489 ^[47]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[46] - Please note that the total number of subjects in this analisys is not n=55 but n=52: n=34 for Reparixin and n=18 for the SoC
[47] - p-values are referred to a two-sided Wilcoxon test for cumulative duration.

Reparixin vs Standard of care

Statistical analysis description

EOS

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[48]

P-value

= 0.486 ^[49]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[48] - Please note that the total number of subjects in this analisys is not n=55 but n=54: n=36 for Reparixin and n=18 for the SoC
[49] - p-values are referred to a two-sided Wilcoxon test for cumulative duration.

Secondary: Phase 2 - Oxygen Cumulative Quantity During the Study

Top of page

End point title

Phase 2 - Oxygen Cumulative Quantity During the Study

End point 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.

End point type

Secondary

End point timeframe

Week 1, EOT and EOS

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[50]	19 ^[51]
Units: litre(s)
arithmetic mean (standard deviation)
Week 1	24.99 ( 22.22 )	29.20 ( 29.51 )
EOT	25.64 ( 22.16 )	29.73 ( 31.53 )
EOS	26.54 ( 22.31 )	33.38 ( 31.64 )

Notes
[50] - n=33 Week 1, EOT n=35 EOS
[51] - n=18 Week 1, EOT, EOS

Reparixin vs Standard of care

Statistical analysis description

Week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[52]

P-value

= 0.79 ^[53]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[52] - Please note that the total number of subjects in this analisys is not n=55 but n=51: n=33 for Reparixin and n=18 for the SoC
[53] - p-values are referred to a two-sided Wilcoxon test for cumulative quantity

Reparixin vs Standard of care

Statistical analysis description

EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.961 ^[55]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[54] - Please note that the total number of subjects in this analisys is not n=55 but n=51: n=33 for Reparixin and n=18 for the SoC
[55] - p-values are referred to a two-sided Wilcoxon test for cumulative quantity

Reparixin vs Standard of care

Statistical analysis description

EOS

Comparison groups

Standard of Care (FAS) v Reparixin (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.619 ^[57]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[56] - Please note that the total number of subjects in this analisys is not n=55 but n=53: n=35 for Reparixin and n=18 for the SoC
[57] - p-values are referred to a two-sided Wilcoxon test for cumulative quantity

Secondary: Phase 2 - Percentage of Subjects Requiring Mechanical Ventilation Use, Overall

Top of page

End point title

Phase 2 - Percentage of Subjects Requiring Mechanical Ventilation Use, Overall

End point 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.

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[58]	19 ^[59]
Units: percentage
number (confidence interval 95%)
Baseline - subjects requiring	11.1 (3.1 to 26.1)	10.5 (1.3 to 33.1)
Day 1 - subjects requiring	11.1 (3.1 to 26.1)	10.5 (1.3 to 33.1)
Day 2 - subjects requiring	11.4 (3.2 to 26.7)	16.7 (3.6 to 41.4)
Week 1 - subjects requiring	8.8 (1.9 to 23.7)	11.8 (1.5 to 36.4)
EOT - subjects requiring	8.6 (1.8 to 23.1)	5.3 (0.1 to 26.0)
EOS - subjects requiring	0.0 (0.0 to 12.8)	0.0 (0.0 to 30.8)

Notes
[58] - n=35 Day 2, EOT n=34 Week 1 n=27 EOS
[59] - n=18 Day 2 n=17 Week 1 n=10 EOS

Reparixin vs Standard of care

Statistical analysis description

Baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1 ^[60]

Method

Fisher exact

Confidence interval

Notes
[60] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Reparixin vs Standard of care

Statistical analysis description

Day 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1 ^[61]

Method

Fisher exact

Confidence interval

Notes
[61] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Reparixin vs Standard of care

Statistical analysis description

Day 2

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[62]

P-value

= 0.678 ^[63]

Method

Fisher exact

Confidence interval

Notes
[62] - Please note that the total number of subjects in this analisys is not n=55 but n=53: n=35 for Reparixin and n=18 for the SoC
[63] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Reparixin vs Standard of care

Statistical analysis description

Week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[64]

P-value

= 1 ^[65]

Method

Fisher exact

Confidence interval

Notes
[64] - Please note that the total number of subjects in this analisys is not n=55 but n=51: n=34 for Reparixin and n=17 for the SoC
[65] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Reparixin vs Standard of care

Statistical analysis description

EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[66]

P-value

= 1 ^[67]

Method

Fisher exact

Confidence interval

Notes
[66] - Please note that the total number of subjects in this analisys is not n=55 but n=54: n=35 for Reparixin and n=19 for the SoC
[67] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Reparixin vs Standard of care

Statistical analysis description

EOS

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[68]

P-value

= 1 ^[69]

Method

Fisher exact

Confidence interval

Notes
[68] - Please note that the total number of subjects in this analisys is not n=55 but n=37: n=27 for Reparixin and n=10 for the SoC
[69] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Secondary: Phase 2 - Cumulative Duration of Mechanical Ventilation Use, Overall

Top of page

End point title

Phase 2 - Cumulative Duration of Mechanical Ventilation Use, Overall

End point 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

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[70]	19 ^[71]
Units: hour
arithmetic mean (standard deviation)
Week 1	162.54 ( 58.92 )	142.42 ( 44.89 )
EOT	149.99 ( 52.23 )	146.86 ( 43.80 )
EOS	179.51 ( 78.30 )	154.86 ( 56.52 )

Notes
[70] - n=4 Week 1, EOT, EOS
[71] - n=3 Week 1, EOT, EOS

Reparixin vs Standard of care

Statistical analysis description

Week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[72]

P-value

= 0.696 ^[73]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[72] - Please note that the total number of subjects in this analisys is not n=55 but n=7: n=4 for Reparixin and n=3 for the SoC
[73] - p-values are referred to a two-sided Wilcoxon test for cumulative duration

Reparixin vs Standard of care

Statistical analysis description

EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[74]

P-value

> 0.999 ^[75]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[74] - Please note that the total number of subjects in this analisys is not n=55 but n=7: n=4 for Reparixin and n=3 for the SoC
[75] - p-values are referred to a-sided Wilcoxon test for cumulative duration

Reparixin vs Standard of care

Statistical analysis description

EOS

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[76]

P-value

= 0.596 ^[77]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[76] - Please note that the total number of subjects in this analisys is not n=55 but n=7: n=4 for Reparixin and n=3 for the SoC
[77] - p-values are referred to a-sided Wilcoxon test for cumulative duration

Secondary: Phase 2 - Percentage of Subjects With Intensive Care Unit (ICU) Admission Need

Top of page

End point title

Phase 2 - Percentage of Subjects With Intensive Care Unit (ICU) Admission Need

End point 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.

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[78]	19 ^[79]
Units: percentage
number (confidence interval 95%)
Baseline - subjects admitted to ICU	2.8 (0.1 to 14.5)	5.3 (0.1 to 26.0)
Day 1 - subjects admitted to ICU	2.8 (0.1 to 14.5)	5.3 (0.1 to 26.0)
Day 2 - subjects admitted to ICU	5.7 (0.7 to 19.2)	5.6 (0.1 to 27.3)
Week 1 - subjects admitted to ICU	2.9 (0.1 to 15.3)	0.0 (0.0 to 19.5)
EOT - subjects admitted to ICU	2.9 (0.1 to 14.9)	0.0 (0.0 to 17.6)
EOS - subjects admitted to ICU	0.0 (0.0 to 12.8)	0.0 (0.0 to 30.8)

Notes
[78] - n=35 Day 2 , EOT n=34 Week 1 n=27 EOS
[79] - n=18 Day 2 n=17 Week 1 n=10 EOS

Reparixin vs Standard of care

Statistical analysis description

Baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1 ^[80]

Method

Fisher exact

Confidence interval

Notes
[80] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Reparixin vs Standard of care

Statistical analysis description

Day 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1 ^[81]

Method

Fisher exact

Confidence interval

Notes
[81] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Reparixin vs Standard of care

Statistical analysis description

Day 2

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[82]

P-value

= 1 ^[83]

Method

Fisher exact

Confidence interval

Notes
[82] - Please note that the total number of subjects in this analisys is not n=55 but n=53: n=35 for Reparixin and n=18 for the SoC
[83] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Reparixin vs Standard of care

Statistical analysis description

Week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[84]

P-value

= 1 ^[85]

Method

Fisher exact

Confidence interval

Notes
[84] - Please note that the total number of subjects in this analisys is not n=55 but n=51: n=34 for Reparixin and n=17 for the SoC
[85] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Reparixin vs Standard of care

Statistical analysis description

EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[86]

P-value

= 1 ^[87]

Method

Fisher exact

Confidence interval

Notes
[86] - Please note that the total number of subjects in this analisys is not n=55 but n=54: n=35 for Reparixin and n=19 for the SoC
[87] - p-values are referred to a two-sided Fisher’s Exact test for proportion

Secondary: Phase 2 - Cumulative ICU Stay

Top of page

End point title

Phase 2 - Cumulative ICU Stay

End point description

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

End point type

Secondary

End point timeframe

Day 1, Day 2, Week 1, EOT, EOS

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[88]	19 ^[89]
Units: days
median (full range (min-max))
Day 1 - cumulative ICU stay	1.0 (1 to 1)	1.0 (1 to 1)
Day 2 - cumulative ICU stay	2.0 (2 to 2)	2.0 (2 to 2)
Week 1 - cumulative ICU stay	7.0 (7 to 7)	3.0 (3 to 3)
EOT - cumulative ICU stay	6.0 (6 to 6)	3.0 (3 to 3)
EOS - cumulative ICU stay	50.0 (50 to 50)	3.0 (3 to 3)

Notes
[88] - n=1 Day 1, Day 2. Week 1, EOT
[89] - n=1 Day 1, Day 2, Week 1, EOT, EOS

No statistical analyses for this end point

Secondary: Phase 2 - Lung Damage Extension by Severity and by Timepoint

Top of page

End point title

Phase 2 - Lung Damage Extension by Severity and by Timepoint

End point 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.

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[90]	19 ^[91]
Units: partecipants
number (not applicable)
Baseline - none	0	0
Baseline -trace	1	2
Baseline - mild	9	3
Baseline - moderate	23	11
Baseline - severe	3	3
Day 1 - none	0	0
Day 1 - trace	0	0
Day 1 - mild	0	1
Day 1 - moderate	1	0
Day 1 - severe	0	0
Day 2 - none	0	0
Day 2 - trace	0	0
Day 2 - mild	0	1
Day 2 - moderate	0	0
Day 2 - severe	1	0
Week 1 - none	0	0
Week 1 - trace	1	0
Week 1 - mild	6	2
Week 1 - moderate	4	0
Week 1 - severe	1	2
EOT - none	1	0
EOT - trace	3	0
EOT - mild	8	2
EOT - moderate	3	0
EOT - severe	1	2
EOS- none	0	0
EOS - trace	0	0
EOS - mild	1	1
EOS - moderate	1	1
EOS - severe	0	0

Notes
[90] - n=1 Day 1 (all groups) , Day 2 (all groups) n=12 Week 1 (all groups) n=16 EOT n=2 EOS
[91] - n=1 Day 1 (all groups), Day 2 (all groups) n=4 Week 1 (all groups)

Reparixin vs Standard of care

Statistical analysis description

Baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.76 ^[92]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[92] - p-values are referred to a two-sided Wilcoxon test

Reparixin vs Standard of care

Statistical analysis description

Week 1

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[93]

P-value

= 0.394 ^[94]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[93] - Please note that the total number of subjects in this analisys is not n=55 but n=16: n=12 for Reparixin and n=4 for the SoC
[94] - p-values are referred to a two-sided Wilcoxon test

Reparixin vs Standard of care

Statistical analysis description

EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[95]

P-value

= 0.141 ^[96]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[95] - Please note that the total number of subjects in this analisys is not n=55 but n=35: n=16 for Reparixin and n=19 for the SoC
[96] - p-values are referred to a two-sided Wilcoxon test

Reparixin vs Standard of care

Statistical analysis description

EOS

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[97]

P-value

> 0.999 ^[98]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[97] - Please note that the total number of subjects in this analisys is not n=55 but n=21: n=2 for Reparixin and n=19 for the SoC
[98] - p-values are referred to a two-sided Wilcoxon test

Secondary: Phase 2 - Lung Exudation by Severity and by Timepoint

Top of page

End point title

Phase 2 - Lung Exudation by Severity and by Timepoint

End point 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.

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[99]	19 ^[100]
Units: partecipants
number (not applicable)
Baseline - none	32	18
Baseline - trace	0	0
Baseline - mild	1	0
Baseline - moderate	3	1
Baseline - severe	0	0
Day 1 -none	0	0
Day 1 - trace	0	0
Day 1 - mild	0	0
Day 1 - moderate	1	1
Day 1 - severe	0	0
Day 2 - none	0	0
Day 2 - trace	0	0
Day 2 - mild	0	1
Day 2 - moderate	0	0
Day 2 - severe	1	0
Week 1 - none	12	3
Week 1 - trace	0	0
Week 1 - mild	0	0
Week 1 - moderate	0	0
Week 1 - severe	0	1
EOT - none	15	3
EOT - trace	0	0
EOT - mild	1	0
EOT - moderate	0	1
EOT - severe	0	0
EOS - none	2	2
EOS - trace	0	0
EOS - mild	0	0
EOS - moderate	0	0
EOS - severe	0	0

Notes
[99] - n=1 Days 1 and 2 (all groups) n=12 Week 1 (all groups) n=16 EOT (all groups) n=2 EOS (all groups)
[100] - n=1 Days 1 and 2 (all groups) n=4 Week 1 (all groups), EOT (all groups) n=2 EOS (all groups)

Reparixin vs Standard of care

Statistical analysis description

Baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5 ^[101]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[101] - p-values are referred to a two-sided Wilcoxon test.

Reparixin vs Standard of care

Statistical analysis description

Week 1

Comparison groups

Standard of Care (FAS) v Reparixin (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[102]

P-value

= 0.112 ^[103]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[102] - Please note that the total number of subjects in this analisys is not n=55 but n=16: n=12 for Reparixin and n=4 for the SoC
[103] - p-values are referred to a two-sided Wilcoxon test.

Reparixin vs Standard of care

Statistical analysis description

EOT

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[104]

P-value

= 0.277 ^[105]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[104] - Please note that the total number of subjects in this analisys is not n=55 but n=20: n=16 for Reparixin and n=4 for the SoC
[105] - p-values are referred to a two-sided Wilcoxon test.

Reparixin vs Standard of care

Statistical analysis description

EOS

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[106]

P-value

> 0.999 ^[107]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[106] - Please note that the total number of subjects in this analisys is not n=55 but n=4: n=2 for Reparixin and n=2 for the SoC
[107] - p-values are referred to a two-sided Wilcoxon test.

Secondary: Phase 2 - Change From Baseline in Partial Arterial Oxygen Pressure (PaO2)

Top of page

End point title

Phase 2 - Change From Baseline in Partial Arterial Oxygen Pressure (PaO2)

End point 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. Plase note that the high number of patients with missing data in the standard of care group did not allow a reliable assessment in this group. So platform forced to insert a fake "0" values in the SD in the SoC SoC for EOT and for EOS.

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[108]	19 ^[109]
Units: mmHg
arithmetic mean (standard deviation)
Baseline	121.69 ( 47.15 )	68.64 ( 9.23 )
to Day 1	-19.61 ( 50.09 )	14.20 ( 25.76 )
to Day 2	12.62 ( 60.20 )	-4.68 ( 14.03 )
to Week 1	11.76 ( 25.26 )	-1.13 ( 54.80 )
to EOT	8.01 ( 36.08 )	-18.70 ( 0 )
to EOS	-35.76 ( 47.84 )	1.80 ( 0 )

Notes
[108] - n=17 Baseline n=8 to Day 1 , to EOS n=13 to Day 2 n=10 to Week 1 n=11 to EOT
[109] - n=8 Baseline n=4 to Days 1 and 2 n=3 to Week 1 n=1 to EOT, to EOS

Reparixin vs Standard of care

Statistical analysis description

Day 1 vs Baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2027 ^[110]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[110] - p-values are referred to a two-sided Wilcoxon test for differences in the change

Reparixin vs Standard of care

Statistical analysis description

Day 2 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[111]

P-value

= 0.3529 ^[112]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[111] - Please note that the total number of subjects in this analysis is not n=55 but n=17: n=13 for Reparixin and n=4 for the SoC
[112] - p-values are referred to a two-sided Wilcoxon test for differences in the change

Reparixin vs Standard of care

Statistical analysis description

week 1 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[113]

P-value

= 0.3581 ^[114]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[113] - Please note that the total number of subjects in this analysis is not n=55 but n=13: n=10 for Reparixin and n=3 for the SoC
[114] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

EOT vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[115]

P-value

= 0.1666 ^[116]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[115] - Please note that the total number of subjects in this analysis is not n=55 but n=12: n=11 for Reparixin and n=1 for the SoC
[116] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

EOS vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[117]

P-value

= 0.0851 ^[118]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[117] - Please note that the total number of subjects in this analysis is not n=55 but n=9: n=8 for Reparixin and n=1 for the SoC
[118] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Secondary: Phase 2 - Change From Baseline in Oxygen Saturation (SpO2)

Top of page

End point title

Phase 2 - Change From Baseline in Oxygen Saturation (SpO2)

End point 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.

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[119]	19 ^[120]
Units: percent of oxigen saturation
arithmetic mean (standard deviation)
Baseline	95.79 ( 3.17 )	94.97 ( 2.60 )
to Day 1	0.17 ( 2.20 )	-0.41 ( 3.57 )
to Day 2	0.38 ( 2.88 )	-0.63 ( 3.86 )
to Week 1	1.18 ( 3.34 )	0.73 ( 3.71 )
to EOT	0.88 ( 3.57 )	1.19 ( 3.89 )
to EOS	0.47 ( 3.17 )	-4.00 ( 1.41 )

Notes
[119] - n=35 Baseline n=29 Day 1, EOT n=32 Day 2 n=30 Week 1 n=10 EOS
[120] - n=18 Baseline, Day 1 n=17 Day 2 n=13 Week 1 n=14 EOT n=2 EOS

Reparixin vs Standard of care

Statistical analysis description

Day 1 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[121]

P-value

= 0.6441 ^[122]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[121] - Please note that the total number of subjects in this analisys is not n=55 but n=47: n=29 for Reparixin and n=18 for the SoC
[122] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

Day 2 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[123]

P-value

= 0.3529 ^[124]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[123] - Please note that the total number of subjects in this analisys is not n=55 but n=49: n=32 for Reparixin and n=17 for the SoC
[124] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

week 1 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[125]

P-value

= 0.3581 ^[126]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[125] - Please note that the total number of subjects in this analisys is not n=55 but n=43: n=30 for Reparixin and n=13 for the SoC
[126] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

EOT vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[127]

P-value

= 0.1666 ^[128]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[127] - Please note that the total number of subjects in this analisys is not n=55 but n=43: n=29 for Reparixin and n=14 for the SoC
[128] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

EOS vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[129]

P-value

= 0.0851 ^[130]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[129] - Please note that the total number of subjects in this analisys is not n=55 but n=12: n=10 for Reparixin and n=2 for the SoC
[130] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Secondary: Phase 2 - Partial Arterial Oxygen Pressure (PaO2) to Fraction of Inspiration O2 (FiO2) Ratio [PaO2/FiO2 Ratio]

Top of page

End point title

Phase 2 - Partial Arterial Oxygen Pressure (PaO2) to Fraction of Inspiration O2 (FiO2) Ratio [PaO2/FiO2 Ratio]

End point 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).

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[131]	19 ^[132]
Units: ratio
arithmetic mean (standard deviation)
Baseline	186.82 ( 64.86 )	196.91 ( 58.49 )
to Day 1	21.58 ( 65.81 )	6.08 ( 125.00 )
to Day 2	48.29 ( 154.49 )	-8.53 ( 71.74 )
to Week 1	160.80 ( 137.83 )	54.28 ( 138.36 )
to EOT	171.27 ( 149.56 )	74.65 ( 113.55 )
to EOS	199.26 ( 85.45 )	84.87 ( 67.92 )

Notes
[131] - n=34 Baseline n=27 Day 1 n=31 Day 2 n=26 Week 1 n=29 EOT n=10 EOS
[132] - n=17 Baseline n=14 Day 1, Week 1 n=15 Day 2 n=12 EOT n=3 EOS

Reparixin vs Standard of care

Statistical analysis description

Day 1 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[133]

P-value

= 0.3359 ^[134]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[133] - Please note that the total number of subjects in this analisys is not n=55 but n=41: n=27 for Reparixin and n=14 for the SoC
[134] - p-values are referred to a two-sided Wilcoxon test for differences in the change

Reparixin vs Standard of care

Statistical analysis description

Day 2 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[135]

P-value

= 0.3136 ^[136]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[135] - Please note that the total number of subjects in this analisys is not n=55 but n=46: n=31 for Reparixin and n=15 for the SoC
[136] - p-values are referred to a two-sided Wilcoxon test for differences in the change

Reparixin vs Standard of care

Statistical analysis description

week 1 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[137]

P-value

= 0.0441 ^[138]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[137] - Please note that the total number of subjects in this analisys is not n=55 but n=40: n=26 for Reparixin and n=14 for the SoC
[138] - p-values are referred to a two-sided Wilcoxon test for differences in the change

Reparixin vs Standard of care

Statistical analysis description

EOT vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[139]

P-value

= 0.0965 ^[140]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[139] - Please note that the total number of subjects in this analisys is not n=55 but n=41: n=29 for Reparixin and n=12 for the SoC
[140] - p-values are referred to a two-sided Wilcoxon test for differences in the change

Reparixin vs Standard of care

Statistical analysis description

EOS vs baseline

Comparison groups

Standard of Care (FAS) v Reparixin (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[141]

P-value

= 0.0519 ^[142]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[141] - Please note that the total number of subjects in this analisys is not n=55 but n=13: n=10 for Reparixin and n=3 for the SoC
[142] - p-values are referred to a two-sided Wilcoxon test for differences in the change

Secondary: Phase 2 - Change From Baseline in Reactive Protein (CRP)

Top of page

End point title

Phase 2 - Change From Baseline in Reactive Protein (CRP)

End point 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.

End point type

Secondary

End point timeframe

Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period)

End point values	Reparixin (FAS)	Standard of Care (FAS)
Number of subjects analysed	36 ^[143]	19 ^[144]
Units: mg/L
arithmetic mean (standard deviation)
Baseline	57.04 ( 41.44 )	58.87 ( 57.25 )
to Day 1	-0.14 ( 73.28 )	38.46 ( 117.19 )
to Day 2	-29.24 ( 37.66 )	-2.15 ( 52.37 )
to Week 1	-39.09 ( 56.56 )	0.52 ( 80.24 )
to EOT	-40.88 ( 50.27 )	-25.28 ( 87.16 )
to EOS	-49.43 ( 57.65 )	-45.20 ( 78.97 )

Notes
[143] - n=35 Baseline n=11 Day 1, EOS n=22 Day 2 n=26 Week 1 n=24 EOT
[144] - n=9 Day 1 n=8 Day 2 n=14 Week 1 n=13 EOT n=7 EOS

Reparixin vs Standard of care

Statistical analysis description

Day 1 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[145]

P-value

= 0.47 ^[146]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[145] - Please note that the total number of subjects in this analysis is not n=55 but n=20: n=11 for Reparixin and n=9 for the SoC
[146] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

Day 2 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[147]

P-value

= 0.425 ^[148]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[147] - Please note that the total number of subjects in this analysis is not n=55 but n=30: n=22 for Reparixin and n=8 for the SoC
[148] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

week 1 vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[149]

P-value

= 0.086 ^[150]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[149] - Please note that the total number of subjects in this analysis is not n=55 but n=40: n=26 for Reparixin and n=14 for the SoC
[150] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

EOT vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[151]

P-value

= 0.6 ^[152]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[151] - Please note that the total number of subjects in this analysis is not n=55 but n=37: n=24 for Reparixin and n=13 for the SoC
[152] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Reparixin vs Standard of care

Statistical analysis description

EOS vs baseline

Comparison groups

Reparixin (FAS) v Standard of Care (FAS)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[153]

P-value

= 0.717 ^[154]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[153] - Please note that the total number of subjects in this analysis is not n=55 but n=18: n=11 for Reparixin and n=7 for the SoC
[154] - p-values are referred to a two-sided Wilcoxon test for differences in the change.

Adverse events

Top of page

Timeframe for reporting adverse events

AE were assessed throughout the study, till day 21.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Reparixin SAF

Reporting group description

Reporting group title

Standard of Care SAF

Reporting group description

Standard of care. Frequently used standard of care medications were dexamethasone (or other corticosteroids), anticoagulants (low-molecular weight heparin), antibiotics, as needed.

Serious adverse events	Reparixin SAF	Standard of Care SAF
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 36 (2.78%)	1 / 19 (5.26%)
number of deaths (all causes)	1	3
number of deaths resulting from adverse events	0	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	1 / 36 (2.78%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Reparixin SAF	Standard of Care SAF
Total subjects affected by non serious adverse events
subjects affected / exposed	1 / 36 (2.78%)	1 / 19 (5.26%)
Injury, poisoning and procedural complications
Post procedural discomfort
subjects affected / exposed	0 / 36 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 36 (2.78%)	1 / 19 (5.26%)
occurrences all number	1	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	1 / 36 (2.78%)	1 / 19 (5.26%)
occurrences all number	1	1

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The low number of patients enrolled, regarded as adequate for a preliminary phase II study which was initially designed as a larger phase II/III study. The open-label study design, regarded as justified in an early phase study.

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Clinical Trial Results: Adaptive phase 2/3, randomized, controlled multicenter study on the efficacy and safety of Reparixin in the treatment of hospitalized patients with COVID-19 pneumonia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 2 - Percentage of participants with Composite endpoint of clinical events

Primary: Phase 2 - Percentage of participants with Composite endpoint of clinical events

Secondary: Phase 2 - Percentage of Patients With Improvement in Clinical Severity Score (as Recommended by WHO for COVID Studies) of at Least Two Points

Secondary: Phase 2 - Percentage of Patients With Improvement in Clinical Severity Score (as Recommended by WHO for COVID Studies) of at Least Two Points

Secondary: Phase 2 - Number of improved subjects in Dyspnea severity, assessed by Liker scale

Secondary: Phase 2 - Number of improved subjects in Dyspnea severity, assessed by Liker scale

Secondary: Phase 2 - Change From Baseline in Dyspnea severity, assessed by VAS Scale

Secondary: Phase 2 - Change From Baseline in Dyspnea severity, assessed by VAS Scale

Secondary: Phase 2 - Changes From Baseline in Body Temperature to Any Post-baseline Timepoints

Secondary: Phase 2 - Changes From Baseline in Body Temperature to Any Post-baseline Timepoints

Secondary: Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to PaO2/FiO2

Secondary: Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to PaO2/FiO2

Secondary: Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to Oxygen Delivery System Classification

Secondary: Phase 2 - Percentage of Subjects Worsened, During Supplemental Oxygen Treatment, From Randomization According to Oxygen Delivery System Classification

Secondary: Phase 2 - Oxygen Cumulative Duration During the Study

Secondary: Phase 2 - Oxygen Cumulative Duration During the Study

Secondary: Phase 2 - Oxygen Cumulative Quantity During the Study

Secondary: Phase 2 - Oxygen Cumulative Quantity During the Study

Secondary: Phase 2 - Percentage of Subjects Requiring Mechanical Ventilation Use, Overall

Secondary: Phase 2 - Percentage of Subjects Requiring Mechanical Ventilation Use, Overall

Secondary: Phase 2 - Cumulative Duration of Mechanical Ventilation Use, Overall

Secondary: Phase 2 - Cumulative Duration of Mechanical Ventilation Use, Overall

Secondary: Phase 2 - Percentage of Subjects With Intensive Care Unit (ICU) Admission Need

Secondary: Phase 2 - Percentage of Subjects With Intensive Care Unit (ICU) Admission Need

Secondary: Phase 2 - Cumulative ICU Stay

Secondary: Phase 2 - Cumulative ICU Stay

Secondary: Phase 2 - Lung Damage Extension by Severity and by Timepoint

Secondary: Phase 2 - Lung Damage Extension by Severity and by Timepoint

Secondary: Phase 2 - Lung Exudation by Severity and by Timepoint

Secondary: Phase 2 - Lung Exudation by Severity and by Timepoint

Secondary: Phase 2 - Change From Baseline in Partial Arterial Oxygen Pressure (PaO2)

Secondary: Phase 2 - Change From Baseline in Partial Arterial Oxygen Pressure (PaO2)

Secondary: Phase 2 - Change From Baseline in Oxygen Saturation (SpO2)

Secondary: Phase 2 - Change From Baseline in Oxygen Saturation (SpO2)

Secondary: Phase 2 - Partial Arterial Oxygen Pressure (PaO2) to Fraction of Inspiration O2 (FiO2) Ratio [PaO2/FiO2 Ratio]

Secondary: Phase 2 - Partial Arterial Oxygen Pressure (PaO2) to Fraction of Inspiration O2 (FiO2) Ratio [PaO2/FiO2 Ratio]

Secondary: Phase 2 - Change From Baseline in Reactive Protein (CRP)

Secondary: Phase 2 - Change From Baseline in Reactive Protein (CRP)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Adaptive phase 2/3, randomized, controlled multicenter study on the efficacy and safety of Reparixin in the treatment of hospitalized patients with COVID-19 pneumonia